Pain

ObjectivePostoperative pain outcomes following spinal fusion surgery remain difficult to predict, as structural and surgical indicators alone offer limited insight into who will experience meaningful relief. A substantial proportion of patients continue to report persistent pain after surgery, underscoring the need for objective markers that can help identify those at risk of poor recovery. Peak alpha frequency (PAF) has emerged as a promising trait-like neural signature of pain sensitivity in experimental models, where individuals with slower PAF tend to exhibit heightened pain sensitivity. Yet despite this link, its ability to forecast longer-term postoperative pain trajectories remains unclear. MethodsSeventeen adults undergoing cervical or lumbar fusion surgery were included. Resting-state, eyes-closed EEG was recorded preoperatively and at multiple visits after surgery. PAF was extracted from central electrodes using the centre-of-mass method. Pain intensity was assessed longitudinally on standardised self-report pain scales. Associations between PAF measures and postoperative pain change were examined using correlation analyses, and receiver operating characteristic (ROC) analyses evaluated discrimination of pain responders ([≥]50% improvement). ResultsPreoperative peak alpha frequency (PAF) was positively associated with longer-term pain reduction at the 3-month follow-up, but showed no consistent relationship with early postoperative pain. Across pain measures, a consistent pattern emerged across the Brief Pain Inventory (BPI), visual analogue scale (VAS), and numerical rating scale (NRS), but not the verbal rating scale (VRS) or Short-Form McGill (SF-MPQ). At the 3-month follow-up, associations reached statistical significance for BPI-Worst ({rho} = 0.67, p = 0.017), and BPI-Average Pain ({rho} = 0.62, p = 0.033). VAS and NRS showed moderate-to-strong effects that approached significance in non-parametric analyses and were significant for VAS when treated as an approximately interval measure (Pearson r = 0.63, p = 0.022). ROC analyses using BPI-Worst pain improvement demonstrated good discriminative ability of preoperative PAF for identifying treatment responders at 3 months (AUC = 0.84; 95% CI: 0.61-1.00), with high specificity and moderate sensitivity at the Youden-optimal threshold of 10.11 Hz. By contrast, changes in PAF over time were not reliably related to changes in pain scores, suggesting that PAF functions more as a stable, trait-like predictor than a dynamic biomarker in this context. ConclusionThis study demonstrates the feasibility and potential clinical value of preoperative EEG for characterising individual differences in postoperative pain recovery following spinal fusion. The results identify faster preoperative PAF as a stable neural signal that captures meaningful variability in longer-term pain reduction, with convergent support across multiple patient-reported measures. While replication in a larger cohort is required, these findings establish a clear foundation for evaluating PAF as a candidate neurophysiological marker to inform preoperative risk profiling and potentially personalised perioperative pain-management strategies in spinal fusion patients.

Background Social disconnection has emerged as a major public health concern, with health risks comparable to established biomedical factors. At the same time, pain remains the leading cause of years lived with disability worldwide, imposing profound individual and societal costs. Although social factors are increasingly implicated in pain perception and chronification, existing evidence is fragmented across heterogeneous and often conflated constructs of social connectedness. It remains unclear whether subjective experiences such as loneliness or structural factors such as social isolation differentially relate to pain outcomes. A comprehensive synthesis directly comparing these dimensions has been lacking. Methods We conducted a preregistered multivariate meta-analysis (PROSPERO: CRD420250643896) including 239 studies, 520 effect sizes, and 1,407,803 participants from clinical and non-clinical populations. Pain outcomes encompassed sensory, affective, cognitive, and functional domains. Social connectedness was operationalized as loneliness, social isolation, social support, and social exclusion. Multilevel random-effects models accounted for within-study dependency, with extensive sensitivity analyses and correction for small-study bias. Results Across populations and social outcomes, greater social connectedness was associated with lower pain (z = -0.09, 95% CI -0.11 to -0.07). Notably, loneliness emerged as the strongest correlate (z = 0.14, 95% CI 0.11 to 0.17). Associations with social isolation were smaller compared to loneliness but were also significant (z = 0.09, 95% CI 0.05 to 0.13). Social support showed modest, significant inverse associations (z = -0.05, 95% CI -0.08 to -0.03), primarily confined to affective and somatic pain components. No reliable association was observed for social exclusion. Associations were consistent across age, sex, and clinical status, and longitudinal evidence supported temporal links between changes in social connectedness and subsequent pain outcomes. Conclusions This large-scale synthesis identifies subjective social disconnection, particularly loneliness, as a robust correlate of pain across populations and pain dimensions, exceeding the relevance of objective social isolation. Given evidence linking loneliness to increased analgesic and psychotropic medication use, social disconnection may contribute to pharmacological burden and polypharmacy risk in vulnerable populations. Social connectedness emerges as a clinically meaningful, non-pharmacological determinant of pain and a potential target for integrative pain prevention and management strategies.

