Contribution of inflammation markers and quantitative sensory testing (QST) indices of central sensitisation to rheumatoid arthritis pain.

BACKGROUND: Pain, the primary complaint in rheumatoid arthritis (RA), is multifaceted, and may be driven by inflammatory disease activity and central sensitisation. We aimed to ascertain what proportion of RA pain severity is explained by markers of inflammation and quantitative sensory testing (QST) indices of central sensitisation. METHODS: This was a cross-sectional analysis of data from individuals with clinically active RA. Pain severity was assessed using numerical rating scales and inflammation via 28-joint Disease Activity Score (DAS28) and Ultrasound (Greyscale, Power Doppler). Pain sensitivity was assessed by 'static' (tibialis anterior or brachioradialis pressure pain detection threshold-PPT-TA/PPT-BR) and 'dynamic' (temporal summation-TS, conditioned pain modulation-CPM) QST. Bivariate associations used Spearman's correlation coefficients, and multivariable linear regression models determined relative contributions to pain severity. RESULTS: In bivariate analyses of N = 96 (age 65 ± 10y, 77% females) people with RA, pain severity was significantly associated with inflammation indices (r = 0.20 to 0.55), and CPM (r=-0.26). In multivariable models that included TS, CPM, age, sex, and body mass index, inflammation indices remained significantly associated with pain severity. Multivariable models explained 22 to 27% of pain variance. Heterogeneity was apparent for associations with pain between subscores for pain now, strongest or average over the past 4-weeks. CONCLUSIONS: In individuals with clinically active RA, markers of inflammatory disease activity best explain RA pain with only marginal contributions from QST indices of central sensitisation. Although inflammation plays a key role in the experience of RA pain, the greater proportion of pain severity remains unexplained by DAS28 and ultrasound indices of inflammation.

Altered Sensory Processing in People Attending Specialist Orthopaedic Consultation for Management of Persistent Shoulder Pain: An Observational Cross-Sectional Study.

OBJECTIVES: The primary objective was to compare sensory processing measures in people attending specialist orthopaedic consultation for management of persistent shoulder pain with control participants. The secondary objective was to compare the groups' sociodemographic, clinical, general health and lifestyle, and psychological characteristics. DESIGN: Observational cross-sectional. METHODS: Participants with shoulder pain for ≥3 months, who attended a public hospital orthopaedic department (n = 119), and community participants without shoulder pain (n = 44) underwent a standardized quantitative sensory testing protocol, measuring pressure pain threshold, temporal summation, and conditioned pain modulation. Sociodemographic, clinical, general health and lifestyle, and psychological characteristics were also collected. RESULTS: Participants with shoulder pain had significantly lower pressure pain thresholds at all sites (ie, local and widespread mechanical hyperalgesia) and significantly decreased conditioned pain modulation effect (ie, descending inhibition of nociception) than control participants. There was no significant difference between groups for temporal summation. Participants with shoulder pain had decreased general health and function, less healthy lifestyles, and poorer psychological health compared with controls. CONCLUSION: People referred to specialist orthopaedic care for management of persistent shoulder pain had clinical signs of altered sensory processing and poor health outcomes. J Orthop Sports Phys Ther 2024;54(10):1-10. Epub 25 July 2024. doi:10.2519/jospt.2024.12512.

Reliability and validity of the pressure algometer in predicting gynecological surgery pain.

