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Background: Kilohertz high-frequency alternating current (KHFAC) stimulation has demonstrated to induce rapid and reversible nerve blocks without causing nerve damage. Previous studies have explored frequency-dependent effects using a transcutaneous approach in humans from 5 to 20 kHz. Nevertheless, its application in humans is limited by the lack of stimulators approved for frequencies above 20 kHz. Therefore, this study aimed to assess the effects and safety of transcutaneous KHFAC stimulation using a novel prototype stimulator, comparing interventions at 30, 40, and 50 kHz to sham stimulation on experimental pain, sensory, motor, and neurophysiological outcomes., Methods: A randomized, double-blind, sham-controlled crossover study involving 34 healthy participants was conducted. Four interventions (30, 40, 50 kHz, and sham) were administered, and stimulation was applied for 20 min to the median nerve of the non-dominant hand. A prototype stimulator capable of delivering frequencies between 1 and 50 kHz, with a maximum peak-to-peak output current intensity of 400 mA was designed. The intensity applied during the stimulation was below motor threshold, evoking a 'strong but comfortable' tingling sensation. Primary outcomes included heat pain threshold (HPT), pressure pain threshold (PPT), and adverse effects. The secondary outcomes included static two-point discrimination sensitivity, isometric pinch strength, and median sensory nerve action potential (SNAP)., Results: Compared with the sham stimulation, all the active interventions exhibited a significantly greater increase in the PPT during and immediately after the stimulation, while only a significant increase was observed at 40 kHz (4.1 N/cm 2 ; 95%CI 0.3 to 7.9) at 15 min post-intervention. Compared to sham stimulation, the 40 kHz intervention had a significantly greater effect on the HPT at all time points, with the greatest difference (1.4 °C; 0.6 to 2.1) occurring immediately post-intervention. Adverse effects during active interventions included petechiae, erythema, and itching, which resolved at 24 h post-intervention. For secondary outcomes, only a significant reduction in the median SNAP velocity was observed in the sham stimulation group compared to the 50 kHz group., Conclusions: Active KHFAC stimulation, particularly at 40 kHz, delivered through a novel stimulator, effectively increased the PPT and HPT without affecting tactile or motor outcomes, inducing mild skin-related adverse effects. These findings have potential implications for people with pain-related pathologies., Trial Registration: NCT05230836., Competing Interests: Declarations Ethics approval and consent to participate Before the initiation of the study, the local research ethics committee (reference number: 805 − 24/11/2021) and the Spanish Agency of Medicines and Medical Devices (reference number: 965/22/EC-R) approved this study. All the participants gave and signed an informed consent to participate in this study. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Abnormal sensory perception, particularly pain insensitivity (PAI), is a typical symptom of autism spectrum disorder (ASD). Despite the role of myelin metabolism in the regulation of pain perception, the mechanisms underlying ASD-related PAI remain unclear., Methods: The pain-associated gene sphingosine-1-phosphate receptor 1 (S1PR1) was identified in ASD samples through bioinformatics analysis. Its expression in the dorsal root ganglion (DRG) tissues of BTBR ASD model mice was validated using RNA-seq, western blot, RT-qPCR, and immunofluorescence. Pain thresholds were assessed using the von Frey and Hargreaves tests. Patch-clamp techniques measured KCNQ/M channel activity and neuronal action potentials. The expression of S1PR1, KCNQ/M, mitogen-activated protein kinase (MAPK), and cyclic AMP/protein kinase A (cAMP/PKA) signaling proteins was analyzed before and after inhibiting the S1P-S1PR1-KCNQ/M pathway via western blot and RT-qPCR., Results: Through integrated transcriptomic analysis of ASD samples, we identified the upregulated gene S1PR1, which is associated with sphingolipid metabolism and linked to pain perception, and confirmed its role in the BTBR mouse model of ASD. This mechanism involves the regulation of KCNQ/M channels in DRG neurons. The enhanced activity of KCNQ/M channels and the decreased action potentials in small and medium DRG neurons were correlated with PAI in a BTBR mouse model of ASD. Inhibition of the S1P/S1PR1 pathway rescued baseline insensitivity to pain by suppressing KCNQ/M channels in DRG neurons, mediated through the MAPK and cAMP/PKA pathways. Investigating the modulation and underlying mechanisms of the non-opioid pathway involving S1PR1 will provide new insights into clinical targeted interventions for PAI in ASD., Conclusions: S1PR1 may contribute to PAI in the PNS in ASD. The mechanism involves KCNQ/M channels and the MAPK and cAMP/PKA signaling pathways. Targeting S1PR1 in the PNS could offer novel therapeutic strategies for the intervention of pain dysesthesias in individuals with ASD., (© 2024. The Author(s).)

Transcutaneous electrical stimulation with repetitive bursts of a kilohertz carrier frequency is thought to be less painful than conventional pulsed currents by reducing the sensitivity of pain receptors. However, no purported benefit has been shown unequivocally. We compared the effects of carrier-frequency stimulation and conventional stimulation on pain tolerance and the thresholds for sensory and motor axons in twelve participants. The ulnar nerve was stimulated transcutaneously with a conventional single pulse and 5 and 10 kHz carrier-frequency waveforms that had 5 and 10 pulses, respectively, when delivered in bursts of ∼1 ms duration. Phase durations were adjusted across waveform types to match the total charge for a given current amplitude. Single bursts of stimulation were delivered from 1 mA up until no longer tolerable. This was repeated with repetitive bursts of stimulation at 20 Hz for 1 s. Participants tolerated higher current amplitudes with both carrier-frequency waveforms than conventional stimulation, with repetitive bursts more painful than single bursts. However, compared to conventional stimulation, carrier-frequency waveforms required more current to produce sensory and motor-threshold responses and to obtain a maximal motor response (M max ). When the current at pain tolerance was normalised to the current at M max , participants tolerated lower stimulus intensities with carrier-frequency waveforms than conventional stimulation. These findings indicate that there is little to no benefit in using carrier-frequency waveforms to minimise the discomfort from electrical stimulation as the increase in stimulus intensity at pain tolerance is more than offset by reduced effectiveness in the activation of sensory and motor axons. KEY POINTS: Transcutaneous electrical stimulation with repetitive bursts of a kilohertz carrier-frequency waveform is thought to be less painful than conventional pulsed currents. For ulnar nerve stimulation, when stimulus waveforms were matched for total phase charge, participants tolerated higher current amplitudes with carrier-frequency stimulation than conventional stimulation. However, compared to conventional stimulation, carrier-frequency waveforms required more current to produce a threshold response in both sensory and motor axons and to produce a maximal motor response (M max ). When current at pain tolerance was normalised to current at M max , participants tolerated lower stimulus intensities with carrier-frequency waveforms than conventional stimulation. Carrier-frequency waveforms provide little to no benefit in minimising the discomfort from transcutaneous electrical stimulation as the increase in stimulus intensity at pain tolerance is more than offset by reduced effectiveness in activating sensory and motor axons., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Objective: This study aims to explores the physiological and psychological mechanisms of exercise-induced hypoalgesia (EIH) by combining the behavioral results with neuroimaging data on changes oxy-hemoglobin (HbO) in prefrontal cortex (PFC)., Methods: A total of 97 healthy participants were recruited and randomly divided into three groups: a single dance movement therapy (DMT) group, a double DMT group, and control group. Evaluation indicators included the pressure pain threshold (PPT) test, the color-word stroop task (CWST) for wearing functional near-infrared spectroscopy (fNIRS), and the self-assessment manikin (SAM). The testing time is before intervention, after intervention, and one hour of sit rest after intervention., Results: 1) Repeated measures ANOVA revealed that, there is a time * group effect on the PPT values of the three groups of participants at three time points. After 30 min of acute dance intervention, an increase in the PPT values of 10 test points occurred in the entire body of the participants in the experimental group with a significant difference than the control group. 2) In terms of fNIRS signals, bilateral DLPFC and left VLPFC channels were significantly activated in the experimental group. 3) DMT significantly awakened participants and brought about pleasant emotions, but cognitive improvement was insignificant. 4) Mediation effect analysis found that the change in HbO concentration in DLPFC may be a mediator in predicting the degree of improvement in pressure pain threshold through dance intervention (total effect β = 0.7140)., Conclusion: In healthy adults, DMT can produce a diffuse EIH effect on improving pressure pain threshold, emotional experience but only showing an improvement trend in cognitive performance. Dance intervention significantly activates the left ventrolateral and bilateral dorsolateral prefrontal cortex. This study explores the central nervous system mechanism of EIH from a physiological and psychological perspective., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Noncancer chronic pain is a clinical challenge because pharmacological treatment often fails to relieve pain. Transcranial direct current stimulation (tDCS) is a treatment that could have the potential for pain relief and improvement in quality of life. However, there is a lack of clinical trials evaluating the effects of tDCS on the pain system. The aim of the present study was to evaluate the effect of 5 days of anodal tDCS treatment on the pain system in patients with chronic noncancer pain using quantitative sensory testing and quality of life questionnaires: (1) Brief Pain Inventory-short form, (2) European Organization for Research and Treatment of Life Questionnaire-C30, and (3) Hospital Anxiety Depression Scale., Methods: Eleven patients with noncancer chronic pain (51 ± 13.6 y old, 5M) participated in the study. Anodal tDCS was applied for 5 consecutive days, followed by sham stimulation after a washout period of at least 2 weeks. Pressure pain thresholds and pain tolerance thresholds (PTT) were assessed in different body regions on days 1 and 5., Results: Anodal tDCS appeared to maintain PTT at C5 (clavicle) on day 5, but sham stimulation decreased PTT ( P = 0.007). In addition, anodal tDCS increased PTT compared with sham at day 5 at Th10 ventral dermatomes ( P = 0.014). Both anodal and sham tDCS decreased the Brief Pain Inventory-short form total and interference scores, and the European Organization for Research and Treatment of Life Questionnaire-C30 fatigue score, but no interaction effect was observed., Conclusion: This study adds to the evidence in the literature that tDCS may be a potential therapeutic tool for the management of noncancer chronic pain., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Considering the growing evidence that psychological variables might contribute to fibromyalgia syndrome (FMS), our study aims to understand the impact of psychological factors in quantitative sensory testing (QST) in FMS patients by performing a systematic review with meta-analysis., Methods: A systematic search was carried out in PubMed/MEDLINE, EMBASE, Web of Science, and PsycINFO databases for records up until January 2024. We included 20 studies ( n = 1623, 16 randomized controlled trials, and 4 nonrandomized controlled trials) with low or moderate risk of bias included., Results: From nonrandomized evidence, our meta-analysis found a baseline relationship between anxiety, depression, and pain catastrophizing and QST measures in FMS patients. Higher pain catastrophizing levels were associated with less efficient conditioned pain modulation. Higher anxiety and depression were associated with lower pain threshold (PT). Randomized evidence showed a statistically significant increase in PT after fibromyalgia treatments (effect size = 0.29, 95% confidence interval = 0.03-0.56). The effect was not influenced by treatment type. Moreover, we found that only anxiety levels before treatment negatively influenced the PT improvements after treatment., Conclusion: FMS patients with higher anxiety levels at baseline showed a smaller increase in PT after the intervention. Depression factor was not significant in either changes in anxiety or depression. Baseline anxiety levels should be monitored as possible confounders of QST measurements. Understanding how psychological factors and QST are related in FMS patients is critical for improving the syndrome's management and treatment.Protocol Registration: CRD42023429397., (Copyright © 2024 by the American Psychosomatic Society.)

