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

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

A flexible capacitive pressure sensor with a hybrid porous PDMS/SA hydrogel structure for touch/pain detection.

Exploring highly sensitive flexible electronic skins (e-skins) that can mimic the tactile and pain perception of human skin is an important prerequisite for achieving biomimetic robots and intelligent prosthetics. However, it is still difficult to realize both touch and pain sensing using a single pressure sensor. Herein, a novel flexible capacitive pressure sensor that can distinguish noxious pressure stimuli is proposed for detecting touch and pain, which is composed of a porous polydimethylsiloxane (PDMS) skeleton and a sodium alginate (SA) hydrogel core. The sensor employs two different working mechanisms depending on the range of external pressure, determining the mechanism of operation for transducing the sense of touch or pain. Such a unique structural design plays a crucial role in enhancing pain perception, leading to maximum sensitivity (14.25 kPa-1) in a large pressure regime (up to 400 kPa) and an adjustable pressure threshold. Moreover, the sensor also exhibits a fast response (45 ms) and recovery speed (70 ms), ensuring a sufficiently fast response to noxious pressure stimuli. Finally, we demonstrate the capabilities of a robotic hand based on the pressure sensor for precisely detecting both touch and pain, which shows great promise in developing intelligent robots and prosthetic limbs to prevent possible damage under external noxious stimuli.

Definition and assessment of fever-related discomfort in pediatric literature: a systematic review.

Guidelines advocate that the symptomatic management of fever should prioritize alleviating the child's discomfort. We investigated the definition and assessment of discomfort in febrile children within the scientific pediatric literature. A systematic review was conducted in accordance with PRISMA 2020 guidelines and preregistered on the Prospero database (CRD42023471590). Databases including PubMed, Embase, and Cochrane were searched. Studies addressing discomfort in febrile children were eligible. Out of 794 initially identified articles, 27 original studies and seven guidelines specifically used the term 'discomfort'. Only 14 original articles provided a definition of discomfort, revealing substantial heterogeneity and no clear-cut definition. Discomfort was often assessed subjectively, predominantly through parent or self-report, and only two studies used a scoring system for assessment. The definitions varied widely, with terms such as crying, irritability, shivering and chills, pain and distress, goosebumps commonly used and evaluation of observable modifications such as facial modifications. Overall, no consensus on a single, standardized definition was available. CONCLUSIONS: This systematic review shows the absence of a standardized definition and assessment of discomfort in febrile children. The findings of the present analysis might be the basis for building a consensus and developing a new tool to evaluate discomfort. WHAT IS KNOWN: • Discomfort is currently considered the main criterion to guide antipyretic administration in children with fever. • Despite this clear-cut recommendation, it has been questioned whether a commonly accepted understanding and assessment of this condition exists. WHAT IS NEW: • This systematic review identifies a significant heterogeneity in definitions and assessment of discomfort in children with fever. • Both subjective parameters and observable modifications in physiological parameters should be included in a new and shared characterization of discomfort.

Validity and reliability of the Pain Assessment in Impaired Cognition 15 (PAIC15) observation scale in persons with aphasia.

BACKGROUND: The use of self-report pain scales in persons with aphasia can be challenging due to communication and cognitive problems, while for assessing pain self-report pain is considered the gold standard (Harrison RA, Field TS. Post stroke pain: identification, assessment, and therapy. Cerebrovasc Dis. 2015;39(3-4):190-201.). An observational scale may be used as an alternative. This study examines the validity and reliability of the observational Pain Assessment in Impaired Cognition (PAIC15) scale in persons with aphasia. METHODS: Persons with aphasia were observed during rest and transfer by two observers using the PAIC15. The PAIC15 comprises 15 items covering the three domains of facial expressions, body movements, and vocalizations. When able, the participant completed four self-report pain scales after each observation. The observations were repeated within one week. For criterion validity, correlations between the PAIC15 and self-report pain scales were calculated and for construct validity, three hypotheses were tested. Reliability was determined by assessing internal consistency, and intra- and interobserver agreement. RESULTS: PAIC15 observations were obtained for 71 persons (mean age 75.5 years) with aphasia. Fair positive correlations (rest: 0.35-0.50; transfer: 0.38-0.43) were reported between PAIC15 and almost all self-report pain scales. Results show that significantly more pain was observed in persons with aphasia during transfer than during rest. No differences were found for observed pain between persons with aphasia who use pain medication and those without, or persons who have joint diseases compared to those without. Results showed acceptable internal consistency. Intra- and interobserver agreement was high for most PAIC15 items, particularly for the domains body movements and vocalizations during rest and transfer. CONCLUSIONS: Recognition of pain in persons aphasia using the PAIC15 showed mixed yet promising results.