OBJECTIVE: The purpose of this study was to determine the reliability and validity of the pressure algometer in predicting gynecological surgery pain. We looked into the predictive value of preoperative pain sensitivity to gynecological pain and the relationship between preoperative pressure pain threshold (PPT), pressure pain tolerance (PTO), and postoperative pain outcomes. METHODS: Reliability test: We recruited 60 volunteers at Nantong University. For three consecutive days, two examiners measured the pain sensitivity of each participant using a pressure algometer. Its test-retest and intra-rater reliability were assessed using the intraclass correlation coefficient (ICC). Validity test: We selected patients who underwent gynecological surgery in a hospital for the validity test. Before surgery, we assessed the patient's pain sensitivity to various stimuli. To determine the relationship between preoperative pain sensitivity and postoperative pain, we collected postoperative Numerical Rating Scale (NRS) and sufentanil consumption data. RESULTS: The algometer revealed a high test-retest and intra-rater reliability. According to the calculation of Youden's index, there was a 73.1% chance of patients with moderate to severe postoperative pain having a PTO <6.22 N, and patients with PTO <6.22 N had an 87.5% probability of moderate to severe postoperative pain. CONCLUSIONS: The pressure algometer has a high degree of accuracy in measuring the PPT and PTO of normal healthy individuals, making it a reliable tool for quantifying pain sensitivity. PTO can be used to predict the occurrence of moderate to severe postoperative pain.

Comparing The Effects of Compression Contrast Therapy and Dry Needling on Muscle Functionality, Pressure Pain Threshold, and Perfusion after Isometric Fatigue in Forearm Muscles of Combat Sports Athletes: A Single-Blind Randomized Controlled Trial.

The aim of this study was to compare the acute effects of compression contrast therapy (CT) and dry needling therapy (DN) on muscle tension (MT), muscle strength (Fmax), pressure pain threshold (PPT), and perfusion (PU) following fatigue of forearm muscles (e.g., flexor carpi radialis) in combat sports athletes. A single-blind randomized controlled trial was employed. Participants first underwent muscle fatigue induction, which involved sustaining an isometric handgrip at 60% of their maximum voluntary contraction in 5-second cycles. This was followed by exposure to one of the regenerative therapies. Forty-five participants were randomly assigned to one of three groups: CT/DN (n = 15), CT/ShDN (n = 15), and ShCT/DN (n = 15). The sham condition (Sh) involved a simulated version of the technique. Measurements were taken at four time points: (i) at rest; (ii) immediately after exercise that led to a state of fatigue; (iii) 5 minutes after therapy (PostTh5min); and (iv) 24 hours after therapy (PostTh24h). Each participant was exposed to one experimental condition and one control condition, thereby undergoing evaluation in two sessions. Significant differences between groups were found in MT during the PostTh5min (p = 0.005), as well as in PU during the PostTh5min (p < 0.001) and PU during the PostTh24h (p < 0.001). All groups showed significant improvements at 5 minutes post-therapy compared to immediately post-muscle fatigue. As conclusions, CT/DN seems to be significantly better for enhancing MT and PU after 5 minutes of muscle fatigue induction. Using either CT, DN, or both combined is recommended to enhance the recovery of muscle functionality and properties, favoring recovery and potentially speeding up performance enhancement.

Effects of a Manual Treatment on Lumbar Microcirculation and Tissue Stiffness Following Submaximal Eccentric Trunk Extensor Exercise: A Randomized Controlled Trial.

Recent studies have shown that the extramuscular connective tissue (ECT) is thickened and stiffened in delayed onset muscle soreness (DOMS). However, contrarily to the normal population, severe DOMS is rare in athletes or highly trained individuals. The present randomized, controlled trial therefore aimed to investigate pain as well as microcirculation and stiffness of the ECT and the erector spinae muscle following submaximal eccentric trunk extension exercise not causing DOMS. The effect of manual treatment by a therapist (myofascial release; MFR) on these parameters was to be studied. Trained healthy participants (n = 21; 31.3 ± 9.6 years; > 4 h exercise per week) performed submaximal eccentric exercise of the trunk extensors. One group was manually treated (n = 11), while the other group (n = 10) received placebo treatment with sham laser therapy. Stiffness of the ECT and the erector spinae muscle (shear wave elastography), microcirculation (white light and laser Doppler spectroscopy), palpation pain (100 mm visual analogue scale, VAS) and pressure pain threshold (indentometry, PPT) were assessed before (t0), 24 h (t24) and 48 h (t48) after conditions. Erector spinae muscle stiffness increased after eccentric exercise from t0 to t24 (0.875 m/s) and from t0 to t48 (0.869 m/s). After MFR, erector spinae muscle stiffness decreased in contrast to placebo treatment at t24 (-0.66 m/s), while ECT stiffness remained unchanged. Oxygen saturation increased (17-20.93%) and relative haemoglobin decreased (-9.1 - -12.76 AU) after eccentric exercise and MFR differed from placebo treatment at t48 (-3.71 AU). PPT differed after MFR from placebo treatment at t48 (20.69 N/mm), while VAS remained unchanged. Multiple linear regression showed that ECT stiffness and group membership predicted erector spinae muscle stiffness. MFR could have a positive effect on pain, microcirculation and muscle stiffness after submaximal eccentric exercise, suggesting better recovery, which needs to be confirmed by future work.