Even in healthy populations, conditioned pain modulation (CPM) magnitude varies. This may be accounted for by (non-)modifiable factors, including physical activity (PA). Yet, little research has thoroughly examined PA and its relation with CPM magnitude in a representative sample. Therefore, the present study investigated the predictive effect of PA on CPM magnitude in 105 healthy adults. PA was assessed during 7 consecutive days by self-report using the International Physical Activity Questionnaire and by monitor-based accelerometry. CPM was examined using a heterotopic noxious-conditioning stimulation protocol during which the effect of a hot water-conditioning stimulus on pressure pain thresholds was evaluated. Comparative, correlation, and hierarchical linear regression analyses were performed. Report-based walking predicts 4.8% of variance in pain-modulatory capacity, moderate PA predicts 10.2% of variance in pain-modulatory capacity, and report-based time spent on total PA predicts 7.0% of variance in pain-modulatory capacity. More metabolic equivalent-minutes/week spent on total PA, including walking and moderate PA, is associated with greater pain-modulatory capacity. The findings of this study add to the limited evidence on the predictive effect of PA on CPM. It urges to consider PA a confounding factor when examining CPM. The current study provides evidence that a physically active lifestyle benefits endogenous pain modulation in healthy adults. Given its potential, walking and moderate-intensity PA might be achievable treatment strategies for pain patients known to have impaired CPM. PERSPECTIVE: The results of this article show that a physically active lifestyle, including larger amounts of walking and moderate activity, predicts greater pain-modulatory capacity. TRIAL REGISTRATION: This study has not been preregistered., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Commonly used models for eliciting muscle pain involve the injection of algesic substances or the induction of delayed onset muscle soreness. The former require invasive procedures, and the time frame for pain induction and subsidence in the latter can be inconvenient. This study presents a detailed spatiotemporal characterization of a new experimental model of muscle pain based on short-wave diathermy (SWD), developed to overcome the limitations of existing models., Methods: The shoulder was selected as target site and the effects of the model were tested in two sessions to assess its reliability. Pain intensity profiles were recorded during the application of SWD, and changes in pressure pain threshold (PPT) in the infraspinatus muscle, together with pain intensity, duration, and quality were assessed 30 min after induction., Results: SWD-induced pain intensity scores averaged 4 points on a visual analogue scale, whereas PPT showed a consistent decrease of about 25% relative to baseline values. Pain was localized in the shoulder area, and was described as continuous, dull, well-delimited, heavy, and bearable. Pain lasted for an average of 145 min without requiring reinduction and was reliably elicited in both experimental sessions., Conclusion: SWD can be used to elicit experimental muscle pain in a non-invasive, long-lasting, and reliable way and allows for repeated within- and between-session testing in the shoulder., Significance Statement: SWD produces deep heating in muscles by converting electromagnetic energy to thermal energy. It was previously shown that it can be used to elicit experimental pain in the forearm muscles, and the present study demonstrates that this can be reliably generalized to other body sites, such as the shoulder. Furthermore, SWD application is non-invasive and presents a convenient time frame for pain induction and subsidence, thus overcoming limitations associated with traditional muscle pain models., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Statement of Problem: The relationship of awake bruxism with pain is still unclear., Purpose: The purpose of this clinical study was to evaluate awake bruxism behavior for 1 week in healthy young adults with ecological momentary assessment, assess its relationship with masticatory muscle tenderness, and the participation of endogenous analgesia., Material and Methods: A total of 150 healthy participants were provided with a smartphone application that sent 10 alerts at random intervals every day. The participants were instructed to report in real time which of the following awake bruxism behaviors best represented their current condition: relaxed jaw muscles, tooth contact, tooth clenching, tooth grinding, or jaw bracing. At baseline, participants underwent recordings of the pressure pain threshold and conditioned pain modulation of the masticatory muscles. Pressure pain threshold recording was also repeated on the last day of the study. A t test was used to compare the first and the last pressure pain threshold recording after 1 week with an ecological momentary assessment evaluation. The Pearson correlation test was performed to evaluate the correlation between variables (α=.05)., Results: Overall compliance was 75.9%. The average frequency of relaxed jaw muscles was 54.5%, tooth contact 29.4%, jaw bracing 5.8%, tooth clenching 9.7%, and tooth grinding 0.6%. The average frequency of a distinct awake bruxism behavior was 45.5%. A statistically significant increase in pressure pain threshold values was found (P=.001; P=.001; P=.045 for right and left anterior temporalis and left masseter, respectively). No significant correlation was found between the frequency of awake bruxism behaviors, the pressure pain threshold, and conditioned pain modulation (P>.05)., Conclusions: The most prevalent behavior was tooth contact (29.4%). No relationship was found between awake bruxism behaviors and masticatory muscle tenderness or endogenous analgesia., (Copyright © 2023 Editorial Council for The Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

Pain is a crucial protective mechanism for the body. It alerts us to potential tissue damage or injury and promotes the avoidance of harmful stimuli. Injury-induced inflammation and tissue damage lead to pain sensitization, which amplifies responses to subsequent noxious stimuli even after an initial primary injury has recovered. This phenomenon, commonly referred to as hyperalgesic priming, was investigated in male and female mice to determine whether it is specific to the site of previous injury. We used 10μl of 50 % Freund's complete adjuvant (CFA) administered to the left hind paw as a model of peripheral injury. Both male and female mice exhibited robust site-specific mechanical hypersensitivity after CFA, which resolved within one-week post-injection. After injury resolution, only male CFA-primed mice showed enhanced and prolonged mechanical sensitivity in response to a chemical challenge or a single 0.5 mA electric footshock. Among CFA-primed male mice, shock-induced mechanical hypersensitivity was expressed in both the left (previously injured) and the right (uninjured) hind paws, suggesting a pivotal role for altered centralized processes in the expression of pain sensitization. These findings indicate that pain history regulates sensory responses to subsequent mechanical and chemical pain stimuli in a sex-specific manner-foot-shock-induced hyperalgesic priming expression among male mice generalized beyond the initial injury site., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

This study aimed to predict temporomandibular disorder (TMD) using machine learning (ML) approaches based on measurement parameters that are practically acquired in clinical settings. 125 patients with TMD and 103 individuals without TMD were included in the study. Pain intensity (with visual analog scale), maximum mouth opening (MMO) and lateral excursion movements (with millimeter ruler), cervical range of motion (with goniometer), pressure pain threshold (PPT; with algometer), oral parafunctional behaviors (with Oral Behaviors Checklist), psychological status (with Hospital Anxiety and Depression Scale), and quality of life (with Oral Health Impact Profile) were evaluated. The measurements were analyzed via over 20 ML algorithms, taking into account an extensive parameter tuning and cross-validation process. Results of variable importance were also provided. Bagging algorithm using Multivariate Adaptive Regression Spline (MARS) algorithm (accuracy = 0.8966, area under receiver operating characteristic curve = 0.9387, F1-score = 0.9032) was the best performing model regarding the performance criteria. According to this model, the 5 most important variables for predicting TMD were pain intensity, MMO, lateral excursion and PPT values of masseter and temporalis anterior muscles, respectively. The Bagging algorithm using the MARS algorithm is a robust model that, in combination with clinical parameters, assists in the detection of patients with TMD in settings with limited capabilities. The clinical parameters and ML algorithm proposed in this study may assist clinicians inexperienced in TMD to make a preliminary detection of TMD in clinics where diagnostic imaging tools are limited., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2024. The Author(s).)

