Pressure Pain Detection Thresholds Research Articles

P111 Reliability of quantitative sensory testing, disease activity score 28, ultrasound and central aspects of pain questionnaire in individuals with rheumatoid arthritis

Abstract Background/Aims Disease Activity Score 28 (DAS28), ultrasound, quantitative sensory testing (QST) and central aspect of pain (CAP) questionnaire measure disease activity and pain hypersensitivity. We investigated their inter-rater and test-retest reliability in Central Aspects of Pain in Rheumatoid Arthritis (CAP-RA) participants. Methods Participants who attended the CAP-RA study visit and agreed to one or more reliability assessments were included. The same two raters completed all assessments, including clinical examination for DAS28, using a single blood sample per participant. QST modalities in the sequence: Pressure Pain detection Threshold (PPT) at the medial joint line of the most painful knee, tibialis anterior and contralateral brachioradialis, Temporal Summation (TS) at rectus femoris of the most painful knee and Conditioned Pain Modulation (CPM), with ischaemic arm pain conditioning and PPT at tibialis anterior. Ultrasound followed the Backhaus 7 protocol, plus the knee. Two trained sonographers scored each joint scan for grey scale (GS), power Doppler and a combined score (PDUS) using EULAR-OMERACT methodology. Joint scores were summated to give an overall score for GS, Doppler and PDUS. Participants could complete questionnaires at invitation, prior to and at baseline, 1-week post-baseline, prior to and at follow-up visit. Any combination of questionnaires completed within 7 days of each other assessed repeatability. Data were assessed for normality, interclass correlation coefficients, and Bland and Altman plots in R studio. Results 196 people were recruited into CAP-RA (median (IQR)) age 66 (58-75) y, 139 (75%) female, 190 (98%) white. 97 (49%) undertook study visits. Characteristics of the 66 people undertaking reliability did not significantly differ from the total population. Measurements are shown in Table 1. Moderate to excellent reliability was found across all measures except CPM (Table 1). The swollen joint count was the least reliable of the DAS28 components. Conclusion Measures of inflammatory disease activity and pain sensitivity are at least moderately reliable within a research context. Only low reliability for CPM might indicate imprecision, or reflect fluctuations in symptoms or pain sensitivity. High reliability of DAS28 and US might reflect relative stability of clinical signs of inflammation. Suppressing day-to-day fluctuations could reduce the unpredictability of rheumatoid arthritis. Disclosure S.L. Smith: None. V. Georgopoulos: None. O. Ifesemen: None. E. Ferguson: None. R.J. Wakefield: None. D. Wilson: None. P. Buckley: None. D. Platts: None. S. Ledbury: None. D.F. McWilliams: Grants/research support; Eli Lilly, Pfizer, GSK, Orion, UCB. D.A. Walsh: Grants/research support; Eli Lilly, Pfizer, GSK, Orion, UCB.

Influence of central aspects of pain on self-management in people with chronic low back pain

ObjectiveThis observational study investigated whether central aspects of pain are associated with self-management domains in individuals with chronic low back pain (CLBP) undertaking a pain management program. MethodsIndividuals with CLBP provided pain sensitivity and self-management data at baseline (n = 97) and 3-months (n = 87). Pressure pain detection threshold (PPT) at the forearm, temporal summation (TS) and conditioned pain modulation (CPM), Widespread Pain Index (WPI), and a Central Aspects of Pain factor (CAPf) were considered as central aspects of pain. Self-management was measured using the 8 domains of the Health Education Impact Questionnaire, as well as Pain Self Efficacy and Health Care Utilisation questionnaires. ResultsPPT, CPM, WPI and CAPf predicted worse performance in several self-management domains at 3-months (r = 0.21 to 0.54, p < 0.05 overall). In multivariable regression models (adjusted for baseline scores of self-management, depression, catastrophization, pain and fatigue) low PPT, high TS, and high CAPf at baseline predicted poorer self-management at 3 months (R2 =0.14 to 0.52, β = −0.37 to 0.35, p < 0.05). ConclusionsCentral aspects of pain are associated with impaired self-management, over and above effects of pain intensity, fatigue, depression and catastrophizing. Practice implicationsTreatments that target central aspects of pain might help improve self-management in people with CLBP.

The interrater and test-retest reliability of 3 modalities of quantitative sensory testing in healthy adults and people with chronic low back pain or rheumatoid arthritis.