Effects of transcranial direct current stimulation on pain and physical function in patients with knee osteoarthritis: a systematic review and meta-analysis.

BACKGROUND: Keen Osteoarthritis (KOA) is a common chronic disabling disease characterized by joint pain and dysfunction, which seriously affects patients' quality of life. Recent studies have shown that transcranial direct current stimulation (tDCS) was a promising treatment for KOA. PURPOSE: Investigate the effects of tDCS on pain and physical function in patients with KOA. METHODS: Randomized controlled trials related to tDCS and KOA were systematically searched in the PubMed, Embase, Medline, Cochrane Library, CINHL, and Web of Science databases from inception to July 23, 2024. The pain intensity was evaluated using the visual analog scale or the numeric rating scale, and the pain sensitivity was assessed using conditioned pain modulation, pressure pain threshold, heat pain threshold, or heat pain tolerance. The physical function outcome was evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index or the Knee injury and Osteoarthritis Outcome Score. Statistical analysis was performed using Review Manager 5.4. RESULTS: Seven studies with a total of 503 participants were included. Compared to sham tDCS, tDCS was effective in reducing the short-term pain intensity (SMD: -0.58; 95% CI: -1.02, -0.14; p = 0.01) and pain sensitivity (SMD: -0.43; 95% CI: -0.70, -0.16; p = 0.002) but failed to significantly improve the long-term pain intensity (SMD: -0.26; 95% CI: -0.59, 0.08; p = 0.13) in KOA patients. In addition, tDCS did not significantly improve the short-term (SMD: -0.13; 95% CI: -0.35, 0.08; p = 0.22) and long-term (SMD: 0.02; 95% CI: -0.22, 0.25; p = 0.90) physical function in patients with KOA. CONCLUSIONS: The tDCS can reduce short-term pain intensity and sensitivity but fails to significantly relieve long-term pain intensity and improve the physical function in patients with KOA. Thus, tDCS may be a potential therapeutic tool to reduce short-term pain intensity and pain sensitivity in patients with KOA.

Pain sensitivity genes as therapeutic targets in knee osteoarthritis: A comprehensive analysis.

Pain sensitivity is a significant factor in knee osteoarthritis (KOA), influencing patient outcomes and complicating treatment. Genetic differences, particularly in pain-sensing genes (PSRGs), are known to contribute to the variability in pain experiences among KOA patients. This study aims to systematically analyze PSRGs in KOA to better understand their role and potential as therapeutic targets. We utilized bulk RNA-seq data from the GSE114007 and GSE169077 datasets to identify differentially expressed genes, with 20 genes found to be significantly altered. Key PSRGs, including PENK, NGF, HOXD1, and TRPA1, were identified using LASSO, SVM, and random forest algorithms. Further, KEGG and GO enrichment analyses revealed pathways such as "Neuroactive ligand-receptor interaction" and "ECM-receptor interaction," which were validated through external datasets. Single-cell RNA-seq analysis from GSE152805, GSE133449, and GSE104782 datasets demonstrated the heterogeneity and dynamic expression of PSRGs across different cell subpopulations in synovium, meniscus, and cartilage samples. UMAP and pseudotime analyses were used to visualize spatial distribution and developmental trajectories of these genes. The findings emphasize the critical roles of PSRGs in KOA, highlighting their potential as therapeutic targets and suggesting that integrating genetic information into clinical practice could significantly improve pain management and treatment strategies for KOA.