Short-term fluctuations in perceived pain are often dismissed as noise. However, evidence from diverse neural systems indicates that moment-to-moment variability reflects fundamental network properties such as stability and flexibility, and in pain, reduced short-term variability has been previously linked to chronic pain conditions. Here, we tested the hypothesis that alterations in such variability mark an early mechanistic transition from subacute to chronic pain. Using a longitudinal dataset of 120 individuals with subacute back pain, followed over one year, we analysed continuous real-time pain ratings alongside fMRI activity during spontaneous pain. We show that patients who develop persistent pain exhibit a marked decrease in moment-to-moment variability by the end of the year, in contrast to recovering individuals whose variability increases over time. Neural activity associated with these fluctuations at pain onset--within thalamo-cortico-limbic and modulatory circuits, including the thalamus, amygdala, dorsomedial and orbitofrontal prefrontal cortices, anterior insula, and sensorimotor regions--successfully predicted clinical outcomes after one year. Gradient boosting classifiers trained on onset data robustly separated recovering and persistent individuals (mean ROC AUC over folds > .8). These findings suggest early loss of dynamical flexibility within pain-regulatory networks as a mechanistic hallmark of pain chronification and suggest short-term variability as a simple, interpretable, and clinically accessible risk marker for chronic pain.

Psychological distress predicts the onset and worsening of persistent pain, but the mechanisms that underpin this influence are poorly understood. Pro-inflammatory signalling is a plausible mechanistic 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 pro-inflammatory cytokines (IL1{beta}, IL6) is a partial mediator between distress and persistent pain, and that it is associated with the secondary hyperalgesia response to an experimental noxious challenge, in people with suppressed HIV. Study participants were 99 adults (mean (range) age: 43(28-64y/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 also showed an association between distress and 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 the evidence on which our hypotheses were based could reflect masking of an effect by differentially trained immune systems or a more complex relationship arising from diverse psychoneuroimmunological interactions in this sample. Our samples combination of HIV status, African genetic ancestry, financial impoverishment, and rich social interconnectedness is poorly represented in current research and represents an opportunity to deepen insight into psychoneuroimmunological interactions related to distress and persistent pain.

Chronic pain (CP) can profoundly strain family systems, yet few population studies have explored CP with high impact on families. We used 2023 National Health Interview Survey Data (n=29,522) to characterize CP with high impact on families of U.S. adults. Findings are: (1) the prevalence of CP with high impact on families (HICP-Family) is 4.4% in U.S. adults and 18.1% in U.S. adults with CP; (2) HICP-Family is almost exclusively reported by those who have high impact chronic pain (HICP) that limits their individual functioning in life and work; (3) yet, among those with HICP, not all (46.3%) report HICP-Family; (4) HICP-Family can feasibly be modeled as a latter transition stage in a tiered cascade of advancing CP-associated impacts; (5) there is a strong association between clinically significant mental health symptoms and HICP-Family; HICP-Family is six times more prevalent among those who screen positive for moderate-to-severe anxiety or depression symptoms. Families highly impacted by CP may not be adequately resourced for adaptive functional resilience. HICP-Family may form an underappreciated barrier to achieving optimal pain and mental health outcomes for people with HICP. Further, without intervention, members of families highly impacted by CP may face heightened susceptibility to onset of suboptimal pain and mental health trajectories of their own. The need to develop effective supports and promote adaptive resilience in families highly impacted by CP is clear. Clinical tools to support person-centered assessment of family and relational functioning, effective family-level interventions, and innovative models of care are needed. IN BRIEFEstablishes prevalence of chronic pain with high impact on families (HICP-Family); situates HICP-Family within emerging pain research frameworks.