Quantitative Sensory Testing (QST) modalities used to assess central pain mechanisms require different protocols in people with different musculoskeletal conditions. We aimed to explore the possible effects of musculoskeletal diagnosis and test site on QST interrater and test-retest reliability. The study included participants with rheumatoid arthritis (RA, n = 18; QST conducted on lower leg) and low back pain (LBP, n = 25; QST conducted on forearm), plus 45 healthy control participants (n = 20 QST on lower leg and n = 25 QST on forearm). Test-retest reliability was assessed from QST conducted 1 to 3 weeks apart. Quantitative sensory testing modalities used were pressure pain detection threshold (PPT) at a site distant to tissue pathology, temporal summation (TS), and conditioned pain modulation (CPM). Temporal summation was calculated as difference or ratio of single and repeated punctate stimuli and unconditioned thresholds for CPM used single or mean of multiple PPTs. Intraclass correlation coefficients (ICCs) were compared between different subgroups. High to very high reliability was found for all assessments of PPT and TS across anatomical sites (lower leg and forearm) and participants (healthy, RA, and LBP) (ICC ≥ 0.77 for PPT and ICC ≥ 0.76 for TS). Reliability was higher when TS was calculated as a difference rather than a ratio. Conditioned pain modulation showed no to moderate reliability (ICC = 0.01-0.64) that was similar between leg or forearm, and between healthy people and those with RA or LBP. PPT and TS are transferable tools to quantify pain sensitivity at different testing sites in different musculoskeletal diagnoses. Low apparent reliability of CPM protocols might indicate minute-to-minute dynamic pain modulation.

Effects of an afforestation activity on thermal and mechanical pain mechanisms: A clinical trial

Sensory stimulation has shown the capacity to modulate pain mechanisms. Yet, the optimal methods of sensory stimulation remain uncertain. Afforestation activities stand out as a potential stimulation method, as they allow individuals to interact with multisensory stimuli produced in green environments. Exposure to natural multisensory stimuli has been shown to induce neurobiological activations in pain-related brain areas in healthy populations. However, the possible impact of the natural multisensory stimuli on the pain mechanisms themselves is yet to be explored. This study aimed to investigate the potential effects of sensory stimulation experienced during participation in an afforestation program on thermal and mechanical pain mechanisms. A single-group, pretest-posttest clinical trial was used. Forty-seven healthy adults performed an afforestation activity for 90 minutes. Measurements included cold pain detection and tolerance thresholds via the Cold Pressor Test, wind-up and mechanical pain sensitivity through a pinprick stimulator, and pressure pain detection and tolerance thresholds utilizing pressure algometry. For both thermal and mechanical pain thresholds, pain intensity was assessed using the 101-point Numeric Rating Scale. The results showed significant reductions in the cold pain intensity at the moment of detection (p = .046), mechanical pain sensitivity (p ≤ .014), and increases in the thresholds of pressure pain detection (p = .005) and tolerance (p ≤ .046). Therefore, the interaction with natural multisensory stimuli could be a possible therapeutic strategy to positively modulate mechanical pain sensitivity and pressure pain thresholds.

Effects of virtual reality on psychophysical measures of pain: superiority to imagination and nonimmersive conditions.

Virtual reality (VR) has been shown to be effective in pain management. However, to date, little is known about the mechanisms by which immersive experiences influence pain processing. The aim of this study was to investigate the direct effects of an immersive VR environment on the perception of experimental pain in individuals with chronic pain and pain-free controls. The immersion in a VR landscape was compared with mental imagery and a nonimmersive control condition. Using a randomized within-crossover design, pressure pain detection and tolerance thresholds, spatial and temporal summation (SSP, TSP), and conditioned pain modulation (CPM) were measured in 28 individuals with chronic pain and 31 pain-free controls using phasic cuff pressure on the legs. Direct comparison between the groups showed that although individuals with pain had significantly lower pain thresholds, reduced CPM effects, and increased TSP, the VR condition had the same pain-inhibitory effect on pain thresholds as in pain-free controls. Conditioned pain modulation effects were reduced by all conditions compared with baseline. There were no significant differences between conditions and baseline for TSP and SSP. Overall, pain modulatory effects were largest for VR and smallest for imagery. These results demonstrate that immersion in a VR environment has an increasing effect on pain thresholds, reduces pain inhibition in a CPM paradigm, and has no effects on TSP. This applies for participants with chronic pain and pain-free controls. These VR effects exceeded the effects of mental imagery on the nonimmersive control condition. This indicates that VR effectively modulates pain perception in both patients and controls irrespective of differences in pain perception.

A systematic review of the psychometric properties of pressure pain detection threshold in evaluating mechanical pain threshold in people with hand or wrist injuries