PIEZO2 is a trimeric mechanically-gated ion channel expressed by most sensory neurons in the dorsal root ganglia. Mechanosensitive PIEZO2 channels are also genetically required for normal touch sensation in both mice and humans. We previously showed that PIEZO2 channels are also strongly modulated by membrane voltage. Specifically, it is only at very positive voltages that all channels are available for opening by mechanical force. Conversely, most PIEZO2 channels are blocked at normal negative resting membrane potentials. The physiological function of this unusual biophysical property of PIEZO2 channels, however, remained unknown. We characterized the biophysical properties of three PIEZO2 ion channel mutations at an evolutionarily conserved arginine (R2756). Using genome engineering in mice we generated Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice to characterize the physiological consequences of altering PIEZO2 voltage sensitivity in vivo. We measured endogenous mechanosensitive currents in sensory neurons isolated from the dorsal root ganglia and characterized mechanoreceptor and nociceptor function using electrophysiology. Mice were also assessed behaviourally and morphologically. Mutations at the conserved Arginine (R2756) dramatically changed the biophysical properties of the channel relieving voltage block and lowering mechanical thresholds for channel activation. Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice that were homozygous for gain-of-function mutations were viable and were tested for sensory changes. Surprisingly, mechanosensitive currents in nociceptors, neurons that detect noxious mechanical stimuli, were substantially sensitized in Piezo2 knock-in mice, but mechanosensitive currents in most mechanoreceptors that underlie touch sensation were only mildly affected by the same mutations. Single-unit electrophysiological recordings from sensory neurons innervating the glabrous skin revealed that rapidly-adapting mechanoreceptors that innervate Meissner's corpuscles exhibited slightly decreased mechanical thresholds in Piezo2 knock-in mice. Consistent with measurements of mechanically activated currents in isolated sensory neurons essentially all cutaneous nociceptors, both fast conducting Aδ-mechanonociceptors and unmyelinated C-fibre nociceptors were substantially more sensitive to mechanical stimuli and indeed acquired receptor properties similar to ultrasensitive touch receptors in Piezo2 knock-in mice. Mechanical stimuli also induced enhanced ongoing activity in cutaneous nociceptors in Piezo2 knock-in mice and hyper-sensitive PIEZO2 channels were sufficient alone to drive ongoing activity, even in isolated nociceptive neurons. Consistently, Piezo2 knock-in mice showed substantial behavioural hypersensitivity to noxious mechanical stimuli. Our data indicate that ongoing activity and sensitization of nociceptors, phenomena commonly found in human chronic pain syndromes, can be driven by relieving the voltage-block of PIEZO2 ion channels. Indeed, membrane depolarization caused by multiple noxious stimuli may sensitize nociceptors by relieving voltage-block of PIEZO2 channels., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Lymphedema of the upper limbs and persistent pain are frequent sequelae after surgical treatment of breast cancer., Aim: The aim of this paper was to analyze the upper limb volume, pressure pain threshold, neural range of motion, pain intensity, kinesiophobia, pain hypervigilance and catastrophizing in patients with and without lymphoedema after breast cancer surgery. Secondly, we aimed to investigated the association between upper limb volume and these variables., Design: Descriptive observational study., Setting: Faculty of Health Sciences of the University of Granada., Population: Fifty-eight post-surgical breast cancer survivors, 29 with upper limb lymphoedema and 29 without lymphoedema., Methods: We measured upper limb volume (perimetric method). Also, pressure pain thresholds were assessed with a digital algometer, neural range of motion (neurodynamic test for radial, ulnar and median nerves), pain intensity (visual analogue scale), kinesiophobia, pain hypervigilance and catastrophizing (validated tests). To detect differences between the groups for the measurement variables we performed a t-test for independent samples analysis. A simple linear regression analysis adjusting for age and body mass index was performed to check the association among upper limb volume and pain variables in the group with lymphoedema., Results: The analysis showed that lymphoedema group had lower pressure pain threshold bilaterally in the masseter (origin P≤0.036; insertion P≤0.046), temporalis (insertion P≤0.021), suboccipitalis (P≤0.036); second (P≤0.014), third (P≤0.001) and tenth rib (P≤0.001); affected side of the temporalis (origin P=0.025); temporomandibular joint (P=0.024); neural range of motion in the median nerve (P=0.047), ulnar (P=0.042) on the affected side and radial (P=0.039) on the unaffected side; and greater kinesiophobia (P=0.042). Linear regression analysis only showed a significant association between upper limb volume and neural range of motion in the radial nerve (P=0.020) in the lymphedema group. No significant associations were obtained for the rest of variables., Conclusions: These findings suggest that the presence of lymphoedema may contribute to an increased level of generalized mechanosensitivity and fear to movement in this population., Clinical Rehabilitation Impact: Upper limb lymphedema can lead to heightened mechanosensitivity and movement-related fear in breast cancer survivors. Therefore, fast track rehabilitation approach should be focus in screening and rehabilitation methods for detection and control this sequalae.

Background: Activation of β 2 adrenergic receptors reduces cutaneous mechanical pain thresholds in rats. While β 2 adrenergic receptor activation may contribute to mechanisms that underlie temporomandibular joint pain, its effect on masticatory muscle pain sensitivity is uncertain., Objectives: The current study sought to determine the extent to which β adrenergic receptors are expressed by masticatory muscle afferent fibres, and to assess the effect of local activation of these receptors on the mechanical sensitivity of masticatory muscle afferent fibres in rats., Methods: Trigeminal ganglion neurons that innervate the rat (n = 12) masseter muscle and lower lip were identified by tissue injection of fluorescent dyes and were then stained with antibodies against β 1 or β 2 adrenergic receptors. Extracellular recordings from 60 trigeminal ganglion neurons that innervate the masticatory muscle were undertaken in a second group of anaesthetised rats of both sexes (n = 37) to assess afferent mechanical activation thresholds. Thresholds were assessed before and after injection of the β adrenergic receptor agonists into masticatory muscle., Results: β 1 and β 2 adrenergic receptor expression was greater in labial skin than in masticatory muscle ganglion neurons (p < .05, one-way ANOVA, Holm-Sidak test). There was a higher expression of β 2 adrenergic receptors in masticatory muscle ganglion neurons in males than in females. The mixed β agonist isoproterenol increased afferent mechanical activation threshold in male but not female rats (p < .05, Mann-Whitney test). In male rats, salbutamol, a β 2 selective agonist, also increased afferent mechanical activation threshold but hydralazine, a vasodilator, did not (p < .05, Mann-Whitney test)., Conclusion: Activation of β 2 adrenergic receptors decreases the mechanical sensitivity of masticatory muscle afferent fibres in a sex-related manner., (© 2024 The Author(s). Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)