Pain resulting from tissue damage, including surgical incision, is often only partially responsive to standard treatments focusing on inflammation, suggesting additional mechanisms are involved. Tissue damage leads to expression in dorsal root ganglion (DRG) sensory neurons of activating transcription factor 3 (ATF3), a known injury-induced transcription factor. ATF3 expression is associated with sensitization of cellular physiology and enhanced amplitude/duration of a nociceptive reflex. It is unclear how tissue damage leads to these changes in the sensory neurons, but it could include direct damage to the tissue-innervating axons and inflammation-associated retrograde biochemical signalling. We examined the necessity and sufficiency of incision, inflammation, and axonal conduction for induction of ATF3 in response to skin incision. Incision outside of a single dermatome, but close enough to induce inflammation inside the dermatome, was not sufficient to induce ATF3 expression in the corresponding DRG. Incision inside the dermatomeled to strong expression of ATF3. Anti-inflammatory treatments did not prevent this induction of ATF3. In rodent models of repeated injury - a major etiological factor for chronic pain - ATF3 expression was synergistically increased and the threshold for paw-withdrawal to mechanical stimulation was significantly decreased for an extended duration. Together, these results suggest that actual damage to axons innervating the skin is both necessary and sufficient for induction of ATF3, expression of which appears additionally increased by repeated injury. Further, pre-treatment of the nerves innervating the incised skin with bupivacaine, a local anesthetic commonly used to reduce surgical pain, did not prevent induction of ATF3, indicating that conduction of action potentials is not necessary for induction of ATF3. We also determined that closure of incision with surgical glue significantly reduced incision-induced expression of ATF3 and GAP-43. Intriguingly, treatment with polyethylene glycol (PEG), known to enhance membrane integrity after injury among other effects, reduced incision-associated ATF3 expression and electrophysiological changes. These results suggest that pain resulting from tissue damage may arise from a mix of ATF3-independent inflammation-related mechanisms as well as ATF3-/axonal-damage-associated mechanism and therefore require a mix of approaches to achieve more complete control some of which we suggest here.. FundingJCP NIH R01NS109936, R21NS120498, KSCHIRT 10-10 BJH NIH R01NS121533 SCOPE statementPain resulting from tissue damage, including surgical incision, is often only partially responsive to anti-inflammatory treatments, suggesting multiple mechanisms at work, including neuropathic. Cutaneous tissue damage leads to expression in DRG sensory neurons of the injury marker ATF3 - associated with physiological sensitization and enhancement of a nociceptive reflex. We examined some of the conditions for induction of ATF3 in response to incision of skin and the impact of interventions. Treatment with anti-inflammatory ketoprofen and/or local anesthetic did not prevent the induction of ATF3, together suggesting that actual damage to axons innervating the skin is both necessary and sufficient for induction of ATF3. Repeated incision induced unique changes in expression of ATF3- and pain-associated genes. Closure with surgical glue reduced incision-induced gene expression compared to closure with staples. Treatment with polyethylene glycol (PEG), known to enhance membrane integrity after axonal injury, reduced induction of ATF3 and electrophysiological changes. These experiments were designed to identify distinct pain-related mechanisms with pre-clinical animal models that reflect existing clinical practice and feasible future practice. These results suggest that pain resulting from tissue damage likely arises from mixed mechanisms - including neuropathic - and therefore require a mix of approaches to achieve more complete control.