PurposeThe aim of this study was to conduct a systematic review of the psychometric properties of Pressure Pain Detection Threshold (PPDT) measures in people with hand or wrist injuries. Study Design and MethodsMEDLINE, Embase, and CINAHL databases were searched to identify eligible studies evaluating psychometric properties of PPDT in samples composed of at least 50% of people with hand or wrist injury. The Consensus-based Standards for the Measurement of Health Instruments' risk of bias checklist was used to critically appraise the included studies, and qualitative synthesis was performed by pooling the results of all studies that presented the same measurement property using Grading of Recommendations, Assessment, Development, and Evaluation. ResultsFrom 415 studies, 11 relevant studies were identified. Of the 11 studies, four hand or wrist injuries were represented; carpal tunnel syndrome, distal radius fractures, osteoarthritis, and complex regional pain syndrome. Intra-rater reliability was considered sufficient (intraclass correlation coefficient 0.64-0.94), with small reported standard error of the mean values (5.3-39.2 kPa). Results of validity and responsiveness could not be synthesized due to heterogeneity. Risk of bias for reliability and measurement error was assessed as very good or adequate, whereas validity and responsiveness were doubtful or inadequate. Overall quality of evidence was low or very low for all measurement properties. ConclusionsInconsistent results and low quality evidence provide little confidence in the overall measurement properties of PPDT in a hand or wrist injury population. No criterion standard for pain further highlights complexities around pain measurement such that the results obtained from PPDT measures in clinical practice cannot be compared to a gold standard measure.

Associations of Muscle Strength with Central Aspects of Pain: Data from the Knee Pain and Related Health in the Community (KPIC) Cohort.

Knee pain is associated with lower muscle strength, and both contribute to disability. Peripheral and central neurological mechanisms contribute to OA pain. Understanding the relative contributions of pain mechanisms to muscle strength might help future treatments. The Knee Pain and related health In the Community (KPIC) cohort provided baseline and year 1 data from people with early knee pain (n = 219) for longitudinal analyses. A cross-sectional analysis was performed with baseline data from people with established knee pain (n = 103) and comparative data from people without knee pain (n = 98). Quadriceps and handgrip strength indicated local and general muscle weakness, respectively. The indices of peripheral nociceptive drive were knee radiographic and ultrasound scores. The indices associated with central pain mechanisms were Pressure Pain detection Threshold (PPT) distal to the knee, and a validated self-report Central Aspects of Pain Factor (CAPF). The associations were explored using correlation and multivariable regression. Weaker quadriceps strength was associated with both high CAPF and low PPT at baseline. Year 1 quadriceps weakness was predicted by higher baseline CAPF (β = -0.28 (95% CI: -0.55, -0.01), p = 0.040). Weaker baseline and year 1 handgrip strength was also associated with higher baseline CAPF. Weaker baseline quadriceps strength was associated with radiographic scores in bivariate but not adjusted analyses. Quadriceps strength was not significantly associated with total ultrasound scores. Central pain mechanisms might contribute to muscle weakness, both locally and remote from the knee.

Sex Differences in Pain and Quantitative Sensory Testing in Patients With Rheumatoid Arthritis.

Women with rheumatoid arthritis (RA) have higher pain and worse functional outcomes compared to men, even when treated with similar medications. The objective of this study was to identify sex differences in pain intensity, pain interference, and quantitative sensory tests (QST), which are independent of inflammation, in patients with RA. This study is a post hoc analysis of participants in the Central Pain in Rheumatoid Arthritis cohort. Pain intensity was assessed using a 0-10 numeric rating scale. Pain interference was measured using a Patient-Reported Outcomes Measurement Information System computerized adaptive test. QST included pressure pain detection thresholds, temporal summation, and conditioned pain modulation. Women and men were compared using multiple linear regression, adjusted for age, education, race, research site, depression, obesity, RA disease duration, swollen joint count, and C-reactive protein. Mean ± SD pain intensity was 5.32 ± 2.29 among women with RA, compared to 4.60 ± 2.23 among men with RA (adjusted difference 0.83 [95% confidence interval (95% CI) 0.14, 1.53]). Women with RA had lower pressure pain detection thresholds at the trapezius (adjusted difference -1.22 [95% CI -1.73, -0.72]), wrist (adjusted difference -0.57 [95% CI -1.07, -0.06]), and knee (adjusted difference -1.10 [95% CI -2.00, -0.21]). No statistically significant differences in pain interference, temporal summation, and conditioned pain modulation were observed. Women reported higher pain intensity and lower pressure pain detection thresholds (higher pain sensitivity) than men. However, pain interference, temporal summation, and conditioned pain modulation did not differ between men and women.

Chronic post-thoracotomy pain after lung cancer surgery: a prospective study of preoperative risk factors.

The objective of this longitudinal cohort study was to investigate if preoperative pain mechanisms, anxiety, and depression increase risk of developing chronic post-thoracotomy pain (CPTP) after lung cancer surgery. Patients with suspected or confirmed lung cancer undergoing surgery by either video-assisted thoracoscopic surgery or anterior thoracotomy were recruited consecutively. Preoperative assessments were conducted by: quantitative sensory testing (QST) (brush, pinprick, cuff pressure pain detection threshold, cuff pressure tolerance pain threshold, temporal summation and conditioned pain modulation), neuropathic pain symptom inventory (NPSI), and the Hospital Anxiety and Depression Scale (HADS). Clinical parameters in relation to surgery were also collected. Presence of CPTP was determined after six months and defined as pain of any intensity in relation to the operation area on a numeric rating scale form 0 (no pain) to 10 (worst pain imaginable). A total of 121 patients (60.2 %) completed follow-up and 56 patients (46.3 %) reported CPTP. Development of CPTP was associated with higher preoperative HADS score (p=0.025), higher preoperative NPSI score (p=0.009) and acute postoperative pain (p=0.042). No differences were observed in relation to preoperative QST assessment by cuff algometry and HADS anxiety and depression sub-scores. High preoperative HADS score preoperative pain, acute postoperative pain intensity, and preoperative neuropathic symptoms were was associated with CPTP after lung cancer surgery. No differences in values of preoperative QST assessments were found. Preoperative assessment and identification of patients at higher risk of postoperative pain will offer opportunity for further exploration and development of preventive measures and individualised pain management depending on patient risk profile.