Background: People with high blood pressure have reduced sensitivity to pain, known as blood pressure hypoalgesia. One proposed mechanism for this is altered baroreceptor sensitivity. In healthy volunteers, stimulating the carotid baroreceptors causes reduced sensitivity to acute pain; however, this effect may be confounded by a rise in blood pressure due to baroreflex stimulation. The present study tests whether baroreceptor unloading contributes to the physiological mechanism of blood pressure-related hypoalgesia., Methods: In the present study, pain perception to thermal stimulation of the forearm was studied in 20 healthy volunteers during baroreceptor unloading by lower body negative pressure (LBNP) at -5 and -20 mmHg. Blood pressure and heart rate were measured continuously throughout. To address issues relating to stimulation order, the sequence of LBNP stimulation was counterbalanced across participants., Results: Increased heart rate was observed at a LBNP of -20 mmHg, but not -5 mmHg, but neither stimulus had an effect on blood pressure. There was no change in warm or cold sensory detection thresholds, heat or cold pain thresholds nor perceived pain from a 30s long thermal heat stimulus during LBNP., Conclusion: Therefore, baroreceptor unloading with maintained systemic blood pressure did not alter pain perception. The current study does not support the hypothesis that an altered baroreflex may underlie the physiological mechanism of blood pressure-related hypoalgesia., Significance: This work provides evidence that, when measured in normotensive healthy young adults, the baroreflex response to simulated hypovolaemia did not lead to reduced pain sensitivity (known as blood pressure hypoalgesia)., (© 2024 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Objective: The present study aimed to investigate whether subjective and objective measures of pain habituation can be used as potential markers for central sensitization across various chronic pain patients., Methods: Two blocks of contact-heat stimuli were applied to a non-painful area in 93 chronic pain patients (low back pain, neuropathic pain, and complex regional pain syndrome) and 60 healthy controls (HC). Habituation of pain ratings, contact-heat evoked potentials (CHEP), and sympathetic skin responses (SSR) was measured., Results: There was no significant difference in any measure of pain habituation between patients and HC. Even patients with apparent clinical signs of central sensitization showed no reduced pain habituation. However, prolonged baseline CHEP and SSR latencies (stimulation block 1) were found in patients compared to HC (CHEP: Δ-latency = 23 ms, p = 0.012; SSR: Δ-latency = 100 ms, p = 0.022)., Conclusion: Given the performed multimodal neurophysiological testing protocol, we provide evidence indicating that pain habituation may be preserved in patients with chronic pain and thereby be of limited use as a sensitive marker for central sensitization. These results are discussed within the framework of the complex interactions between pro- and antinociceptive mechanism as well as methodological issues. The prolonged latencies of CHEP and SSR after stimulation in non-painful areas may indicate subclinical changes in the integrity of thermo-nociceptive afferents, or a shift towards antinociceptive activity. This shift could potentially affect the relay of ascending signals., Significance: Our findings challenge the prevailing views in the literature and may encourage further investigations into the peripheral and central components of pain habituation, using advanced multimodal neurophysiological techniques., Competing Interests: Declarations of interest There are no conflicts of interest to declare., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Exercise induces a hypoalgesic response and improves affect. However, some individuals are unable to exercise for various reasons. Motor imagery, involving kinesthetic and visual imagery without physical movement, activates brain regions associated with these benefits and could be an alternative for those unable to exercise. Virtual reality also enhances motor imagery performance because of its illusion and embodiment. Therefore, we examined the effects of motor imagery combined with virtual reality on pain sensitivity and affect in healthy individuals., Design: Randomized crossover study., Setting: Laboratory., Subjects: Thirty-six participants (women: 18) were included., Methods: Each participant completed three 10-min experimental sessions, comprising actual exercise, motor imagery only, and motor imagery combined with virtual reality. Hypoalgesic responses and affective improvement were assessed using the pressure-pain threshold and the Positive and Negative Affect Schedule, respectively., Results: All interventions significantly increased the pressure-pain threshold at the thigh (P < .001). Motor imagery combined with virtual reality increased the pressure-pain threshold more than motor imagery alone, but the threshold was similar to that of actual exercise (both P ≥ .05). All interventions significantly decreased the negative affect of the Positive and Negative Affect Schedule (all P < .05)., Conclusions: Motor imagery combined with virtual reality exerted hypoalgesic and affective-improvement effects similar to those of actual exercise., Clinical Trials Registration: The study was enrolled in the UMIN Clinical Trials Registry (registration number: UMIN000046095). The website for registration information is https://center6.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000052614., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The Pain Sensitivity Questionnaire (PSQ) was developed to assess general pain sensitivity., Objective: This study aimed to validate the Greek version of PSQ., Methods: The questionnaire was translated into Greek (PSQ-GR) and piloted in a small sample of patients with chronic pain (n = 35). A total of 146 chronic pain patients and healthy volunteers completed the PSQ-GR, the Pain Catastrophizing Scale (PCS), Hospital Anxiety and Depression Scale (HADS) and Central Sensitization Inventory (CSI). To evaluate the test-retest reliability, 36 volunteers completed the PSQ-GR twice over 7 ± 2 days., Results: Internal consistency was excellent (Cronbach's alpha 0.90-0.96) for PSQ-total, PSQ-minor, and PSQ-moderate. The Intraclass Correlation Coefficient was estimated at 0.90-0.96 for PSQ-total, PSQ-minor and PSQ-moderate and the SEM was 0.59-0.90 for PSQ-total, PSQ-minor and PSQ-moderate approximately. The smallest detectable change was 0.48 for PSQ-total, 0.47 for PSQ-minor and 0.44 for PSQ-moderate. Positive and significant correlations were observed between PSQ-GR and HADS (r = 0.38, p < 0.01), PCS (r = 0.41, p < 0.01) and CSI (r = 0.30, p < 0.01). Statistically significant differences in PSQ-GR scores were identified between the healthy volunteers and the chronic pain patients., Conclusion: The PSQ-GR is a reliable and valid tool that can assess pain sensitivity in healthy individuals and chronic musculoskeletal pain patients., (© 2024 John Wiley & Sons Ltd.)

Background: Vagal activity has analgesic effects that are attributed to exercise-induced hypoalgesia (EIH). High vagal tone and low pain sensitivity are reported in individuals who routinely exercise yet, their association is unclear. Furthermore, it is unknown if the heightened vagal tone following high physical activity predicts and intensifies EIH., Methods: Fifty-one healthy participants (27 low-moderately physically active; 27 females) underwent a resting-state electrocardiogram followed by heart rate variability analysis. Pain measurements, including pressure (PPT) and heat (HPT) pain thresholds, ratings of tonic heat pain (THP) and conditioned pain modulation (CPM) paradigm, were conducted pre- and post-exercise on a cycle ergometer., Results: The highly active group demonstrated higher vagal tone compared to the low-moderately active (root mean square of successive differences between R-R intervals: 63.96.92 vs. 34.78 ms, p = 0.018; percentage of successive R-R intervals that exceed 50 ms: 24.41 vs. 11.52%, p = 0.012). Based on repeated-measure ANOVA, the highly active group showed higher PPT at pre-exercise, compared to the low-moderately active group (382 kPa vs. 327 kPa; p = 0.007). Post-exercise, both groups demonstrated EIH, increased HPT (p = 0.013) and decreased THP ratings (p < 0.001). Linear regression revealed that only in the low-moderately active group, higher vagal tone was associated with more efficient pre-exercise CPM and a greater reduction in THP ratings post-exercise (p ≤ 0.01)., Conclusions: Highly active individuals demonstrate greater vagal tone and lower pain sensitivity but no greater EIH. Vagal tone moderates pain inhibition efficiency and EIH only in low-moderately active individuals. These findings suggest that physical activity level moderates the vagal-pain association via the endogenous analgesia system., Significance: Highly physically active individuals exhibit greater vagal tone and reduced sensitivity to experimental pain, yet they do not benefit more from exercise-induced hypoalgesia (EIH) compared to low-moderately active individuals. Moreover, low-moderately active individuals with greater vagal tone exhibited more efficient endogenous pain inhibition and greater EIH, suggestive of the moderation effect of physical activity level on vagal-pain associations., (© 2024 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Background: Acute physical activity leads to exercise-induced hypoalgesia (EIH). However, to what degree it can be induced by very short but highly intensive exercise is largely unknown. This study aims to investigate the effects of two different short all-out isokinetic exercise sessions on EIH., Methods: Twenty young male participants underwent three different interventions (90, 15 s all-out isokinetic cycling, respectively, and control) after an individualized low-intensity warm-up in a randomized-controlled-crossover design. Before (pre), after warm-up (post 1) as well as immediately post-intervention (post 2) pain sensitivity was measured employing pressure pain thresholds (PPT; in N) at the elbow, knee and ankle joints as well as the sternum and forehead. Performance parameters (e.g. lactate, perceived exertion, heart rate) were documented., Results: A 'time' × 'intervention' × 'body site' interaction effect (p < 0.001, η 2 partial = 0.110) was observed for PPT. Both isokinetic interventions resulted in EIH at all body sites, even after ruling out any warm-up effects, while effects were larger for 90 s (maximum increase of 25.7 ± 11.7 N) compared to 15 s (maximum increase of 19.3 ± 18.9 N), and control (maximum increase of 8.0 ± 6.1 N). Compared to control, 15 s also resulted in hypoalgesic effects and differences were not observed at all sites. In this study, 90 s resulted in higher lactate, subjective exhaustion and heart rate levels compared to 15 s and control (p < 0.001), while higher values were also observed for 15 s compared to control., Conclusion: Global EIH assessed immediately after exercise can be induced by short highly intensive exercises. The effects are greater when the subjective and the objective exertion are higher as induced by the 90 s intervention., Significance Statement: This study investigates the potential for brief, highly intensive exercise sessions to induce exercise-induced hypoalgesia (EIH). The research demonstrates that EIH can indeed be triggered by such short workouts, with greater effects observed during a 90 s session compared to a 15 s one, most likely due to higher subjective and objective exertion. These findings offer insights into the potential for extremely brief but intense exercises to alleviate pain, impacting exercise recommendations and pain management strategies., (© 2024 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Homeostasis models posit that nonsuicidal self-injury (NSSI) serves, in part, to upregulate the endogenous opioid system in order to compensate for an opioid deficiency. A few studies have demonstrated lower basal levels of beta-endorphin (BE), an endogenous opioid, in individuals with NSSI. However, longitudinal studies are missing. Hence, the present study aimed to investigate the longitudinal associations between NSSI, comorbid psychopathology (i.e., borderline personality disorder and depressive symptoms), pain sensitivity and basal BE levels in adolescents with NSSI. N = 53 adolescents with NSSI disorder undergoing specialized treatment participated in baseline and one-year follow-up assessments. BE was measured in plasma; pain sensitivity was assessed with a heat pain stimulation paradigm. Associations between BE and change in NSSI, borderline personality disorder and depressive symptoms as well as pain sensitivity were examined using negative binomial and linear regression analyses. We found that an increase in basal BE was significantly associated with a decrease in depressive symptoms. No associations between BE and NSSI, borderline personality disorder symptoms or pain sensitivity were observed. Our findings may confirm a role of plasma BE in the etiology of depressive symptoms but challenge current models of endogenous opioid homeostasis in NSSI., Competing Interests: Declaration of competing interest The authors have nothing to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Abstract: Adverse childhood experiences (ACEs) affect approximately half of all children worldwide. These experiences have been linked to increased pain sensitivity in adulthood and a higher likelihood of developing severe chronic pain. However, most studies have assessed the effects of ACEs retrospectively, long after they occurred, leaving room for other factors to influence the observed outcomes. We investigated, for the first time, the association between ACEs and concurrent pain perception among young children who live in a conflict zone and are consistently exposed to potentially traumatic experiences. Participants were 60 elementary school children (ages 8-11 years) living in conflict regions (n = 39) or nonconflict regions (n = 21). Posttraumatic stress symptom (PTSS) severity, traumatic exposure, pressure pain threshold (PPT), and mechanical detection threshold (MDT) were measured. Trauma-exposed children had significantly lower PPT than did controls, but MDT was similar across groups. Pressure pain threshold correlated positively with proximity to the conflict zone and inversely with traumatic exposure magnitude and PTSS severity. In addition, PTSSs moderated the relationship between repeated traumatic exposure and PPT. Children with higher PTSS severity displayed pain hypersensitivity regardless of their traumatic exposure level, whereas in children with lower PTSS severity, greater traumatic exposure correlated with pain hypersensitivity. The results suggest that ACEs among children lead to concurrent pain hypersensitivity and distress and may put them at elevated risk of chronic pain early in life. In addition, our findings emphasize the need for identifying children with various PTSS levels to provide tailored interventions and mitigate the long-term negative effects of ACEs., (Copyright © 2024 International Association for the Study of Pain.)