Understanding inter-individual variability of experimental pain habituation and conditioned pain modulation in healthy individuals.

Although reduced experimental pain habituation is proposed as a proxy of diminished endogenous pain modulatory capacity in chronic pain, prior studies show contradictory findings. Even across healthy participants, pain habituation varies substantially, which may relate to another measure of endogenous pain modulation, i.e., conditioned pain modulation (CPM). Hence, this study investigated the relationship between pain habituation and CPM. Pain habituation was assessed in 45 healthy participants between two blocks of 15-20 contact-heat stimuli applied to the hand. Habituation of subjective pain ratings and objective neurophysiological readouts (contact-heat evoked potential (CHEP) and palmar sympathetic skin response (SSR)) was investigated. CPM was assessed by comparing heat pain thresholds before and after hand immersion in a noxious cold (9 °C) and lukewarm water bath (32 °C, to control for repeated measures effects). Pain habituation showed a large variability, with subjective but not objective pain habituation correlating with cold-induced CPM effects (r = 0.50; p = 0.025). This correlation was not observed for 'true' CPM effects (corrected for repeated measures effects) nor for CPM effects induced by a lukewarm water bath. These findings suggest that the observed variability in subjective pain habituation may be influenced by both descending endogenous pain modulation and peripheral adaptation processes associated with repeated measures. Objective pain habituation readouts, i.e., CHEPs and SSRs, capture different, complementary aspects of endogenous pain modulation.

The impact of different music genres on pain tolerance: emphasizing the significance of individual music genre preferences.

Music is a promising (adjunctive) treatment for both acute and chronic pain, reducing the need for pharmacological analgesics and their side effects. Yet, little is known about the effect of different types of music. Hence, we investigated the efficacy of five music genres (Urban, Electronic, Classical, Rock and Pop) on pain tolerance. In this parallel randomized experimental study, we conducted a cold pressor test in healthy volunteers (n = 548). The primary outcome was pain tolerance, measured in seconds. No objective (tolerance time) or subjective (pain intensity and unpleasantness) differences were found among the five genres. Multinomial logistic regression showed that overall genre preference positively influenced pain tolerance. In contrast, the music genres that participants thought would help for pain relief did not. Our study was the first to investigate pain tolerance at genre level and in the context of genre preference without self-selecting music. In conclusion, this study provides evidence that listening to a favored music genre has a significant positive influence on pain tolerance, irrespective of the kind of genre. Our results emphasize the importance of individual music (genre) preference when looking at the analgesic benefits of music. This should be considered when implementing music in the clinical setting.

Effects of adding electro-massage to manual therapy for the treatment of individuals with myofascial temporomandibular pain: a randomized controlled trial.

OBJECTIVE: To evaluate the effect of the addition of dynamic cervical electrical stimulation (electro-massage, ES) to manual therapy (MT), compared to MT by itself, in individuals with myofascial temporomandibular pain. METHODOLOGY: A total of 46 participants with bilateral myofascial temporomandibular pain for at least three months were distributed into two groups. Group 1 (n=21) received local MT consisting of soft tissue mobilization and release techniques over the neck and temporomandibular regions. Group 2 (n=25) received an ES procedure in the cervical region combined with the same intervention as group 1. All participants underwent a 2-week protocol. The primary outcomes were pain intensity (Visual Analogue Scale), pressure pain threshold (PPT) at the masseter and upper trapezius muscles (algometer), and pain-free vertical mouth opening (manual gauge). The secondary outcome was active cervical range-of-movement. Measurements were taken at baseline, immediately after intervention, and at a 4-week follow-up. RESULTS: The ANOVA revealed significant changes over group*time, with better results for group 2 (large effect sizes) regarding pain intensity (p< 0.001; η2>0.14), pressure pain sensitivity and mouth opening (p<0.001; η2>0.14). Similar findings were observed for active cervical range-of-movement in all directions (p<0.001; η2>0.14), except rotation (p≥0.05). CONCLUSION: Electrical stimulation therapy over the cervical region combined with a MT protocol over the neck and temporomandibular joint shows better clinical benefits than MT by itself in subjects with myofascial temporomandibular pain. Registration code: NCT04098952.