Quality of life, pain and use of analgesic, anxiolytic and antidepressant medication, in people living in care homes.

BACKGROUND: People living in care homes often have problems with pain, anxiety and depression. Whether being on analgesia, anxiolytics or antidepressants has any bearing on pain severity and quality of life (QoL) in this population, requires further investigation. OBJECTIVES: (i) to examine the relationship between pain, anxiety and depression and medication use in care home residents and (ii) to compare those on medications to treat pain, anxiety and depression, and those who were not, and associations with pain severity and overall QoL. METHODS: This was a secondary analysis of a randomised controlled trial testing a falls prevention intervention in care homes. We recorded pain, anxiety and depression, QoL measurements and prescribed medication use. RESULTS: In 1589 participants, the mean age was 84.7 years (±9.3 SD), 32.2% were male and 67.3% had a diagnosis of dementia. 54.3% and 53.2% of participants had some level of pain and anxiety or depression respectively, regardless of prescribed medication use. There was a direct association between pain severity and being on any analgesia, opioid analgesia, and antidepressants, but no associations between pain severity and use of paracetamol and anxiolytics. QoL was best for residents with no pain and not on any analgesia, anxiolytics or antidepressants and worst for those with moderate-extreme pain and taking at least two of these classes of medications. CONCLUSION: Many care home residents live with pain, anxiety and depression. Addressing residents' pain may also increase their quality of life, but using medication alone to reach this goal may be inadequate.

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

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

Can electroencephalography (EEG) identify the different dimensions of pain in fibromyalgia? A pilot study.

BACKGROUND: Electroencephalography (EEG) is a promising tool for identifying the physiological biomarkers of fibromyalgia (FM). Evidence suggests differences in power band and density between individuals with FM and healthy controls. EEG changes appear to be associated with pain intensity; however, their relationship with the quality of pain has not been examined. We aimed to investigate whether abnormal EEG in the frontal and central points of the 10-20 EEG system in individuals with FM is associated with pain's sensory-discriminative and affective-motivational dimensions. The association between EEG and the two dimensions of emotional disorders (depression and anxiety) was also investigated. METHODS: In this cross-sectional pilot study, pain experience (pain rating index [PRI]) and two dimensions of emotional disorders (depression and anxiety) were assessed using the McGill Pain Questionnaire (PRI-sensory and PRI-affective) and Hospital Anxiety and Depression Scale (HADS), respectively. In quantitative EEG analysis, the relative spectral power of each frequency band (delta, theta, alpha, and beta) was identified in the frontal and central points during rest. RESULTS: A negative correlation was found between the relative spectral power for the delta bands in the frontal (r= -0.656; p = 0.028) and central points (r= -0.624; p = 0.040) and the PRI-affective scores. A positive correlation was found between the alpha bands in the frontal (r = 0.642; p = 0.033) and central points (r = 0.642; p = 0.033) and the PRI-affective scores. A negative correlation between the delta bands in the central points and the anxiety subscale of the HADS (r = -0.648; p = 0.031) was detected. CONCLUSION: The affective-motivational dimension of pain and mood disorders may be related to abnormal patterns of electrical activity in patients with FM. TRIAL REGISTRATION: Retrospectively registered on ClinicalTrials.gov (NCT05962658).

Using joint probability density to create most informative unidimensional indices: a new method using pain and psychiatric severity as examples.