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., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This study aimed to assess the sensory function of the infraorbital nerve in patients with fractures of the zygomatic complex who underwent open reduction and internal fixation at different time points using quantitative sensory testing, which was established by the German Neuropathic Pain Research Network, comprising a 7-item mechanical and thermal sensory test. A total of 21 patients (age range 17-46 y, 14 males) with unilateral zygomatic complex fractures were included. Quantitative sensory testing was conducted before the operation and at 1 week, 3 months, and 6 months operatively, with cold detection threshold, warmth detection threshold, cold pain threshold, heat pain threshold, mechanical detection threshold, mechanical pain threshold, pressure pain threshold, and vibration detection threshold being measured in bilateral infraorbital regions. Notable changes in sensitivity were observed in all values except for the mechanical pain threshold. In the majority of patients with zygomaticomaxillary complex fractures, infraorbital hypoesthesia was significantly improved within 3 months postoperatively, and almost complete recovery could be achieved by 6 months postoperatively., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Abstract: Nocebo hyperalgesia is a pervasive problem in which the treatment context triggers negative expectations that exacerbate pain. Thus, developing ethical strategies to mitigate nocebo hyperalgesia is crucial. Emerging research suggests that choice has the capacity to reduce nocebo side effects, but choice effects on nocebo hyperalgesia have not been explored. This study investigated the impact of choice on conditioned nocebo hyperalgesia using a well-established electrocutaneous pain paradigm where increases in noxious stimulation were surreptitiously paired with the activation of a sham device. In study 1, healthy volunteers (N = 104) were randomised to choice over (nocebo) treatment administration, nocebo administration without choice, or a natural history control group. Nocebo hyperalgesia was greater for those with choice than no choice, suggesting that choice increased rather than diminished nocebo hyperalgesia. Study 2 tested whether providing positive information about the benefits of choice in coping with pain could counteract heightened nocebo hyperalgesia caused by choice. A different sample of healthy adults (N = 137) were randomised to receive nocebo treatment with choice and positive choice information, choice only, or no choice. The positive choice information failed to attenuate the effect of choice on nocebo hyperalgesia. The current results suggest that, rather than decreasing nocebo hyperalgesia, treatment choice may exacerbate pain outcomes when a painful procedure is repeatedly administered. As such, using choice as a strategy to mitigate nocebo outcomes should be treated with caution., (Copyright © 2024 International Association for the Study of Pain.)

The association between sleep and pain has been investigated widely. However, inconsistent results from animal studies compared with human data show the need for a validated animal model in the sleep-pain association field. Our study aims to validate common neuropathic pain models as a tool for evaluating the sleep-pain association. Electrodes electroencephalogram (EEG) and electromyogram (EMG) were surgically implanted to measure sleep. The von Frey test was used to measure pain sensitivity. Following the baseline data acquisition, two pain-modelling procedures were performed: sciatic nerve crush injury (SCI) and common peroneal nerve ligation (CPL). Post-injury measurements were performed on days 1, 5, 10, and 15 post-surgery. The results presented decreased paw withdrawal thresholds and reduced NREM sleep duration in both models on the first post-surgery day. In the SCI model, NREM sleep duration was negatively correlated with paw withdrawal thresholds (p = 0.0466), but not in the CPL model. Wake alpha and theta EEG powers were also correlated with the pain threshold. The results confirm that the SCI model shows disturbed sleep patterns associated with increased pain sensitivity, suggesting it is a reliable tool for investigating sleep disturbances associated with neuropathic pain., (© 2024 European Sleep Research Society.)

The attentional bias literature has consistently failed to take context into account. We developed a novel paradigm in immersive virtual reality (VR) with pain stimuli where it would be adaptive or nonadaptive to attend to the stimuli. Participants had to indicate the location of the stimuli. Seventy participants were recruited. The VR-attention task assessed overall attentional bias (the tendency to prioritize pain compared with nonpain stimuli) and attentional alignment (the tendency to attend to pain more in adaptive than nonadaptive situations). Pain tolerance and threshold were measured using electrocutaneous stimulation and thermal pain. We conducted 2 (context: adaptive vs nonadaptive) × 2 (congruence: congruent vs incongruent) Analysis of Covariance, controlling for threat. Participants responded to pain probes more quickly in adaptive than nonadaptive contexts. There was an overall bias away from pain-related stimuli (avoidance) in reaction time to the target. There was also an interaction where avoidance was greater in nonadaptive contexts, indicative of attentional alignment. For gaze behavior, both attentional alignment and attentional bias were observed for latency to first fixation on the target, such that participants showed vigilance for pain particularly in the adaptive context. Attentional alignment was correlated with threshold and tolerance from electrocutaneous stimulation but not thermal pain. In conclusion, we found overall attentional biases indicating vigilance (latency to first fixation) and avoidance (response to target). We also found that participants evidenced a pattern of attention favoring adaptive over nonadaptive contexts (attentional alignment). It was attentional alignment, but not overall attentional bias, that predicted pain tolerance and threshold. PERSPECTIVE: The study explored attentional processes in pain through a novel paradigm designed in VR. The results found that positive attentional alignment, or the tendency to attend to pain more in adaptive contexts rather than nonadaptive contexts, predicted pain outcomes., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

We compared the magnitude of exercise-induced hypoalgesia and conditioned pain modulation between blood-flow restriction (BFR) resistance exercise (RE) and moderate-intensity RE. Twenty-five asymptomatic participants performed unilateral leg press in two visits. For moderate-intensity RE, subjects exercised at 50% 1RM without BFR, whereas BFR RE exercised at 30% 1RM with a cuff inflated to 60% limb occlusion pressure. Exercise-induced hypoalgesia was quantified by pressure pain threshold changes before and after RE. Conditioned pain modulation was tested using cold water as the conditioning stimulus and mechanical pressure as the test stimulus and quantified as pressure pain threshold change. Difference in conditioned pain modulation pre- to post-RE was then calculated. The differences of RE on pain modulations were compared using paired t-tests. Pearson's r was used to examine the correlation between exercise-induced hypoalgesia and changes in conditioned pain modulation. We found greater hypoalgesia with BFR RE compared to moderate-intensity RE (p=0.008). Significant moderate correlations were found between exercise-induced hypoalgesia and changes in conditioned pain modulation (BFR: r=0.63, moderate-intensity: r=0.72). BFR RE has favorable effects on pain modulation in healthy adults and the magnitude of exercise-induced hypoalgesia is positively correlated with conditioned pain modulation activation., Competing Interests: Nicholas Rolnick is the founder of The BFR PROS and teaches BFR training workshops to fitness and rehabilitation practitioners using a variety of BFR training devices. Ericka Merriwether is a Member of the Board of Directors for the United States Association for the Study of Pain (USASP).No conflict of interested from other authors., (Thieme. All rights reserved.)

Fibromyalgia (FM) is a common chronic pain condition for which acupuncture treatment is increasingly utilized. However, there is no universally accepted measure to predict whether a specific patient will benefit from acupuncture. This is a single-center, single-blind, sham-controlled, randomized, noncrossover, longitudinal trial of 76 subjects with FM, assigned to either electroacupuncture (EA) or a placebo control, mock laser (ML) acupuncture. Outcome measures included clinical pain severity (Brief Pain Inventory [BPI]), degree of nociplastic pain (Fibromyalgia Survey Questionnaire), and pressure pain tolerance (PPtol). Baseline measures of temporal summation of pain and expectations for treatment relief were used as predictors. Individuals in both treatment groups experienced significant reductions in BPI (EA: P < .001, ML: P = .018) and Fibromyalgia Survey Questionnaire (EA: P = .032, ML: P = .002) after treatment; however, neither group showed a significant increase in PPtol. Lower temporal summation at baseline was correlated with greater post-treatment improvement in BPI in the EA group (rho = .389, P = .025) but not in the ML group (rho = -.272, P = .109). Lower-baseline temporal summation was correlated with greater decreases in PPtol following EA (rho = .400, P = .040), whereas the opposite was seen for ML (rho = -.562, P = .001). Treatment expectancy at baseline was not correlated with any outcome after EA or ML treatments. Our results support using a quantitative sensory testing metric, temporal summation of pain, but not expectations, to predict analgesia following acupuncture treatment for pain. PERSPECTIVE: A randomized study of acupuncture in FM found baseline temporal summation, but not expectations of pain relief, to be predictive of treatment response. CLINICAL TRIAL REGISTRATION: Registered under ClinicalTrials.gov identifier NCT02064296., (Copyright © 2024. Published by Elsevier Inc.)

