Robert Randolph Edwards

The skull bone marrow (SBM) is emerging as a critical hub for neuroimmune signaling, yet its role in chronic pain is unknown. Using integrated positron emission tomography/magnetic resonance imaging, here, we show that the levels of 18-kilodalton translocator protein (TSPO), a putative marker of immune cell density, are elevated in the SBM of individuals with chronic pain [ n = 125; chronic low back pain (cLBP), n = 88; knee osteoarthritis (KOA), n = 37] compared with healthy controls ( n = 22). These elevations were widespread, generally more pronounced for KOA than cLBP, associated with pain and pain-comorbid symptoms in partially segregated spatial patterns, and supported by preliminary immunohistochemical evidence in human SBM samples from a donor with a history of chronic pain (compared with a healthy donor). Because TSPO is highly expressed in myeloid cells, these results link SBM immune dysregulation with chronic pain and its associated psychological and functional impairments. These findings provide a strong rationale for investigating this previously overlooked structure, which remains largely underexplored in the context of pain.

Objective: There is a bidirectional relationship between emotional distress and pain. However, this relationship is understudied in people with HIV in low-resource settings. This study sought to describe the temporal relationship between emotional distress and pain in people with HIV. Design: Longitudinal observational study. Methods: Participants with virally suppressed HIV, reporting either no pain or persistent pain at baseline, provided weekly remote ratings of distress, worst pain, and average pain using 0-10 visual analogue scales. Within-individual fluctuations in distress and pain were visualised over time. Group-level correlations were determined using Spearman’s correlation tests. Cumulative link mixed models assessed whether distress and pain each predicted the other in the following week. Results: 72 participants provided responses over 49 weeks. The participants had a median (IQR) age of 43 (37-51) years, 63% (n=45) were unemployed and most were females (n=51;71%). Distress and pain fluctuated concurrently within individuals: distress was positively correlated with worst pain (ρ=0.66, 95% CI= 0.60-0.72, p<0.001) and average pain (ρ=0.70, 95% CI=0.64-0.75, p<0.001) intensity within the same week. Worst pain (OR=1.42, 95% CI=1.17-1.71, p<0.001) and average pain (OR=1.43, 95% CI=1.20-1.71, p<0.001) intensity both predicted distress in the next week. Distress predicted worst pain intensity (OR=1.25, 95% CI=1.07-1.46, p=0.023) but not average pain intensity (OR=1.19, 95% CI=1.01-1.40, p=0.152) in the next week. Conclusions: The temporal relationship between distress and worst pain intensity was bidirectional, whereas distress did not temporally predict average pain intensity. Both pain and emotional distress should receive attention from HIV research and clinical care in low-resource settings.

Objectives: Clinicians who treat patients with chronic pain often rely on self-report impressions of how things have changed since last seen. The aim of this study was to examine factors that contributed to perceived day-to-day impressions of change among these patients. Methods: Two hundred twenty-two subjects (N = 222) with chronic pain used a smartphone pain application (app) as part of previous clinical trials. All participants completed baseline questionnaires and monitored their daily condition on the app for up to 30 days. They reported their progress every day by rating their pain intensity, activity interference, sleep disturbances, and negative affect and answered whether they perceived their overall condition as having improved or gotten worse on a 0 to 10 visual analogue scale. Results: Multilevel models using lagged analyses showed that current sense of change was significantly influenced by ratings of pain intensity, sleep disturbances, activity interference, and depression and anxiety the day before the rating ( P < 0.001). Multilevel logistic regression analyses further showed that previous day sleep problems and negative mood had the greatest influence on perceived worsening the following day ( P < 0.05). Those with high pain catastrophizing, younger age, and positive opioid use status were most prone to report their condition worsening. Conclusion: This study highlights the importance of inquiring not only about pain intensity but also about sleep disturbances and mood in understanding changes between clinic visits. Clinicians with access to pain app data have increased opportunities to accurately identify those individuals who are most prone to report perceived worsening.