BackgroundThe transition from acute to chronic pain represents a failure of physiological resolution. While systemic immune cell counts and androgen levels have been associated with this transition, the specific molecular mediators remain poorly understood. We sought to identify the functional proteomic drivers of long-term pain persistence and determine their independence from systemic factors. MethodsWe identified a longitudinal persistence cohort (N=3,221) within the UK Biobank who reported acute pain at baseline and were followed for resolution or persistence. Using the Olink Explore 3072 platform, we screened 2,923 serum proteins. Multivariable competition models were employed to evaluate the independent predictive power of top proteomic hits alongside systemic monocyte counts and circulating free testosterone levels, adjusted for age and sex. ResultsOur proteome-wide screen identified Lactoperoxidase (LPO) as a dominant and highly significant predictor of pain persistence. In the fully adjusted competition model, each standard deviation increase in LPO was associated with a 59% increase in the odds of persistence (OR 1.59, 95% CI 1.25-2.07, p < 0.001). Notably, after accounting for LPO, systemic monocyte counts (OR 0.93, p = 0.55) and testosterone levels (OR 0.82, p = 0.46) were no longer significant predictors. Nogo Receptor (RTN4R) also remained a significant predictor in independent models (OR 1.44, p = 0.002). ConclusionsThese exploratory findings demonstrate that long-term pain persistence is associated with specific functional molecular signatures rather than broad systemic cell quantity. The dominance of LPO suggests that secretory peroxidase-driven pathways may be a primary barrier to pain resolution. Furthermore, the association of RTN4R identifies neural repair inhibition as a candidate driver of persistence. These proteins are candidates for further mechanistic investigation.

Senescence of peripheral sensory neurons has recently been associated with increased nociceptive signalling and pain chronification. Whether this association is found across pain conditions and independent study settings remains to be investigated. In this study, we made use of publicly available whole-genome transcriptome data sets on rodent dorsal root ganglion (DRG) tissue to investigate pain-related peripheral sensory neuron senescence across pain models and independent study settings. We focused on Cdkn1a (p21) and Cdkn2a (p16) expression levels as two widely-used senescence markers, and to explore their potential role in peripheral sensory neuron senescence. We found that Cdkn1a but not Cdkn2a RNA is significantly increased across different axotomy- and lesion-based neuropathic pain models, but less consistent in other pain models including inflammatory pain. We observed a sex-dependent effect of Cdkn1a upregulation following nerve injury, with significantly increased Cdkn1a RNA levels in DRG cells from female but not male rats. Lastly, Cdkn1a RNA levels are increased among all DRG neuronal subtypes, seem to reach their maximum three to seven days following nerve injury, and afterwards go back to baseline. These data suggest that Cdkn1a upregulation in DRG neurons is a widespread response to nerve injury that is found across independent study settings. SummaryAnalysis of publicly available whole-genome transcriptome data sets shows that senescence-associated Cdkn1a but not Cdkn2a expression is upregulated in DRG neurons across neuropathic pain models.

Chronic pain is attributable to both local and systemic pathology. To investigate the latter, we focused on genetic risk shared among 24 chronic pain conditions in the UK Biobank. We conducted genome-wide association studies (GWAS) on all conditions and estimated genetic correlations among them, using these to model a factor structure in Genomic SEM. This revealed a general factor explaining most of the shared genetic variance in all conditions and an additional musculoskeletal pain-selective factor. Network analyses revealed a large cluster of highly genetically inter-connected conditions, with arthropathic, back, and neck pain showing the highest centrality. Functional annotation (FUMA) showed organogenesis, metabolism, transcription, and DNA repair as associated pathways, with enrichment for associated genes exclusively in brain tissues. Cross-reference with previous GWAS showed genetic overlap with cognition, mood, and brain structure. In sum, our results identify common genetic risks and suggest neurobiological and psychosocial mechanisms of vulnerability to chronic pain.