Serum Metabolome Analysis Identified Amino-Acid Metabolism Associated With Pain in People With Symptomatic Knee Osteoarthritis – A Cross-Sectional Study

Osteoarthritis (OA) is the most common arthritis affecting synovial joints such as knees and hips of millions of people globally. Usage-related joint pain and reduced function are the most common symptoms experienced by people with OA. To improve pain management, there is a need to identify validated biomarkers predicting therapeutic responses in targeted clinical trials. Our study aimed to identify the metabolic biomarkers for pain and pressure pain detection thresholds (PPTs) in participants with knee pain and symptomatic OA using metabolic phenotyping. Metabolite and cytokine measurements were done on serum samples using LC-MS/MS (liquid gas chromatography integrated magnetic resonance mass spectrometry) and Human Proinflammatory panel 1 kit respectively. Regression analysis was done in a test (n = 75) and replication study (n = 79) to investigate the metabolites associated with current knee pain scores and pressure pain detection thresholds (PPTs). Meta-analysis and correlation were done estimating precision of associated metabolites and identifying relationship between significant metabolites and cytokines respectively. Acyl ornithine, carnosine, cortisol, cortisone, cystine, DOPA, glycolithocholic acid sulphate (GLCAS), phenylethylamine (PEA) and succinic acid were found to be significantly (FDR <.1) associated with pain scores in meta-analysis of both studies. IL-10, IL-13, IL-1β, IL2, IL8 and TNF-α were also found to be associated with the significant metabolites. Significant associations of these metabolites and inflammatory markers with knee pain suggests that targeting relevant pathways of amino acid and cholesterol metabolism may modulate cytokines and these could be targeted as novel therapeutics development to improve knee pain and OA management. PerspectiveForeseeing the global burden of knee pain in Osteoarthritis (OA) and adverse effects of current pharmacological therapies, this study is envisaged to investigate serum metabolites and molecular pathways involved in knee pain. The replicated metabolites in this study suggests targeting amino-acid pathways for better management of OA knee pain.

Feasibility of quantitative sensory testing in juvenile idiopathic arthritis

ObjectiveJuvenile Idiopathic Arthritis (JIA) is a childhood-rheumatic disease with pain as a major early complaint, and in 10–17% pain remains a major symptom. Very few data exist on sensory threshold changes at the knee in JIA, a location in which inflammation often manifests. We determined whether JIA is associated with sensory threshold changes at the knee by using Quantitative Sensory Testing (QST) and established reference values at the knee of children.MethodsSixteen patients with JIA aged 9–18 years with one affected knee and a patient-reported pain by Visual Analog Scale (VAS) > 10 on a 0–100 scale, and 16 healthy controls completed the study and were included for the analysis. QST was assessed in compliance with the German Research Network on Neuropathic Pain (DFNS) standard. Disease severity was determined using Juvenile Disease Activity Score (JADAS. Perceived pain was assessed with a visual analogue scale(0–100). Feasibility of QST was tested in patients aged 6–9.ResultsUnder the age of 9, QST testing showed not to be feasible in 3 out of 5 JIA patients. Patients with JIA aged 9 and older reported an average VAS pain score of 54.3. QST identified a significant reduction in pressure pain threshold (PPT) and increase in cold detection threshold (CDT) compared to healthy controls. PPT is reduced in both the affected and the unaffected knee, CDT is reduced in the unaffected knee, not the affected knee.ConclusionIn a Dutch cohort of Patients with JIA, QST is only feasible from 9 years and up. Also, sensory threshold changes at the knee are restricted to pressure pain and cold detection thresholds in Patients with JIA.PerspectiveThis article shows that in a Dutch population, the extensive QST protocol is only feasible in the age group from 9 years and older, and a reduced set of QST tests containing at least pressure pain thresholds and cold detection thresholds could prove to be better suited to the pediatric setting with arthritis.

An observational study of centrally facilitated pain in individuals with chronic low back pain.