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., (© 2024. The Author(s).)

Objective: The aims of the current study were to investigate the presence of widespread pressure hyperalgesia, the presence of structural changes in the wrist extensor tendon and muscle, and their association in people with lateral epicondylalgia (LE)., Methods: Thirty-seven patients with LE (43% women; mean age = 45.5 [SD = 9.5] years) and 37 controls matched for age and sex and free of pain participated in this study. Pressure pain thresholds (PPTs) were assessed bilaterally over the symptomatic area (elbow), 2 segment-related areas (C5-C6 joint, second intermetacarpal space), and 1 remote area (tibialis anterior) in a blinded design. Ultrasound measurements (eg, cross-sectional area, thickness, and width) of the common wrist extensor tendon and extensor carpi radialis brevis muscle as well as the thickness of the supinator muscle were assessed., Results: Patients with LE exhibited lower PPTs bilaterally at all points and lower PPTs at the lateral epicondyle and second intermetacarpal space on the symptomatic side as compared to the nonsymptomatic side (η2 from 0.123-0.369; large effects). Patients exhibited higher cross-sectional area and width of the common wrist extensor tendon (η2 from 0.268-0.311; large effects) than controls bilaterally, whereas tendon thickness was also higher (η2 = 0.039; small effects) on the painful side than on the nonpainful side., Conclusions: This study reported bilateral widespread pressure pain hyperalgesia and morphological changes in the tendon, but not the muscle, in LE. Pressure pain sensitivity and morphological changes were not associated in individuals with LE., Impact: Management of LE should consider altered nociceptive pain processing and structural tendon changes as 2 different phenomena in patients with LE., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 (t 0 ), 24 h (t 24 ) and 48 h (t 48 ) after conditions. Erector spinae muscle stiffness increased after eccentric exercise from t 0 to t 24 (0.875 m/s) and from t 0 to t 48 (0.869 m/s). After MFR, erector spinae muscle stiffness decreased in contrast to placebo treatment at t 24 (-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 t 48 (-3.71 AU). PPT differed after MFR from placebo treatment at t 48 (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., (© Journal of Sports Science and Medicine.)

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., (© Journal of Sports Science and Medicine.)

Abstract: In humans and animals, high-frequency electrocutaneous stimulation (HFS) induces an "early long-term potentiation-like" sensitisation, where synaptic plasticity is underpinned by an ill-defined interaction between peripheral input and central modulatory processes. The relative contributions of these processes to the initial pain or nociceptive response likely differ from those that underpin development of the heightened response. To investigate the impact of HFS-induced hyperalgesia on pain and nociception in perception and neural terms, respectively, and to explore the impact of descending inhibitory pathway activation on the development of HFS-induced hyperalgesia, we performed parallel studies utilising identical stimuli to apply HFS concurrent to (1) a conditioned pain modulation paradigm during psychophysical testing in healthy humans or (2) a diffuse noxious inhibitory controls paradigm during in vivo electrophysiological recording of spinal neurones in healthy anaesthetised rats. High-frequency electrocutaneous stimulation alone induced enhanced perceptual responses to pinprick stimuli in cutaneous areas secondary to the area of electrical stimulation in humans and increased the excitability of spinal neurones which exhibited stimulus intensity-dependent coded responses to pinprick stimulation in a manner that tracked with human psychophysics, supporting their translational validity. Application of a distant noxious conditioning stimulus during HFS did not alter perceived primary or secondary hyperalgesia in humans or the development of primary or secondary neuronal hyperexcitability in rats compared with HFS alone, suggesting that, upon HFS-response initiation in a healthy nervous system, excitatory signalling escapes inhibitory control. Therefore, in this model, dampening facilitatory mechanisms rather than augmenting top-down inhibitions could prevent pain development., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Secondary mechanical hypersensitivity, a common symptom of neuropathic pain, reflects increased responsiveness of nociceptive pathways and can be induced temporarily in healthy volunteers using high-frequency electrical stimulation of the skin. Expectations modulate acute pain perception and fear of pain has been shown to attenuate and amplify the placebo and nocebo effects, respectively. However, the role of expectations and fear in the development of mechanical secondary hypersensitivity remains unclear. The modulatory role of fear and expectations in the development of mechanical secondary hypersensitivity remains so far mainly correlational. Here, we randomly assigned healthy participants (women) to a placebo, nocebo, or control group. In the experimental groups, participants' expectations of pain were manipulated using verbal suggestions accompanied by an inert treatment. Fear of pain was evaluated both in terms of fear of pain and via questionnaires. Sensitivity to mechanical stimulation was assessed by self-reported pinprick ratings before and after high-frequency stimulation; pinprick-evoked potentials elicited by the stimulation were recorded. The placebo group developed the least mechanical secondary hypersensitivity (smaller proximal-distal spread), while the nocebo group developed the most, but only when outliers were excluded. Higher expectations of pain predicted a greater development of mechanical secondary hypersensitivity. Anticipatory pain-related fear only mediated the relationship between unpleasantness expectations and perceived pinprick unpleasantness. Dispositional fear of pain moderated the relationship between expectations and the perceived intensity and unpleasantness of pinpricks. No group differences were observed in pinprick-evoked potentials. We provide preliminary evidence that both expectations and fear impact the development of mechanical secondary hypersensitivity. PERSPECTIVE: Expectations of pain may influence the development of secondary mechanical hypersensitivity. This effect is moderated by dispositional fear of pain and partially mediated by situational fear of pain., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Abstract: Vulnerability to chronic pain is found to depend on age and sex. Most patients with chronic pain are elderly women, especially with posttraumatic pain after bone fracture that prevails beyond the usual recovery period and develops into a complex regional pain syndrome (CRPS). There, a distal bone fracture seems to initiate a pathophysiological process with unknown mechanism. To investigate whether sex, age, and alpha adrenergic receptors also contribute to a CRPS-like phenotype in animals, we performed experiments on tibia-fractured mice. Those mice commonly are resilient to the development of a CRPS-like phenotype. However, we found them to be vulnerable to long-lasting pain after distal bone fracture when they were of old age. These mice expressed mechanical and thermal hypersensitivity, as well as weight-bearing and autonomic impairment following bone trauma, which persisted over 3 months. Site-specific and body side-specific glycinergic and α1D-noradrenergic receptor expression in the spinal cord and the contralateral locus coeruleus were misbalanced. Aged female tibia-fractured mice lost descending noradrenergic inhibition and displayed enhanced spinal activity on peripheral pressure stimuli. Together, changes in the noradrenergic, hence, glycinergic system towards excitation in the pain pathway-ascending and descending-might contribute to the development or maintenance of long-lasting pain. Conclusively, changes in the noradrenergic system particularly occur in aged female mice after trauma and might contribute to the development of long-lasting pain. Our data support the hypothesis that some patients with chronic pain would benefit from lowering the adrenergic/sympathetic tone or antagonizing α1(D)., (Copyright © 2024 International Association for the Study of Pain.)