Randomized, placebo-controlled study on the effects of intravenous GSK3858279 (anti-CCL17) on a battery of evoked pain tests in healthy participants.

C-C Motif Chemokine Ligand 17 (CCL17) is a chemokine that binds and signals through the G-protein coupled CC-chemokine receptor 4 and has been implicated in the development of inflammatory and arthritic pain. GSK3858279 is a high-affinity, first-in-class, monoclonal antibody, binding specifically to CCL17 and inhibiting downstream signaling. In this phase I, randomized, single-center, double-blind, placebo-controlled, three-period, incomplete-block crossover study (NCT04114656), the analgesic effects and safety of intravenous GSK3858279 were assessed in a battery of evoked acute pain assessments on healthy, adult (aged ≥18 years), male participants. Participants were randomized 1:1 to receive either one placebo (0.9% w/v NaCl) dose followed by two GSK3858279 doses (PAA treatment sequence), or one GSK3858279 dose followed by two placebo doses (APP treatment sequence). The co-primary end points were ultraviolet B heat pain detection threshold (°C), cold pressor time to pain tolerance threshold (PTT, sec), and electrical PTT (mA, single stimulus). Twenty-one participants were enrolled (PAA = 11; APP = 10). Mean age (standard deviation) was 29.3 (7.9) years for PAA, 31.1 (7.7) years for APP. No significant differences were observed in the analgesic effect between GSK3858279 and placebo for any end point. Exposure to GSK3858279 was similar between Period 1 (APP sequence), and Periods 2 and 3 (PAA sequence), with some GSK3858279 carry-over. Changes in serum CCL17 levels were consistent with the expected GSK3858279 activity. All drug-related adverse events were mild in intensity and caused no discontinuations. The absence of an efficacy signal in this acute pain model does not preclude efficacy in chronic pain states.

Effect of Humour on Pain Perception among Young Healthy Indian Adults Using Cold Pressor Task.

Background Currently there is little research, especially in India, which has looked at the physiological effects of humour on pain perception. Objective To compare pain sensitivity across the three arms of intervention (control, neutral and funny videos). And to investigate the relationship between a) cardiovascular responses across and within each arm, b) pain sensitivity and resting blood pressure, pulse rate, c) humour trait with pain sensitivity. Method Subjects were exposed in random order to cold pressor task, during which they either watched a 'neutral video' or 'funny video' or did not watch any video. During the intervention, pain threshold and tolerance were recorded. Systolic and diastolic blood pressure, and pulse rate were measured before and after intervention. Pain unpleasantness was recorded post intervention. Result Neither humorous nor neutral videos had a significant effect on pain threshold, tolerance and unpleasantness and cardiovascular responses. There was significant difference between the pre and post values of cardiovascular measures within neutral and funny video arms. In the 'no video' arm, negative correlations were found between resting blood pressure and pain unpleasantness, and between delta diastolic blood pressure and pain threshold. Humour trait and subject's self-rating of pain tolerance had no effect on both pain sensitivity and cardiovascular responses to cold pain. Conclusion Humorous distraction had no effect on objective or subjective pain measures or cardiovascular responses to cold pain exposure. There was a significant difference in the pre-post values of cardiovascular measures within neutral and funny video arms.

Effects of Chronic Prenatal Alcohol Exposure on Nociceptive Responses to Mechanical and Thermal Stimuli in Rats.