Central pain facilitation can hinder recovery in people with chronic low back pain (CLBP). The objective of this observational study was to investigate whether indices of centrally facilitated pain are associated with pain outcomes in a hospital-based cohort of individuals with CLBP undertaking a pain management programme. Participants provided self-report and pain sensitivity data at baseline (n = 97) and again 3 months (n = 87) after a cognitive behavioural therapy-based group intervention including physiotherapy. Indices of centrally facilitated pain were pressure pain detection threshold, temporal summation and conditioned pain modulation at the forearm, Widespread Pain Index (WPI) classified using a body manikin, and a Central Mechanisms Trait (CMT) factor derived from 8 self-reported characteristics of anxiety, depression, neuropathic pain, fatigue, cognitive dysfunction, pain distribution, catastrophizing, and sleep. Pain severity was a composite factor derived from Numerical Rating Scales. Cross-sectional and longitudinal regression models were adjusted for age and sex. Baseline CMT and WPI each was associated with higher pain severity (CMT: r = 0.50, P < 0.001; WPI: r = 0.21, P = 0.04) at baseline and at 3 months (CMT: r = 0.38, P < 0.001; WPI: r = 0.24, P = 0.02). High baseline CMT remained significantly associated with pain at 3 months after additional adjustment for baseline pain (β = 2.45, P = 0.04, R 2 = 0.25, P < 0.0001). Quantitative sensory testing indices of pain hypersensitivity were not significantly associated with pain outcomes at baseline or at 3 months. Central mechanisms beyond those captured by quantitative sensory testing are associated with poor CLBP outcome and might be targets for improved therapy.

Different genes may be involved in distal and local sensitization: A genome-wide gene-based association study and meta-analysis.

BackgroundNeuropathic pain symptoms and signs of increased pain sensitization in osteoarthritis (OA) patients may explain persistent pain after total joint replacement (TJR). Therefore, identifying genetic markers associated with pain sensitization and neuropathic‐like pain phenotypes could be clinically important in identifying targets for early intervention.MethodsWe performed a genome‐wide gene‐based association study (GWGAS) using pressure pain detection thresholds (PPTs) from distal pain‐free sites (anterior tibia), a measure of distal sensitization, and from proximal pain‐affected sites (lateral joint line), a measure of local sensitization, in 320 knee OA participants from the Knee Pain and related health in the Community (KPIC) cohort. We next performed gene‐based fixed‐effects meta‐analysis of PPTs and a neuropathic‐like pain phenotype using genome‐wide association study (GWAS) data from KPIC and from an independent cohort of 613 post‐TJR participants, respectively.ResultsThe most significant genes associated with distal and local sensitization were OR5B3 and BRDT, respectively. We also found previously identified neuropathic pain‐associated genes—KCNA1, MTOR, ADORA1 and SCN3B—associated with PPT at the anterior tibia and an inflammatory pain gene—PTAFR—associated with PPT at the lateral joint line. Meta‐analysis results of anterior tibia and neuropathic‐like pain phenotypes revealed genes associated with bone morphogenesis, neuro‐inflammation, obesity, type 2 diabetes, cardiovascular disease and cognitive function.ConclusionsOverall, our results suggest that different biological processes might be involved in distal and local sensitization, and common genetic mechanisms might be implicated in distal sensitization and neuropathic‐like pain. Future studies are needed to replicate these findings.SignificanceTo the best of our knowledge, this is the first GWAS for pain sensitization and the first gene‐based meta‐analysis of pain sensitization and neuropathic‐like pain. Higher pain sensitization and neuropathic pain symptoms are associated with persistent pain after surgery hence, identifying genetic biomarkers and molecular pathways associated with these traits is clinically relevant.

Central nervous system monoaminergic activity in hip osteoarthritis patients with disabling pain: associations with pain severity and central sensitization.

Monoaminergic activity modulates nociceptive transmission in the central nervous system (CNS). Although pain is the most disabling symptom of osteoarthritis (OA), limited knowledge exists regarding the CNS mechanisms that amplify pain and drive sensitization processes in humans. The main objective of this study was to evaluate associations between cerebrospinal fluid (CSF) monoamine metabolites, pain severity, and central sensitization in patients with OA undergoing total hip arthroplasty (THA). Patients with OA (n = 52) and pain-free controls (n = 30) provided CSF samples for measurement of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), noradrenaline (3-methoxy-4-hydroxyphenylglycol [HMPG]), and dopamine (homovanillic acid [HVA]) monoamine metabolites. Patients with OA completed longitudinal evaluation of pain using clinical measures and quantitative sensory testing. Patients with OA had higher HMPG levels when compared with controls (P = 0.036). Within patients with OA undergoing THA, higher 5-HIAA and HVA levels were consistently associated with higher preoperative pain severity. Higher concentrations of 5-HIAA and HVA were also associated with lower conditioned pain modulation levels, whereas higher HMPG levels were linked to more efficient conditioned pain modulation. Patients with higher levels of CSF HVA exhibited increased pressure pain sensitivity (arm pressure pain detection threshold < 250 kPa vs ≥ 250 kPa, P = 0.042). Higher preoperative levels of CSF 5-HIAA predicted poorer pain control 6 months postoperatively (brief pain inventory pain severity; adjusted β = 0.010, 95% CI 0.001-0.019). In OA patients with disabling pain, higher CSF levels of serotonin and dopamine metabolites are associated with increased pain severity and central sensitization. Increased noradrenergic activity may be associated with more efficient pain inhibitory capacity.