Over 50% of individuals with sickle cell disease (SCD) experience chronic pain that is phenotypically distinct from their acute, vaso-occlusive crisis pain. Chronic SCD pain is commonly managed with opioid-based drugs that are associated with unwanted side effects, incomplete pain relief, and - in this population - accessibility issues. Thus, new treatments for chronic SCD pain are desperately needed. Here, we examined the analgesic efficacy of acute minocycline treatment in transgenic SCD mice. SCD mice exhibit gut dysbiosis and chronic inflammation. Therefore, we hypothesized that minocycline would provide robust analgesia in this model given the drugs antibiotic and anti-inflammatory properties respectively. Six days of minocycline treatment reversed chronic mechanical hypersensitivity only in male SCD mice. We identified two potential mechanisms underlying these sex-specific effects. First, we observed increased microgliosis only in the dorsal horn of male SCD mice. Minocycline treatment had opposite effects on microglial number in male and female SCD spinal cords. Second, minocycline treatment altered the gut microbiota in a sex-specific fashion; fecal microbiota transplant (FMT) from minocycline-treated female SCD mice induced widespread pain in recipients whereas FMT from minocycline-treated male SCD mice did not. In summary, these experiments highlight novel sex-specific mechanisms of minocycline analgesia and support future exploration of minocycline use for SCD pain management, but only in male patients.

Conditioned pain modulation (CPM) paradigms provide a proxy measure of activity in the descending pain modulatory system. Cuff-pressure-algometry offers a standardised CPM assessment tool although comprehensive validation in large samples is lacking. To address this, we pooled cuff-algometry CPM data from 324 healthy participants across 8 studies. CPM magnitude was calculated as pain detection (PDT) and tolerance (PTT) threshold changes, assessed on the dominant leg in the presence and absence of a painful "conditioning" cuff stimulus on the contralateral leg. CPM-effects were robust for both changes in PDT and PTT (p<0.001). Using a classification approach where a [&ge;]20% change in threshold designated a CPM responder, 69% of participants were CPM-responders for PDT and 59% for PTT. Test-retest reliability data were assessed in a subset of participants (n=72; interval 16.49{+/-}18.39days) using intraclass correlation coefficients (ICC). Test-retest reliability was poor for CPM-effects (ICC=0.25-0.37) despite moderate-to-good reliability for PDT and PTT (ICC=0.69-0.87). Responder classification showed none-to-minimal agreement across sessions (Cohens {kappa}=0.17-0.21), with 38% of participants switching classification for both PDT and PTT. Bootstrap analysis revealed that smaller samples provide highly variable ICC estimates, potentially explaining discrepancies with previous reliability reports. Despite producing large group-level CPM-effects, poor test-retest reliability of cuff algometry suggests it captures dynamic, state-dependent processes rather than a stable trait-like individual characteristic. This highlights the need to consider the temporal instability of CPM when interpreting data and considering its deployment within precision pain medicine.

Neural activity varies dramatically across time. While such variability has been associated with cognition, its relationship with pain remains largely unexplored. Here, we systematically investigated the relationship between neural variability and pain, particularly pain discriminability, in five large electroencephalography (EEG) datasets (total N = 489), collected from healthy individuals (Datasets 1-4) and patients with postherpetic neuralgia (PHN; Dataset 5) who had received painful or nonpainful sensory stimuli. We found robust correlations between neural variability and interindividual pain discriminability. These correlations were (1) replicable in multiple datasets, (2) pain selective, as no significant correlations were observed in nonpain modalities, and (3) clinically relevant, as they were partly disrupted in patients with PHN. Importantly, variability and amplitude of EEG signals were mutually independent and had distinct temporal and oscillatory profiles in encoding pain discriminability. These findings demonstrate that neural variability is a replicable and selective indicator of pain discriminability above and beyond amplitude, thereby enhancing the understanding of neural encoding of pain discriminability and underscoring the value of neural variability in pain studies.