Introduction: Chronic pain is highly prevalent yet heterogeneous among former American-style football (ASF) players. Pain sensitivity, which differs by age and race, contributes to individual differences in clinical pain in the general population but has not been examined among elite athletes. Objectives: The aim of the current cross-sectional study was to (1) assess pain sensitivity using quantitative sensory testing (QST); (2) examine the impact of age and race on pain sensitivity; and (3) identify the extent to which pain sensitivity is associated with clinical pain intensity and whether this varies across age and race among former ASF players. Methods: Former players (N = 110; N _Black = 59; N _White = 51; M _age = 49) completed questionnaires and underwent QST. Results: Results of Wilcoxon rank-sum and Fisher exact tests indicate age- and race-related differences in QST whereby older and Black players reported greater painful temporal summation aftersensations (M _older = 2.89; SD _older = 6.89; M _Black = 18.03; SD _Black = 20.85) than younger and White players (M _younger = 0.32; SD _younger = 1.16; P < 0.01; M _White = 9.19; SD _White = 12.70; P = 0.03), and Black players demonstrated a lower tolerance for cold pain (M = 105.79; SD = 68.95) than White players (M = 144.66; SD = 57.15; P < 0.01). Results of multivariate linear and logistic regression models indicate the relationship between QST and clinical pain intensity differed by age and race. Greater cold pain tolerance was associated with less clinical pain but only for older players. Race differences in the relationship between QST and clinical pain varied across pain modalities. Conclusion: Results demonstrate that age- and race-related pain disparities persist among former ASF players. Moreover, age and race differences in pain sensitivity may be contributing to these disparities.

Osteoarthritis, especially knee osteoarthritis, is a leading cause of disability and reduced quality of life. The etiology of pain in osteoarthritis is multifactorial, and one promising potential treatment approach involves targeting chemokine systems. The present study was a phase 2, multisite, multiperiod randomized crossover trial of CNTX-6970, a small molecule and selective oral cytokine chemokine receptor type 2 (CCR2) and CCR5 antagonist, in patients with painful knee osteoarthritis (OA). It represents the first trial performed within the National Institutes of Health's Early Phase Pain Investigation Clinical Network. The primary objectives were to evaluate the safety and efficacy of CNTX-6970, relative to placebo, for the treatment of moderate to severe pain related to knee OA. A total of 55 participants were randomized in this multiperiod crossover trial. Linear mixed effects models revealed no significant pain-related benefits of active medication; indeed, trial participants reported slightly higher knee pain intensity when taking the novel chemokine antagonist CNTX-6970 than when taking placebo. In addition, biomarker analysis revealed notably higher level of serum monocyte chemoattractant protein 1 levels when patients were on CNTX-6970 compared to placebo. Overall, although CNTX-6970 was safe and relatively well-tolerated, pharmacologic blockade of specific chemokine receptors with this compound was not effective in reducing moderate-to-severe knee osteoarthritis pain.

Introduction: More than three-fourths of people with fibromyalgia complain of cognitive difficulties, including memory and attention problems, which result in impaired job performance and disability. Cognitive behavioral therapy (CBT) is efficacious in treating people with attention deficits, depression, anxiety, and chronic pain (eg, fibromyalgia). Objectives: In this study, we examined the efficacy of CBT for improving attention in patients with fibromyalgia. Methods: Sixty-nine women with fibromyalgia (M = 42; SD = 13) were randomly assigned to receive CBT or an education control, and completed computer-based attention tasks and surveys at baseline (before receiving treatment) and at the follow-up (after receiving 8 treatment sessions). We hypothesized that CBT would lead to greater improvement in attention compared with fibromyalgia education. We conducted repeated-measures analyses of variance to examine the effects of time (pre- vs postintervention) and whether CBT resulted in greater improvement (time × condition effects) for attention span, attentional switching, and divided attention. Results: Results indicated an effect of time such that patients in both groups improved from baseline to follow-up for attention span (F = 8.26, P = 0.01) and switch cost response time (F = 4.45, P = 0.04). However, the time by condition interaction was not significant ( P s > 0.05), indicating that improvement in attentional performance did not differ across intervention groups. Conclusion: Our results support the possibility of practice effects such that completing tasks that engage attentional processes could serve as potential interventions for attentional deficits observed in fibromyalgia.