This study investigated the sex-specific associations between pain perception and testosterone levels in healthy controls (HCs) and patients with migraine. Male and female HCs and migraine patients were recruited. A series of questionnaires were completed by the participants to evaluate their psychosocial profiles, which included data on mood, stress, and sleep quality. Heat pain thresholds and suprathreshold pain ratings at 45 °C (referred to as the pain perception score [PPS]) were assessed using the Thermode system. Salivary testosterone levels were analyzed using a commercial enzyme-linked immunosorbent assay kit. A total of 88 HCs (men/women: 41/47, age: 29.9 ± 7.7 years) and 75 migraine patients (men/women: 30/45, age: 31.1 ± 7.7 years) completed all assessments. No significant differences were observed in either the psychosocial profiles or heat pain thresholds and PPSs between the sexes in the control and migraine groups. A positive correlation between testosterone levels and PPSs was identified in the male controls (r = .341, P = .029), whereas a negative correlation was identified in the female controls (r = -.407, P = .005). No such correlations were identified in the migraine group. This study confirms that a negative association is present between PPSs and testosterone levels in female controls, which is in line with the findings that testosterone is associated with reduced pain perception. Our study is the first to demonstrate a sex-specific association between PPSs and testosterone levels in HCs. Moreover, this study also revealed that the presence of migraine appears to disrupt this association. PERSPECTIVE: This study revealed that testosterone levels demonstrate opposite associations with pain perception in healthy men and women. However, the presence of migraine appears to disrupt this sex-specific association., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Cutaneous laser stimulation has commonly been employed to investigate the thermal properties of the nociceptive system. The aim of this study was to investigate how a temperature-controlled laser system improves the assessment of directional discrimination in the nociceptive system., Methods: In total, twenty healthy volunteers participated in this study. To determine the directional discrimination threshold (stimulation length 50% correct, expressed in mm), thermal stimuli were delivered using a diode laser and the laser beam was perpendicularly displaced across the skin to give a linear stimulation in four different directions (distal, proximal, lateral and medial) and displacement lengths (3 for lateral-medial and 5 for distal-proximal). Two temperature control modes were used in the stimulation system, open-loop and closed-loop control. The subjects had to report the perceived stimulus direction, the degree of certainty regarding the perceived direction and the intensity of the perceived stimulus (0-10 numerical rating scale, 3: pain threshold)., Results: During closed-loop control, the orientation of stimuli was discriminated significantly more accurately than during open-loop control. During closed-loop control, the directional discrimination threshold was 31.9 and 26.1 mm for distal-proximal and lateral-medial directed stimuli, respectively. A numerical rating scale was significantly higher for the lateral/medial directions. Moreover, the variability of the discrimination threshold is reduced in the closed-loop control system., Conclusions: The findings show that discrimination ability is better in the lateral-medial directions compared to the distal-proximal directions. This study indicates that using a system enabling closed-loop temperature control, allows more robust probing of the temporo-spatial mechanisms in the nociceptive system., Significance: This study shows that a newly developed temperature-controlled laser stimulation system enhances the possibilities to investigate the nociceptive temporo-spatial integration, as shown by a less variable directional discrimination threshold. The results also show that different orthogonal directions are discriminated differently. This new method allows a better investigation of the combined temporal and spatial mechanisms in the nociceptive system., (© 2024 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Abstract: Knowledge is needed regarding mechanisms acting between physical activity (PA) and chronic pain. We investigated whether cold pain tolerance mediates an effect of leisure-time physical activity on the risk of chronic pain 7 to 8 years later using consecutive surveys of the population-based Tromsø Study. We included participants with information on baseline leisure-time PA (LTPA) and the level of cold pressor-assessed cold pain tolerance, who reported chronic pain status at follow-up as any of the following: chronic pain for ≥3 months, widespread chronic pain, moderate-to-severe chronic pain, or widespread moderate-to-severe chronic pain. We included 6834 participants (52% women; mean age, 55 years) in counterfactual mediation analyses. Prevalence decreased with severity, for example, 60% for chronic pain vs 5% for widespread moderate-to-severe chronic pain. People with one level higher LTPA rating (light to moderate or moderate to vigorous) at baseline had lower relative risk (RR) of 4 chronic pain states 7 to 8 years later. Total RR effect of a 1-level LTPA increase was 0.95 (0.91-1.00), that is, -5% decreased risk. Total effect RR for widespread chronic pain was 0.84 (0.73-0.97). Indirect effect for moderate-to-severe chronic pain was statistically significant at RR 0.993 (0.988-0.999); total effect RR was 0.91 (0.83-0.98). Statistically significantly mediated RR for widespread moderate-to-severe chronic pain was 0.988 (0.977-0.999); total effect RR was 0.77 (0.64-0.94). This shows small mediation of the effect of LTPA through pain tolerance on 2 moderate-to-severe chronic pain types. This suggests pain tolerance to be one possible mechanism through which PA modifies the risk of moderate-to-severe chronic pain types with and without widespread pain., (Copyright © 2024 International Association for the Study of Pain.)

Objective: To examine associations of vibration sensitivity and pressure pain sensitivity with knee osteoarthritis (OA) outcomes across sex and race, which may relate to known sex and race disparities in clinical outcomes., Design: Data were from the 2013-2015 visit of the Johnston County Osteoarthritis Project. Exposures were vibration perception threshold (VPT) measured at the bilateral medial femoral condyle (MFC) and first metatarsophalangeal joint (MTP), and pressure pain threshold (PPT) measured at the bilateral upper trapezius. Outcomes were knee pain severity and presence of knee symptoms, radiographic knee OA, and symptomatic knee OA in each knee. Cross-sectional associations of the exposures with the outcomes were examined using logistic regression models, overall and separately by sex and race., Results: In the VPT and PPT analyses, 851 and 862 participants (mean age 71 years, 68% female, 33% Black, body mass index 31 kg/m 2 ) and 1585 and 1660 knees were included, respectively. Higher VPT (lower vibration sensitivity) at the MFC and first MTP joint was associated with all outcomes. Lower PPT (greater pressure pain sensitivity) was associated with greater knee pain severity. Associations of VPT and PPT with all outcomes were similar among females and males and Black and White individuals., Conclusions: Diminished vibration perception and greater pressure pain sensitivity were cross-sectionally associated with worse knee OA outcomes. Despite differences in VPT and PPT among females and males and Black and White adults, associations with knee OA outcomes did not differ by sex or race, suggesting neurophysiological differences do not relate to established disparities., Competing Interests: Conflict of interest CYL: None; LMT: NIH/NIAMS funding outside this work, Editorial Board Member of Arthritis Care & Research; CA: Editorial Board Member of Arthritis Care & Research; DLG: None; AEN: Associate Editor of Osteoarthritis and Cartilage, Editorial Board Member of Arthritis Care & Research, NIH/NIAMS funding outside this work, honoraria from Nestle Health and MedScape; APG: NIH/NIAMS funding outside this work; KCF: NIH/NIAMS funding outside this work; YMG: Associate Editor of Osteoarthritis and Cartilage, Editorial Board Member of Arthritis Care & Research, NIH/NIAMS funding outside this work., (Copyright © 2024 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Pain hypersensitivity is present in some people with acute low back pain (LBP) and thought to be involved in the development of chronic LBP. Early evidence suggests that pain hypersensitivity in acute LBP precedes poor long-term outcome. We aimed to examine whether the presence of pain hypersensitivity in acute LBP influenced recovery status at 6 months and differentiated how pain and disability changed over time. Participants with acute nonspecific LBP (<6 weeks after pain onset, N = 118) were included in this longitudinal study. Quantitative sensory testing, including pressure and heat pain thresholds, and conditioned pain modulation and questionnaires were compared at baseline and longitudinally (at 3 and 6 months) between recovered and unrecovered participants. Using k-means clustering, we identified subgroups based on baseline sensory measures alone, and in combination with psychological factors, and compared pain and disability outcomes between subgroups. Sensory measures did not differ at baseline or longitudinally between recovered (N = 50) and unrecovered (N = 68) participants. Subgrouping based on baseline sensory measures alone did not differentiate pain or disability outcomes at any timepoint. Participants with high psychological distress at baseline (N = 19) had greater disability, but not pain, at all timepoints than those with low psychological distress, regardless of the degrees of pain sensitivity. Our findings suggest that pain hypersensitivity in acute LBP does not precede poor recovery at 6 months or differentiate how pain and disability change over time. High psychological distress during acute LBP is associated with unremitting and pronounced disability, while pain severity is unaffected. PERSPECTIVE: Pain hypersensitivity is thought to be involved in the transition to chronic LBP. Contradictory to prevailing hypothesis, our findings suggest pain hypersensitivity alone in acute LBP does not precede poor recovery. High psychological distress in acute LBP has a stronger influence than pain hypersensitivity on long-term disability, but not pain outcomes., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Pain catastrophizing has been linked to amplified pain sensitivity assessed using quantitative sensory testing (QST) in adults; pediatric data are limited, particularly in youth with functional abdominal pain (FAP). With increasing use of QST to evaluate somatosensory function and predict pain outcomes, we examined the associations between QST and clinical pain in adolescents with FAP and tested the moderating effects of pain catastrophizing. Seventy-seven adolescents (mean age 16.6 years, 85.7% female, 72.7% White, 90.8% non-Hispanic) who fulfilled diagnostic criteria for FAP completed QST assessment (pressure pain threshold and tolerance, heat pain threshold, conditioned pain modulation) and measures of abdominal pain intensity, pain interference, and pain catastrophizing. Adjusting for age and sex, only higher heat pain threshold was associated with higher abdominal pain intensity (Beta per 1-standard deviation = .54, P = .026). Contrary to hypothesis, for youth with higher pain catastrophizing, higher pressure pain tolerance was associated with greater abdominal pain intensity, but associations were not significant for youth with lower catastrophizing (P = .049). Similarly, for those with higher pain catastrophizing (in contrast to lower pain catastrophizing), higher pressure pain thresholds and tolerance were associated with higher pain interference (P = .039, .004, respectively). Results highlight the need to investigate the influence of pain catastrophizing on QST. PERSPECTIVE: This study demonstrated unexpected findings of pain catastrophizing moderating the relationships between pressure pain threshold and tolerance, and clinical pain in adolescents with FAP. This raised questions regarding our understanding of psychological contributions to QST findings in pediatric populations with chronic pain., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The current standard to evaluate the presence of somatosensory dysfunctions is quantitative sensory testing, but its clinical utility remains limited. Low-cost and time-efficient clinical sensory testing (CST) batteries have thus been developed. Recent studies show moderate to substantial reliability in populations with neuropathic pain. This study evaluates the inter- and intra-tester reliability of people with spine-related leg and arm pain, representing mixed pain mechanisms., Methods: Fifty-three patients with spine-related leg (n = 41) and arm pain (n = 12) attended three CST sessions. The CST battery consisted of eleven tests, determining loss and gain of sensory nerve function. CST was performed by the same investigator twice and by an additional investigator to determine inter- and intra-tester reliability. Fleiss' (inter-tester) and Cohen's (intra-tester) kappa were calculated for dichotomized and intraclass correlation coefficients (ICC) for continuous outcomes., Results: Fleiss' kappa varied among modalities from fair to substantial (κ = 0.23-0.66). Cold, warm, and vibration detection thresholds and cold and pressure pain thresholds reached kappa >0.4 (moderate to substantial reliability). Cohen's kappa ranged from moderate to substantial (κ = 0.45-0.66). The reliability of the windup ratio was poor (ICC <0.18)., Conclusion: CST modalities with moderate to substantial inter-tester reliability could be of benefit as a screening tool. The moderate to substantial intra-tester reliability for all sensory modalities (except windup ratio) supports their potential use in clinical practice and research to monitor somatosensory changes over time in patients with spine-related limb pain of mixed pain mechanisms., Significance: We already know that most modalities of clinical sensory test (CST) batteries achieve moderate to substantial inter- and intra-tester reliability in populations with neuropathic pain. This study evaluates the reliability of a CST battery in populations with mixed pain mechanisms. We found inter-tester reliability varied from poor to substantial for sensory modalities, questioning the value of some CST modalities. The CST battery showed moderate to substantial intra-tester reliability, suggesting its usefulness to monitor sensory changes over time in this cohort., (© 2024 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Objectives: First, we explored the association between Gender Role Expectations of Pain (GREP), and psychophysical measures of sensitization in people with knee osteoarthritis (OA). Second, we explored whether the association differed by level of GREP items (high vs low scores)., Design: We conducted secondary analyses of a cohort study. Those who were (i) age of ≥40, English or French speaking, ii) diagnosed with knee OA using American College of Rheumatology criteria and iii) consulting with an orthopedic surgeon were included. GREP items pertaining to pain sensitivity and pain endurance of the typical man or woman were rated by males and females respectively. Psychophysical tests consisted of pressure pain thresholds (PPTs), Temporal Summation (TS), and Conditioned Pain Modulation (CPM). Multiple linear regression models for males and females were run with GREP scores (independent variables) and psychophysical tests (dependent variables). Next models stratified on the median split of GREP scores were run. Models were adjusted for age, BMI, pain catastrophizing, anxio-depressive symptoms, and radiographic severity., Results: 280 participants (57% females; age (SD): 63.9 (9.6) and BMI (SD): 31.3 (8.40)) were included. GREP pain sensitivity scores in males were associated with CPM values (β: 95% CI: 0.09 (0.01 to 0.17)). Males with low GREP pain sensitivity or pain endurance had very small to small positive associations with PPT and CPM values., Conclusion: This first exploration of gendered pain sensitivity and pain endurance by males and females has small and clinically unimportant associations with measures of pain sensitization requiring further validation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Abstract: According to the neurocognitive model of attention to pain, when the attentional resources invested in a task unrelated to pain are high, limited cognitive resources can be directed toward the pain. This is supported by experimental studies showing that diverting people's attention away from acute pain leads to experiencing less pain. Theoretical work has suggested that this phenomenon may present a top-down modulatory mechanism for persistent pain as well. However, conclusive empirical evidence is lacking. To fill this gap, we used a preregistered, double-blind, between-subject study design to investigate whether performing a tailored, demanding, and engaging working memory task unrelated to pain (difficult) vs a task that requires less mental effort to be performed (easy), could lead to lower development of secondary hypersensitivity-a hallmark of central sensitization. Eighty-five healthy volunteers, randomly assigned to one of the 2 conditions, performed a visual task with a different cognitive load (difficult vs easy), while secondary hypersensitivity was induced on their nondominant forearm using high-frequency stimulation. To assess the development of secondary hypersensitivity, sensitivity to mechanical stimuli was measured 3 times: T0, for baseline and 20 (T1) and 40 (T2) minutes after the procedure. We did not observe any significant difference in the development of secondary hypersensitivity between the 2 groups, neither in terms of the intensity of mechanical sensitivity nor its spatial extent. Our results suggest that a top-down modulation through attention might not be sufficient to affect pain sensitization and the development of secondary hypersensitivity., (Copyright © 2024 International Association for the Study of Pain.)