The present study sought to investigate the effects of chronic prenatal alcohol exposure (PAE) on nociceptive responses to mechanical and thermal stimuli in rats. The Von Frey and Hot Plate tests were employed to assess the nociceptive responses of 10 control rats and 7 experimental rats whose mothers had been administered ethanol from day 5 to day 20 of gestation. In healthy animals, a decrease in pain sensitivity was observed between days 28 and 70, which was not observed in the experimental group. The findings also indicated that rats with PAE exhibited diminished sensitivity to nociceptive stimuli during the early postnatal period, as evidenced by a higher threshold response to mechanical stimuli at day 28 than in the control group. However, those observations did not apply to thermal stimuli. It appears that this may be a result of distinctiveness in neural pain pathways for particular stimuli at the receptor or ion channel level, while a disruption in the equilibrium between the sympathetic and parasympathetic nervous systems may be a contributing factor. The results of this study highlight a critical aspect of the harmful systemic effects of alcohol, while also underscoring the need for further research to elucidate the underlying mechanisms, including the role of the hypothalamic-pituitary-adrenal axis and the serotonergic system in modulating pain responses in individuals prenatally exposed to alcohol.

Pressure algometry in the general adult population: Age and sex differences.

Experimental pain studies have revealed inter-individual variations in pain perception that are influenced by age, sex, and country of origin. This study aimed to explore the age and sex differences in pressure pain thresholds within the Iranian general population. To assess the pressure pain thresholds, a handheld pressure algometer was applied bilaterally to the middle fingers of both hands. The participants also completed the short form of the McGill Pain Questionnaire to provide a clinical pain rating. This cross-sectional study included 1610 adult subjects (54.96% female, mean age 40.13 ±â€…10.18 years). The findings indicated that females generally exhibited lower pain thresholds than males when assessing pain detection and tolerance parameters (P < .001). Females also demonstrated a significant lower pressure thresholds and clinical pain ratings compared with men (P < .001). Additionally, significant differences were observed between age groups in terms of pain detection and tolerance thresholds (P = .02 and P = .03, respectively). However, the interaction between sex and age was not significant. No significant differences in pain detection thresholds were observed between the right and left hand (P = .11). This study underscores the potential utility of algometry as a valuable tool for objectifying pain in the Iranian population.

Ventral posteromedial nucleus of the thalamus gates the spread of trigeminal neuropathic pain.

BACKGROUND: Widespread neuropathic pain usually affects a wide range of body areas and inflicts huge suffering on patients. However, little is known about how it happens and effective therapeutic interventions are lacking. METHODS: Widespread neuropathic pain was induced by partial infraorbital nerve transection (p-IONX) and evaluated by measuring nociceptive thresholds. In vivo/vitro electrophysiology were used to evaluate neuronal activity. Virus tracing strategies, combined with optogenetics and chemogenetics, were used to clarify the role of remodeling circuit in widespread neuropathic pain. RESULTS: We found that in mice receiving p-IONX, along with pain sensitization spreading from the orofacial area to distal body parts, glutamatergic neurons in the ventral posteromedial nucleus of the thalamus (VPMGlu) were hyperactive and more responsive to stimulations applied to the hind paw or tail. Tracing experiments revealed that a remodeling was induced by p-IONX in the afferent circuitry of VPMGlu, notably evidenced by more projections from glutamatergic neurons in the dorsal column nuclei (DCNGlu). Moreover, VPMGlu receiving afferents from the DCN extended projections further to glutamatergic neurons in the posterior insular cortex (pIC). Selective inhibition of the terminals of DCNGlu in the VPM, the soma of VPMGlu or the terminals of VPMGlu in the pIC all alleviated trigeminal and widespread neuropathic pain. CONCLUSION: These results demonstrate that hyperactive VPMGlu recruit new afferents from the DCN and relay the extra-cephalic input to the pIC after p-IONX, thus hold a key position in trigeminal neuropathic pain and its spreading. This study provides novel insights into the circuit mechanism and preclinical evidence for potential therapeutic targets of widespread neuropathic pain.

Effects of voluntary chronic intermittent access to ethanol on the behavioral performance in adult C57BL/6 J mice.