The Potential Clinical Utility of Pressure-Based vs. Heat-Based Paradigms to Measure Conditioned Pain Modulation in Healthy Individuals and Those With Chronic Pain.

Conditioned pain modulation (CPM) is a physiological measure thought to reflect an individual's endogenous pain modulation system. CPM varies across individuals and provides insight into chronic pain pathophysiology. There is growing evidence that CPM may help predict individual pain treatment outcome. However, paradigm variabilities and practical issues have impeded widespread clinical adoption of CPM assessment. This study aimed to compare two CPM paradigms in people with chronic pain and healthy individuals. A total of 30 individuals (12 chronic pain, 18 healthy) underwent two CPM paradigms. The heat CPM paradigm acquired pain intensity ratings evoked by a test stimulus (TS) applied before and during the conditioning stimulus (CS). The pressure CPM paradigm acquired continuous pain intensity ratings of a gradually increasing TS, before and during CS. Pain intensity was rated from 0 (no pain) to 100 (worst pain imaginable); Pain50 is the stimulus level for a response rated 50. Heat and pressure CPM were calculated as a change in TS pain intensity ratings at Pain50, where negative CPM scores indicate pain inhibition. We also determined CPM in the pressure paradigm as change in pressure pain detection threshold (PDT). We found that in healthy individuals the CPM effect was significantly more inhibitory using the pressure paradigm than the heat paradigm. The pressure CPM effect was also significantly more inhibitory when based on changes at Pain50 than at PDT. However, in individuals with chronic pain there was no significant difference in pressure CPM compared to heat or PDT CPM. There was no significant correlation between clinical pain measures (painDETECT and Brief Pain Inventory) and paradigm type (heat vs. pressure), although heat-based CPM and painDETECT scores showed a trend. Importantly, the pressure paradigm could be administered in less time than the heat paradigm. Thus, our study indicates that in healthy individuals, interpretation of CPM findings should consider potential modality-dependent effects. However, in individuals with chronic pain, either heat or pressure paradigms can similarly be used to assess CPM. Given the practical advantages of the pressure paradigm (e.g., short test time, ease of use), we propose this approach to be well-suited for clinical adoption.

Exploring the relationship between meaningful conditioned pain modulation and stress system reactivity in healthy adults following exposure to the cold pressor task

BackgroundThe sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis have been implicated in conditioned pain modulation (CPM). As there has recently been a push to identify meaningful CPM responses based on ± 2 SEM of the test stimulus, we sought to evaluate if meaningful CPM had relationships with both SNS and HPA axis reactivity. Methods50 university-aged healthy participants (25 males, 25 females) underwent evaluation of pressure pain detection threshold (PPDT), conditioned pain modulation (CPM), galvanic skin response (GSR) and salivary cortisol before and after a cold pressor test (CPT). Meaningful CPM was evaluated based on change ±2 SEM of baseline PPDT to classify participants as experiencing inhibition of pain, facilitation, or non-response. ResultsAs a group, there were no significant changes in PPDT or salivary cortisol after exposure to noxious cold. GSR was significantly elevated from baseline values during the CPT, and 10 min after (p < 0.001). When meaningful CPM was assessed, only 30% of participants experienced inhibitory CPM. Within this group, there was a large positive correlation ranging from r = 0.63 to 0.69 (p < 0.01) between CPM and the absolute change in GSR from baseline to immersion, and the immediate 5 min after immersion. ConclusionsThis work continues to support the growing body of literature suggesting that CPM is not universally experienced. Inhibitory CPM may be associated with an increase in SNS activity for healthy participants in reaction to noxious cold. Future work is required to ascertain individual characteristics (e.g., age, sex) that relate to CPM responses.

Decreased pain sensitivity and alterations of cerebrospinal fluid and plasma inflammatory mediators after total hip arthroplasty in patients with disabling osteoarthritis.