Racism increases pain sensitization and contributes to racialized pain inequities; however, research has not tested interventions targeting racism to reduce pain. In this study, we examined whether White bystanders can act to mitigate racism's pain-sensitizing effects. To simulate racial exclusion in the laboratory, Black young adults (age 18-30; N = 92) were randomly assigned to be included or excluded by White players in a ball-tossing game (Cyberball). For half of the excluded participants, White bystanders acknowledged and apologized for the racial exclusion. Participants completed a cold pressor task to assess pain threshold, tolerance, and unpleasantness, and completed a survey assessing psychological needs (ie, belongingness, self-esteem, meaningful existence, and self-control). Participants who experienced racial exclusion reported significantly more threatened psychological needs and increased laboratory pain sensitization (ie, lower pain threshold and tolerance) than those who were included. However, when a White bystander acknowledged the racism, excluded participants reported higher levels of self-control, self-esteem, and decreased pain sensitization (pain threshold and tolerance) relative to excluded participants whose experience was not acknowledged. Our findings support that racism increased Black people's pain sensitivity and provide initial evidence for White bystander acknowledgment as a health intervention. PERSPECTIVE: Continual exposure to racism likely contributes to inequities in pain sensitization. We demonstrate that acute exposure to mild racism increases acute pain sensitization. Results suggest that a bystander acknowledging witnessed racism can buffer the acute sensitizing effects of racism on pain, pointing to the potential of interpersonal interventions targeting racism. TRIAL REGISTRATION: Clinicaltrials.gov NCT06113926., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Hyperglycemia and high adiposity are risk factors for pain in diabetes. To clarify these links with pain, the effects of a glucose load on sensory detection, pain sensitivity, conditioned pain modulation (primary aims), and autonomic and endothelial functions (secondary aims) were examined in 64 pain-free participants: 22 with normal adiposity (determined by dual-energy X-ray absorptiometry), 29 with high adiposity, and 13 with combined high adiposity and elevated glycated hemoglobin (HbA1c; including prediabetes and type 2 diabetes). Participants ingested either 37.5 g glucose or 200 mg sucralose (taste-matched) in the first session and crossed over to the other substance in the second session 1 month later. At baseline, painful temple cooling (the conditioning stimulus) inhibited pressure- and heat-pain in the ipsilateral arm (the test stimuli) immediately after cooling ceased (partial η 2 's > .32). Glucose ingestion weakened pressure-pain inhibition irrespective of HbA1c levels (partial η 2 = .11). However, a larger reduction in pressure-pain inhibition after ingesting glucose was associated with a higher waist/hip ratio (r = .31), suggesting a role of central obesity. Heat-pain inhibition was absent at baseline in unmedicated participants with elevated HbA1c, and these participants reported more occlusion-induced pain after ingesting glucose (partial η 2 's > .17). Glucose ingestion interfered with parasympathetic activity in all participants (partial η 2 = .11) but did not affect endothelial function (measured by reactive hyperemia) or alter other sensations (eg, feet vibration detection). The disruptive effect of hyperglycemia on conditioned pain modulation increases in line with central obesity, which might facilitate pain in diabetes. PERSPECTIVE: Ingesting 37.5 g glucose (approximately 350 mL soft drink) interfered with pain modulation in pain-free adults with normal adiposity or with combined high adiposity and HbA1c levels. The interference was stronger alongside increasing central obesity, suggesting that controlling blood glucose and body fat mass might help preserve pain modulation., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Preclinical and clinical studies have shown a wide-range of individual differences in response to stressors or novel environments which can affect the susceptibility to develop abnormal behaviors and neuropsychiatric disorders. Both vulnerability and resiliency have been observed in animals and humans experiencing stressful events. Chronic unpredictable mild stress (CUMS) is a rodent depression model consisting of various stressors. This protocol leads to depressive- and anhedonic-like behaviors in rodents. The present study aimed to evaluate potential individual differences in response to CUMS in rats, with respect to the expression level of brain-derived neurotrophic factor (BDNF) and glycogen synthase kinases 3-beta (GSK3-β) (proteins involved in the modulation of mood, neuroplasticity, and cognition) in the hippocampus. CUMS was performed for four consecutive weeks. Depressive-like behavior, locomotor activity, anxiety-like behavior, and pain threshold were also evaluated using forced swim test (FST), open field test (OFT), and the hot plate (HP), respectively. Real-time PCR was used to evaluate BDNF and GSK3-β expression levels. The results showed that CUMS rats can be classified as two clusters: affected and non-affected (depressed and non-depressed). Affected rats showed depressive- and anxiety-like behaviors, decreased locomotor activity, and increased pain threshold. However, non-affected rats were similar to controls. In addition, there was a downregulation of BDNF and upregulation of GSK3-β in affected rats. Spearman correlation analysis also showed a relationship between BDNF and GSK3-β expression levels with individual differences. In conclusion, the present study showed that BDNF and GSK3-β may be involved in individual differences in CUMS rats., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)