Social factors are consequences and determinants of chronic pain, yet little is known about how informal social support operates for people with chronic pain and HIV. The overlapping burdens of emotional distress and chronic pain in people living with HIV raise the need to identify targets for culturally resonant treatments. This qualitative study explored how people living with chronic or recurrent pain and HIV seek informal social support for pain and distress from their social networks, how these networks operate, and how social support is influenced by socio-ecological factors. Adults with virally suppressed HIV who endorsed pain over repeated weeks were purposively sampled (n=18). Semi-structured, individual in-depth interviews explored individuals’ experiences of living with HIV and chronic pain, distress and its relationship to pain, and help-seeking behaviours for chronic pain and distress. Codebook thematic analysis was used within an interpretivist epistemological approach. Support for pain involved more tangible actions by fewer people than support for distress. Disruptions in social support were more likely when the person with pain was irritable, socially withdrawn, or unable to fulfil social roles. Interpersonal conflict could also cause or increase pain and distress. Current pain assessments rarely identify the social interference of pain identified here. This work identified potential targets for individual-level interventions to sustain informal social support: individuals’ abilities to cope with daily stressors, pain self-management strategies to facilitate socialisation and engagement in valued life activities, and strategies to prevent support fatigue in informal social networks.

Chronic pain may arise from overlapping pain pathways, including nociceptive pain driven by peripheral tissue damage and nociplastic pain arising from central nervous system dysregulation, as seen in fibromyalgia. This study investigated how electroacupuncture (EA) produces analgesia by modulating these pain mechanisms via changes in brain activation and functional connectivity (FC). Following 4-weeks of EA, reductions in widespread pain, a marker of central nociplastic pain, were associated with increased pressure-pain tolerance to peripheral nociceptive stimuli. This nociplastic-nociceptive relationship was mediated by increased somatosensory activation (S1) and S1–insula FC, suggesting that EA operates through a “bottom-up” mechanism of action: afferent input from the needle modulates central sensory networks to reduce nociplastic pain. In contrast, the sham group reduced widespread pain via a “top-down” centrally inhibiting mechanism, characterized by decreased precuneus activation and reduced precuneus–insula FC. These findings elucidate contributions of bottom-up versus top-down circuits in mediating pain relief.

Psychological distress predicts the onset and worsening of persistent pain, but the mechanisms that underpin this influence are poorly understood. Proinflammatory signalling is a plausible link, given its known connections to distress, pain, and neural upregulation. Sustained distress may prime the inflammatory system to respond more strongly to a phasic noxious challenge, supporting neuroimmune upregulation of central nociceptive signalling and persistent pain. This cross-sectional study tested the hypotheses that in vitro endotoxin-provoked expression of typically proinflammatory cytokines (IL1β, IL6) is a partial mediator between distress and persistent pain, and that it is associated with experimentally induced secondary hyperalgesia, in people with suppressed HIV. Study participants were 99 adults (mean [range] age: 43 [28-64 y/o; 72 females]) with either no pain (n = 54) or persistent pain (n = 45), mostly of black South African ethnicity, low socio-economic status, and with high social support. The results replicated previous reports that distress is associated with persistent pain status and pain severity, and distress was associated with the anatomical extent of pain. However, distress was not associated with provoked cytokine expression, nor was provoked cytokine expression associated with secondary hyperalgesia. The conflict between our findings and prior evidence could reflect the influence of differentially trained immune systems or a more complex relationship arising from diverse psychoneuroimmunological interactions in this sample. This sample's combination of HIV status, African genetic ancestry, financial impoverishment, and rich social interconnectedness is poorly represented in current research and provides an opportunity to deepen insight into psychoneuroimmunological interactions in persistent pain.