BACKGROUND: Chronic alcohol drinking increases the risk of alcohol use disorders, causing various neurological disorders. However, the impact of different ethanol levels on a spectrum of behaviors during chronic drinking remains unclear. In this study, we established an intermittent access to ethanol in a two-bottle choice (IA2BC) procedure to explore the dose-dependent effects of ethanol on the behavioral performance of C57BL/6 J mice. METHODS: Adult male C57BL/6 J mice were provided voluntary access to different ethanol concentrations (0 %, 5 %, 10 %, and 20 % ethanol) under a 12-week IA2BC paradigm. A battery of behavioral tests was administered to assess alterations in pain threshold, anxiety-like behaviors, locomotor activity, motor coordination, and cognition. Ethanol consumption and preference were monitored during each session. Moreover, the liver, heart, and lung tissues were examined using pathological microscopy. RESULTS: The average (standard deviation) ethanol consumption of mice under the IA2BC paradigm increased dose-dependently to 5.1 (0.2), 8.7 (0.7), and 15.9 (0.8) g/kg/24 h with 5 %, 10 %, and 20 % ethanol, respectively. However, there is no significant difference in ethanol preference among all the ethanol groups. Chronic ethanol drinking caused hyperalgesia, cognitive impairment, and motor incoordination, but caused no changes in body temperature, locomotor activity, or anxiety-like behaviors. Minor histopathological alterations in the liver were detected; however, no major abnormal pathology was observed in the heart or lungs. CONCLUSION: These findings clarify the link between ethanol dosage and behavioral changes in mice over a 12-week IA2BC paradigm, thereby bridging the knowledge gap regarding the effects of chronic ethanol drinking on neurological disorders.

Mechanical and thermal thresholds before and after application of a conditioning stimulus in healthy Göttingen Minipigs.

Minipigs are widely used in biomedical research for translational studies. However, information about pain elicited by experimental procedures is lacking. Non-invasive methods as quantitative sensory testing and conditioned pain modulation are particularly attractive. Our overarching aim was to explore and refine these methods for assessing post-operative pain in minipigs after myocardial infarction. As first step, we aimed at defining mechanical and thermal thresholds in healthy adults Göttingen Minipigs, evaluating their reliability, and testing their modifications after the application of a conditioning stimulus. Thresholds were assessed at different body sites before and after a painful conditioning stimulus (CS) (cuffed tourniquet) and sham CS (uncuffed tourniquet) in eleven animals. Thresholds' reliability was assessed using interclass correlation coefficient (ICC). The effect of the CS was assessed calculating absolute change, percentage change of the thresholds and standard error of measurement. Baseline mechanical thresholds (Newton) were: left hindlimb 81 [73; 81]; left forearm 81 [72.1; 81]; right forearm 81 [76; 81]; left chest 80.5 [68; 81]; right chest 81 [76.5; 81]; left neck 81 [70.3; 81]; right neck 74.8 [62.3; 80.5]. Reliability of mechanical thresholds was good at right chest (ICC = 0.835) and moderate at left chest (ICC = 0.591), left hindlimb (ICC = 0.606) and left neck (ICC = 0.518). Thermal thresholds showed poor reliability in all the tested sites. A modulatory effect was present at right chest, but it was seen when both a painful CS and a sham CS was applied. Minipigs tendentially showed a pro-nociceptive profile (i.e. conditioning pain facilitation). The measured thresholds are a reference for future trials in this species. Mechanical thresholds showed to be more reliable and, therefore, more useful, than thermal ones. The pain facilitation might be explained by the phenomenon of stress induced hyperalgesia, but this finding needs to be further investigated with a stricter paradigm.

Mechanical pain sensitivity is associated with hippocampal structural integrity.