Proinflammatory mechanisms are implicated in pain states. Recent research indicates that patients with osteoarthritis (OA) with signs of central sensitization exhibit elevated cerebrospinal fluid (CSF) levels of interferon gamma-induced protein 10 (IP-10), Fms-related tyrosine kinase 1 (Flt-1), and monocyte chemoattractant protein 1 (MCP-1). The current prospective cohort study, including 15 patients with OA, primarily aimed to evaluate associations among alterations in CSF IP-10, Flt-1, MCP-1, and pain sensitization following total hip arthroplasty (THA). Participants provided CSF and blood samples for analysis of 10 proinflammatory mediators, and underwent detailed clinical examination and quantitative sensory testing, immediately preoperative and 18 months after surgery. Neurophysiological measures of pain showed markedly reduced pain sensitivity long-term postoperative. Increases in remote site pressure pain detection thresholds (PPDTs) and decreased temporal summation indicated partial resolution of previous central sensitization. Compared to preoperative, CSF concentrations of IP-10 were increased (p=0.041), whereas neither Flt-1 (p=0.112) nor MCP-1 levels changed (p=0.650). Compared to preoperative, plasma concentrations of IP-10 were increased (p=0.006), whereas interleukin (IL)-8 was decreased (p=0.023). Subjects who exhibited increases in arm PPDTs above median showed greater increases in CSF IP-10 compared to those with PPDT increases below median (p=0.028). Analyses of plasma IP-10 and IL-8 indicated higher levels of peripheral inflammation were linked to decreased pressure pain thresholds (unadjusted β=-0.79, p=0.006, and β=-118.1, p=0.014, respectively). THA leads to long-term decreases in pain sensitivity, indicative of resolution of sensitization processes. Changes in CSF and plasma levels of IP-10, and plasma IL-8, may be associated with altered pain phenotype.

Simple Quantitative Sensory Testing Reveals Paradoxical Co-existence of Hypoesthesia and Hyperalgesia in Diabetes.

Background: Diabetic neuropathy is characterized by the paradoxical co-existence of hypo- and hyperalgesia to sensory stimuli. The literature shows consistently sensory differences between healthy and participants with diabetes. We hypothesized that due to differences in pathophysiology, advanced quantitative sensory testing (QST) might reveal sensory discrepancies between type 1 (T1D) and type 2 diabetes (T2D). Furthermore, we investigated whether vibration detection thresholds (VDT) were associated with sensory response.Method: Fifty-six adults with T1D [43 years (28–58)], 99 adults with T2D [65 years (57–71)], and 122 healthy individuals [51 years (34–64)] were included. VDT, pressure pain detection thresholds (pPDT) and tolerance (pPTT), tonic cold pain (hand-immersion in iced water), and central pain mechanisms (temporal summation and conditioned pain modulation) were tested and compared between T1D and T2D. VDT was categorized into normal (< 18 V), intermediary (18–25 V), or high (> 25 V).Results: In comparison to healthy, analysis adjusted for age, BMI, and gender revealed hypoalgesia to tibial (pPDT): p = 0.01, hyperalgesia to tonic cold pain: p < 0.01, and diminished temporal summation (arm: p < 0.01; abdomen: p < 0.01). In comparison to participants with T2D, participants with T1D were hypoalgesic to tibial pPDT: p < 0.01 and pPTT: p < 0.01, and lower VDT: p = 0.02. VDT was not associated with QST responses.Conclusion: Participants with T1D were more hypoalgesic to bone pPDT and pPTT independent of lower VDT, indicating neuronal health toward normalization. Improved understanding of differentiated sensory profiles in T1D and T2D may identify improved clinical endpoints in future trials.

Central Aspects of Pain in Rheumatoid Arthritis (CAP-RA): protocol for a prospective observational study

BackgroundPain and fatigue are persistent problems in people with rheumatoid arthritis. Central sensitisation (CS) may contribute to pain and fatigue, even when treatment has controlled inflammatory disease. This study aims to validate a self-report 8-item questionnaire, the Central Aspects of Pain in Rheumatoid Arthritis (CAP-RA) questionnaire, developed to measure central pain mechanisms in RA, and to predict patient outcomes and response to treatment. A secondary objective is to explore mechanisms linking CS, pain and fatigue in people with RA.Methods/designThis is a prospective observational cohort study recruiting 250 adults with active RA in secondary care. The CAP-RA questionnaire, demographic data, medical history, and patient reported outcome measures (PROMs) of traits associated with central sensitization will be collected using validated questionnaires. Quantitative sensory testing modalities of pressure pain detection thresholds, temporal summation and conditioned pain modulation will be indices of central sensitization, and blood markers, swollen joints and ultrasound scans will be indices of inflammation. Primary data collection will be at baseline and 12 weeks. The test-retest reliability of CAP-RA questionnaire will be determined 1 week after the baseline visit. Pain and fatigue data will be collected weekly via text messages for 12 weeks. CAP-RA psychometric properties, and predictive validity for outcomes at 3 months will be evaluated.DiscussionThis study will validate a simple self-report questionnaire against psychophysical indices of central sensitization and patient reported outcome measures of traits associated with CS in a population of individuals with active RA. The application of this instrument in the clinical environment could provide a mechanism-based stratification tool to facilitate the provision of targeted therapy to individuals with pain and fatigue in RA, alongside treatments that target joint inflammation.Trial registrationClinicaltrials.gov NCT04515589. Date of registration 17 August 2020.