BACKGROUND: Dimension reduction methods do not always reduce their underlying indicators to a single composite score. Furthermore, such methods are usually based on optimality criteria that require discarding some information. We suggest, under some conditions, to use the joint probability density function (joint pdf or JPD) of p-dimensional random variable (the p indicators), as an index or a composite score. It is proved that this index is more informative than any alternative composite score. In two examples, we compare the JPD index with some alternatives constructed from traditional methods. METHODS: We develop a probabilistic unsupervised dimension reduction method based on the probability density of multivariate data. We show that the conditional distribution of the variables given JPD is uniform, implying that the JPD is the most informative scalar summary under the most common notions of information. B. We show under some widely plausible conditions, JPD can be used as an index. To use JPD as an index, in addition to having a plausible interpretation, all the random variables should have approximately the same direction(unidirectionality) as the density values (codirectionality). We applied these ideas to two data sets: first, on the 7 Brief Pain Inventory Interference scale (BPI-I) items obtained from 8,889 US Veterans with chronic pain and, second, on a novel measure based on administrative data for 912 US Veterans. To estimate the JPD in both examples, among the available JPD estimation methods, we used its conditional specifications, identified a well-fitted parametric model for each factored conditional (regression) specification, and, by maximizing the corresponding likelihoods, estimated their parameters. Due to the non-uniqueness of conditional specification, the average of all estimated conditional specifications was used as the final estimate. Since a prevalent common use of indices is ranking, we used measures of monotone dependence [e.g., Spearman's rank correlation (rho)] to assess the strength of unidirectionality and co-directionality. Finally, we cross-validate the JPD score against variance-covariance-based scores (factor scores in unidimensional models), and the "person's parameter" estimates of (Generalized) Partial Credit and Graded Response IRT models. We used Pearson Divergence as a measure of information and Shannon's entropy to compare uncertainties (informativeness) in these alternative scores. RESULTS: An unsupervised dimension reduction was developed based on the joint probability density (JPD) of the multi-dimensional data. The JPD, under regularity conditions, may be used as an index. For the well-established Brief Pain Interference Inventory (BPI-I (the short form with 7 Items) and for a new mental health severity index (MoPSI) with 6 indicators, we estimated the JPD scoring. We compared, assuming unidimensionality, factor scores, Person's scores of the Partial Credit model, the Generalized Partial Credit model, and the Graded Response model with JPD scoring. As expected, all scores' rankings in both examples were monotonically dependent with various strengths. Shannon entropy was the smallest for JPD scores. Pearson Divergence of the estimated densities of different indices against uniform distribution was maximum for JPD scoring. CONCLUSIONS: An unsupervised probabilistic dimension reduction is possible. When appropriate, the joint probability density function can be used as the most informative index. Model specification and estimation and steps to implement the scoring were demonstrated. As expected, when the required assumption in factor analysis and IRT models are satisfied, JPD scoring agrees with these established scores. However, when these assumptions are violated, JPD scores preserve all the information in the indicators with minimal assumption.

Comparative Efficacy of Interventions for Analgesia During Heel Prick in Newborn Infants - A Systematic Review and Network Meta-Analysis.

CONTEXT: Heel prick is one among the common painful procedures in neonates. We performed a systematic review and network meta-analysis (NMA) to compare the efficacy of different interventions for analgesia during heel prick in neonates. EVIDENCE ACQUISITION: Medline, Cochrane, Embase and CINAHL databases were searched from inception until February 2023. Randomized and quasi-randomized trials that evaluated different pharmacological and non-pharmacological interventions for analgesia during heel prick for neonates were included. Data from the included trials were extracted in duplicate. A NMA with a frequentist random-effects model was used for data synthesis. Certainty of evidence (CoE) was assessed using GRADE. We adhered to the PRISMA-NMA guidelines. RESULTS: One-hundred-and-three trials comparing 51 different analgesic measures were included. Among the 38 interventions, for pain "during" heel prick, non-nutritive suckling (NNS) plus sucrose [SMD -3.15 (-2.62, -3.69)], followed by breastfeeding, glucose, expressed breast milk (EBM), sucrose, NNS and touch massage, had a high certainty of evidence (CoE) to reduce pain scores when compared to no intervention. Among the 23 interventions for pain at 30 seconds after heel-prick, moderate CoE was noted for facilitated tucking plus NNS plus music, glucose, NNS plus sucrose, sucrose plus swaddling, mother holding, EBM, sucrose and NNS. CONCLUSIONS: Oral sucrose 2 minutes before combined with NNS during the procedure, was the best intervention for reducing pain during heel prick. It also effectively reduced pain scores 30 seconds and 1 minute after the procedure. Other interventions with moderate to high CoE for a significant reduction in pain during and at 30 seconds after heel prick are oral sucrose, oral glucose, EBM and NNS. All these are low-cost and feasible interventions for most of the settings.