ABSTRACT: Rodents and human studies indicate that the hippocampus, a brain region necessary for memory processing, responds to noxious stimuli. However, the hippocampus has yet to be considered a key brain region directly involved in the human pain experience. One approach to answer this question is to perform quantitative sensory testing on patients with hippocampal damage-ie, medial temporal lobe epilepsy. Some case studies and case series have performed such tests in a handful of patients with various types of epilepsy and have reported mixed results. Here, we aimed to determine whether mechanical pain sensitivity was altered in patients diagnosed with temporal lobe epilepsy. We first investigated whether mechanical pain sensitivity in patients with temporal lobe epilepsy differs from that of healthy individuals. Next, in patients with temporal lobe epilepsy, we evaluated whether the degree of pain sensitivity is associated with the degree of hippocampal integrity. Structural integrity was based on hippocampal volume, and functional integrity was based on verbal and visuospatial memory scores. Our findings show that patients with temporal lobe epilepsy have lower mechanical pain sensitivity than healthy individuals. Only left hippocampal volume was positively associated with mechanical pain sensitivity-the greater the hippocampal damage, the lower the sensitivity to mechanical pain. Hippocampal measures of functional integrity were not significantly associated with mechanical pain sensitivity, suggesting that the mechanisms of hippocampal pain processing may be different than its memory functions. Future studies are necessary to determine the mechanisms of pain processing in the hippocampus.

Words matter: Effects of instructional cues on pressure pain threshold values in healthy people.

BACKGROUND: Pressure pain threshold (PPT) measurements require standardised verbal instructional cues to ensure that the increasing pressure is stopped at the correct time consistently. This study aimed to compare how PPT values and their test-retest reliability were affected by different instructional cues. METHODS: At two separate sessions, two PPT measurements were taken at the anterior knee for each of four different instructional cues: the cue of the German Neuropathic Research Network instructions ('DFNS'), the point where pressure first feels uncomfortable ('Uncomfortable'), 3/10 on the numerical pain rating scale ('3NPRS'), and where pain relates to an image from the pictorial-enhanced NPRS scale ('Pictorial'). Linear mixed modeling was used to quantify differences between pairs of instructional cues. Test-retest reliability was estimated using intraclass correlation coefficients (ICC[2,1] and ICC[2,k]). RESULTS: Twenty participants were recruited. The cue resulting in greatest PPT value was DFNS (394.32 kPa, 95%CI [286.32 to 543.06]), followed by Pictorial (342.49 kPa, 95%CI [248.68 to 471.68]), then Uncomfortable (311.85 kPa, 95%CI [226.43 to 429.48]), and lastly 3NPRS (289.78 kPa, 95%CI [210.41 to 399.09]). Five of six pairwise contrasts were statistically significant. Regardless of the cues, the point estimates of ICC (2,1) ranged from 0.80 to 0.86, and the ICC (2,k) values ranged from 0.89 to 0.93. No statistically significant differences were found between any pairwise contrasts of reliability indices. CONCLUSION: Words matter when instructing people when to stop testing in pressure algometry. Clinicians should use the same instructional cue when assessing pain thresholds to ensure reliability.

Pressure pain threshold of the whole foot: Protocol and dense 3D sensitivity map.

When designing footwear products, designers and kinesiologists usually factor in plantar surface pressure, motion capture data, and subjective comfort evaluations. However, these factors alone are not sufficient to guide the design of truly comfortable shoes. Pressure pain threshold (PPT) is a parameter that establishes a connection between psychological quantities and physical quantities. The purpose of this study was to construct a high-precision PPT map of the whole foot. Overall, 20 participants were included in this study, and an electronic, mechanical algometer was used to apply constant pressure to the participants' feet. A MATLAB graphical user interface was developed to simplify the data-collecting process and generate visual representations of the data. Finally, several high-precision unisex, different sex, and dominant side PPT maps were generated. The findings revealed that the foot dorsum area and the medial foot region exhibited the lowest PPTs (indicative of high sensitivity). Notably, the foot dorsum area near the toes displayed the highest pain sensitivity (indicative of the lowest PPT), while the plantar area demonstrated comparatively lower pain sensitivity. The heel area exhibited the lowest pain sensitivity. Simultaneously, the study observed that women's feet exhibited lower pain thresholds than men's. In the future, it is imperative to delve deeper into the correlation between short-term pain sensitivity and the daily, long-term exercise state, as well as other physiological data. This exploration will contribute to a more nuanced guide for footwear comfort design.