Associations of peripheral and central pain mechanisms with voluntary muscle strength in people with knee pain

Purpose: Knee pain is a major cause of disability and approximately 25% of people, aged 55 years and over in the UK, experience knee pain. Pain might be caused by local structural changes or inflammation linked to knee osteoarthritis (OA), and might be associated with alterations in central nervous system pain processing. People with knee pain commonly report weakness or giving way of their knees, despite often a lack of evidence of structural instability. Knee pain can reduce quadriceps voluntary contractions, a process referred to as reflex inhibition. "Central mechanisms trait" (CMT), a composite self-report tool, was designed to measure central pain augmentation in individuals with knee pain (Akin-Akinyosoye et al. Osteoarthritis Cartilage 2020; 28(2):173-81). It can be measured using 8 questionnaire items addressing anxiety, depression, catastrophizing, neuropathic-like pain, fatigue, sleep disturbance, pain distribution, and cognitive impact. This study aimed to explore possible effects of central and peripheral pain mechanisms on muscle strength in people with knee pain. Methods: This is a sub-study embedded in the Nottingham Knee Pain and Health in the Community (KPIC) cohort study in the East Midlands region of the UK including 9506 men and women aged ≥ 40 years at baseline. 322 participants that reported knee pain took part in additional baseline clinical assessments and were invited for repeat assessment at 1 year. The “Early Knee Pain” group at baseline was defined as pain commencing within the past 3 years, with the “Established Knee Pain” group being those reporting moderate to severe knee pain that lasted more than 3 years. Clinical assessment related to central pain mechanisms comprised CMT and pressure pain detection thresholds (PPT) at the proximal tibia ipsilateral to the index knee. Assessment related to peripheral pain mechanisms were total radiographic OA score (Nottingham Line Drawing Atlas), and ultrasound synovitis score. The mean value of 3 repeats of maximum quadriceps voluntary contraction (MVC) for index knee was assessed by ‘Nicholas Manual Muscle Tester’ (Lafayette Instruments, Indiana). The index knee was selected based on the only (unilateral) or most painful knee (bilateral). A knee was randomly selected if all scores were the same. The index knee was the only knee that was analysed in this study. The dominant hand grip strength was measured by the mean value of 3 repeats using a JAMAR hydraulic dynamometer (Lafayette, Indiana). Associations were explored using Spearman’s correlation coefficient and multiple linear regression models. Results were presented with standardized coefficients beta (β value), 95% Confidence Interval (CI), and p-value. Results: Of the 322 participants that provided baseline data, 219 had early and 103 had established knee pain. Quadriceps and hand grip strength were each associated with knee pain severity both at baseline and in longitudinal analyses. In cross-sectional analyses at baseline, PPT and CMT were associated with quadriceps strength, more strongly than were radiographic OA scores, while ultrasound synovitis score was not significantly associated with muscle strength. CMT was associated with hand grip strength. At 1 year, 255 people were reassessed (181 with early knee pain and 74 with established knee pain). The correlations between baseline variables and year 1 quadriceps strength were examined for baseline index knee pain (r=-0.32, p<0.001), age (r= -0.08, p=0.2), female sex (r=-0.46, p<0.001), study group (r= -0.25, p<0.001), CMT (r=-0.44, p<0.001), PPT (r=0.29, p<0.001), global X-ray score (r=-0.13, p=0.001) and total ultrasound score (r=-0.01, p=0.9). In longitudinal regression analysis (after adjustment for the above variables plus baseline quadriceps strength) baseline CMT was associated with year 1 quadriceps strength (β=-0.20 (95%CI:-0.34 to -0.06); p=0.005; Table 1). Baseline CMT was also associated with year 1 hand grip strength (Table 1). Conclusions: Central mechanisms of pain are associated with reduced muscle strength, both at the index knee and at a distant site (hand). Central pain mechanisms appeared to drive these associations, whereas local radiographic changes did not appear to be strongly linked. Addressing central pain augmentation has potential to improve muscle strength and reduce frailty in people with knee pain.Tabled 1Baseline and longitudinal regression analyses for muscle strengthAnalysesDependent variableIndependent variablesBeta95% CIpBaseline regressionBaseline quadriceps strengthCMT-0.19-0.33 to -0.040.012PPT0.130.01 to 0.250.037Global X-ray-0.11-0.24 to 0.020.102Total ultrasound score0.03-0.10 to 0.160.645Baseline hand grip strengthCMT-0.21-0.33 to -0.080.001PPT0.190.08 to 0.300.001Longitudinal regressionYear 1 quadriceps strengthCMT-0.20-0.34 to -0.060.005PPT0.04-0.07 to 0.150.485Global X-ray0.01-0.12 to 0.140.831Total ultrasound score-0.03-0.15 to 0.090.637Year 1 hand grip strengthCMT-0.24-0.40 to -0.080.004PPT0.04-0.07 to 0.160.454 Open table in a new tab