Construct validity of PROMIS pain interference, fatigue, and physical function as patient-reported outcomes in adults with idiopathic inflammatory myopathies: An international study from the OMERACT myositis working group.

BACKGROUND: Validated patient-reported outcome measures to assess disease impact in patients with adult idiopathic inflammatory myopathies (IIMs) are needed. The objective of this study was to assess the construct validity of PROMIS Pain Interference, Fatigue, and Physical Function measures in comparison with core disease activity measures. METHODS: Adults with IIM, excluding inclusion body myositis, from OMERACT Myositis Working Group (MWG) clinic sites completed PROMIS Short Form v1.0-Pain Interference 6a, PROMIS Short Form v1.0-Fatigue 7a, and PROMIS Short Form v2.0-Physical Function 8b measures. Core disease activity measures including patient and physician global disease activity assessments, manual muscle testing, serum creatine kinase activity, and Health Assessment Questionnaire Disability Index (HAQ-DI) were simultaneously assessed. To evaluate construct validity, a priori hypotheses for the expected correlations between PROMIS measures, age, and core disease measures were determined by >70 % agreement among MWG members and were compared against observed Pearson's correlations. Internal consistency of items and floor or ceiling effects for the PROMIS measures were also assessed. Subgroup analysis according to IIM subtype (dermatomyositis vs. non-dermatomyositis IIM) was performed. RESULTS: 135 adults with IIM from 5 countries across North America, Europe, Asia, and Australia were included. For construct validity, a priori hypotheses were confirmed for 5 of 6 (83 %) PROMIS Pain Interference, 4 of 5 (80 %) PROMIS Fatigue, and 3 of 4 (75 %) PROMIS Physical Function correlations. Internal consistency was high for each PROMIS measure (Cronbach's alpha >0.9). Ceiling effects were observed only for PROMIS Pain Interference, with low/no pain in 29 % of patients. Subgroup analysis between dermatomyositis (n = 65) and non-dermatomyositis (n = 70) subtypes demonstrated similar correlations between PROMIS measures and disease activity measures. CONCLUSIONS: PROMIS Short Form v1.0-Pain Interference 6a, PROMIS Short Form v1.0-Fatigue 7a, and PROMIS Short Form v2.0-Physical Function 8b measures demonstrate strong construct validity when compared to core disease activity measures in IIM, with consistent results across IIM subtypes. These findings support the use of these selected PROMIS measures to assess core domains of interest for measuring life impact in IIMs.

An approach to the detection of pain from autonomic and cortical correlates.

OBJECTIVE: To assess the value of combining brain and autonomic measures to discriminate the subjective perception of pain from other sensory-cognitive activations. METHODS: 20 healthy individuals received 2 types of tonic painful stimulation delivered to the hand: electrical stimuli and immersion in 10 Celsius degree (°C) water, which were contrasted with non-painful immersion in 15 °C water, and stressful cognitive testing. High-density electroencephalography (EEG) and autonomic measures (pupillary, electrodermal and cardiovascular) were continuously recorded, and the accuracy of pain detection based on combinations of electrophysiological features was assessed using machine learning procedures. RESULTS: Painful stimuli induced a significant decrease in contralateral EEG alpha power. Cardiac, electrodermal and pupillary reactivities occurred in both painful and stressful conditions. Classification models, trained on leave-one-out cross-validation folds, showed low accuracy (61-73%) of cortical and autonomic features taken independently, while their combination significantly improved accuracy to 93% in individual reports. CONCLUSIONS: Changes in cortical oscillations reflecting somatosensory salience and autonomic changes reflecting arousal can be triggered by many activating signals other than pain; conversely, the simultaneous occurrence of somatosensory activation plus strong autonomic arousal has great probability of reflecting pain uniquely. SIGNIFICANCE: Combining changes in cortical and autonomic reactivities appears critical to derive accurate indexes of acute pain perception.

Benefits of home-based foot neuromuscular electrical stimulation on self-reported function, leg pain and other leg symptoms among community-dwelling older adults: a sham-controlled randomised clinical trial.

INTRODUCTION: Lower leg pain and symptoms, and poor leg circulation are common in older adults. These can significantly affect their function and quality of life. Neuromuscular electrical stimulation (NMES) applied via the feet as 'foot NMES' activates the leg musculovenous pump. This study investigated the effects of foot NMES administered at home using Revitive® among community-dwelling older adults with lower leg pain and/or other lower leg symptoms such as cramps, or sensations of tired, aching, and heavy feeling legs. METHODS: A randomised placebo-controlled study with three groups (2 NMES, 1 Sham) and three assessments (baseline, week 8, week 12 follow-up) was carried out. Self-reported function using Canadian occupational performance measure (COPM), leg pain, overall leg symptoms score (heaviness, tiredness, aching, or cramps), and ankle blood flow were assessed. Analysis of covariance (ANCOVA) and logistic regression were used to compare the groups. Statistical significance was set at p < 0.05 (two-sided 5%). RESULTS: Out of 129 participants enrolled, 114 completed the study. The improvement in all outcomes were statistically significant for the NMES interventions compared to Sham at both week 8 (p < 0.01) and week 12 (p < 0.05). The improvement in COPM met the minimal clinically important difference (MCID) for the NMES interventions compared to Sham at both week 8 (p < 0.005) and week 12 (p < 0.05). Improvement in leg pain met MCID at week 8 compared to Sham (p < 0.05). Ankle blood flow increased approximately 3-fold during treatment compared to Sham. Compliance with the interventions was high and no device-related adverse events were reported. CONCLUSIONS: The home-based foot NMES is safe, and significantly improved self-reported function, leg pain and overall leg symptoms, and increased ankle blood flow compared to a Sham among older adults. TRIAL REGISTRATION: The trial was prospectively registered in ISRCTN on 17/06/2019 with registration number ISRCTN10576209. It can be accessed at https://www.isrctn.com/ISRCTN10576209 .

Trajectories of pain and their associations with long-term cognitive decline in older adults: evidence from two longitudinal cohorts.

BACKGROUND: Pain is a dynamic experience that varies over time, but it remains unknown whether trajectories of pain are associated with subsequent cognitive decline. The purpose of this study was to identify distinct trajectories of pain presence and activity-limiting pain and investigate their longitudinal associations with the rate of subsequent cognitive decline in older adults. METHODS: A total of 5685 participants from the English Longitudinal Study of Ageing (ELSA) and 7619 participants from the Health and Retirement Study (HRS) were included. Pain presence trajectories were identified over eight years in the ELSA and 10 years in the HRS, while trajectories of activity-limiting pain were identified over 10 years in the HRS. We utilised linear mixed-effects models to investigate the long-term relationship between pain trajectories and the rate of cognitive decline across various domains, including memory, orientation, executive function and global cognition. RESULTS: Three pain presence trajectories were identified. Moderate-increasing and high-stable groups exhibited steeper declines in global cognition than the low-stable group. Furthermore, individuals in the moderate-increasing group experienced a more rapid decline in executive function, while the high-stable group showed a faster decline in orientation function. Two trajectories of activity-limiting pain were identified, with the moderate-increasing group experiencing a faster decline in orientation function and global cognition. CONCLUSIONS: The trajectories of both pain presence and activity-limiting pain are linked to the rate of subsequent cognitive decline among older people. Interventions for specific pain trajectories might help to delay the decline rate of cognition in specific domains.

Digital Glomus Tumor - A Commonly Undiagnosed Cause of Finger Pain: Case Report.

Glomus tumors are rare vascular hamartomas most commonly found in the subungual region of the fingers. They present with a classic triad of paroxysmal pain, point tenderness, and cold sensitivity. The diagnosis is often missed for several years due to under recognition of this condition. A 42-year-old female presented with a several year history of pain in the middle finger when it was struck or exposed to cold. She had point tenderness on the fingernail, and increased curvature of the nail. Magnetic Resonance Imaging (MRI) revealed a 7mm subungual glomus tumor. The tumor was surgically excised via a transungual approach, resulting in complete relief of her pain. Glomus tumors are diagnosed clinically based on the presence of classic symptoms and positive provocative tests. These tests include point tenderness on palpation and pain when ice is placed on the digit. MRI imaging can be used when the diagnosis is unclear or to localize the tumor prior to surgery. Increased awareness of this condition among physicians could reduce the time to diagnosis and treatment.