Recent research has linked individual peak alpha frequency (PAF) to pain sensitivity, but whether PAF alterations can influence pain remains unclear. Our study investigated the effects of nicotine on pain sensitivity and whether pain changes are mediated by PAF changes. In a randomised, double-blind, placebo-controlled experiment, 62 healthy adults (18-44 years) received either 4 mg nicotine (n=29) or placebo gum (n=33). Resting state EEG and pain ratings during prolonged heat and pressure models were collected before and after nicotine intake. The nicotine group showed a small decrease in heat-pain ratings compared to the placebo group when controlling for confounders, and a small increase in PAF across the scalp from pre- to post-gum, both with and without confounder adjustment. These effects were most pronounced in the central-parietal and right-frontal electrodes. However, mediation analysis did not support the notion that PAF changes mediate nicotine's effects on pain sensitivity. While a growing body of literature supports a link between PAF and both acute and chronic pain, further work is needed to understand the mechanisms of this link.

Pain is commonly described in sensory terms, yet its spatial characteristics-localization and distribution-are rarely quantified. We investigated whether lay beliefs about pain distribution (PD) influence theoretical decisions to seek care and treatment preferences. In a representative cross-sectional survey (N=503; 49% with pain), participants completed thought experiments in which both visually presented PD patterns (small, moderate or large) and pain intensity (NRS 2, 5, 8/10) were systemically varied. For each scenario, they rated the likelihood of (i) seeking professional help (LoSH) and (ii) taking analgesic medication (LoTM). Participants also completed a spatial-intensity trade-off task (SITT), in which they chose between a fixed 20% reduction in intensity and variable reductions in PD (20-80%). A reversed version contrasted a fixed 80% reduction in PD with variable reductions in pain intensity. LoSH and LoTM increased significantly with greater PD (p<0.001), mirroring the gradient observed for pain intensity. In the SITT, participants' choice followed a sigmoid-like function (p<0.001): 1% reduction in intensity was treated as equivalent to approximately a 3% reduction in distribution, indicating a systematic valuation of PD. This ratio was lower in individuals experiencing pain compared to pain-free individuals. Moreover, 63% reported that PD should be routinely considered in pain management alongside intensity. Results suggest that PD is not merely a trivial descriptor, but a meaningful determinant of healthcare-related decision-making beliefs. Incorporating spatial metrics into clinical assessment and research may better capture how individuals implicitly evaluate pain severity.

Naturally occurring pain and itch disorders in the domestic dog represent an important and underexploited opportunity for translational sensory neuroscience. These conditions largely mirror human disease, highlighting the need for detailed comparative understanding of canine somatosensory neurobiology. Here, we present a single-cell transcriptomic characterisation of the canine dorsal root ganglion (DRG), providing molecular insights into sensory neuron diversity in a species of direct veterinary and biomedical relevance. We develop a novel mechanical dissociation and fluorescence-activated cell sorting strategy enabling purification of intact whole neurons from adult canine DRG, followed by deep, full-length RNA sequencing using FLASH-seq. This approach yields high-quality transcriptional profiles with molecular depth analogous to deep neuronal profiling in human DRG, enabling resolution of neuronal identities and subtype-specific gene programs. Using these data, we identify canine sensory neuron clusters conforming to conserved principles of DRG molecular organization observed across species, including peptidergic and non-peptidergic nociceptors, low-threshold mechanoreceptors, proprioceptors, and thermosensory populations. Cross-species comparisons with human and mouse DRG datasets reveal broad conservation of pain- and itch-relevant pathways and therapeutic targets, alongside biologically meaningful divergence. We further identify species-specific differences in subtype-restricted expression of the pharmacologically relevant receptors IL31RA and SSTR2, which we validate using in situ hybridization and contextualize with human spatial transcriptomic data. Finally, we provide evidence that domestication-associated genes are non-randomly enriched in specific sensory neuron populations, suggesting that evolutionary history may have shaped somatosensory function. These data represent a resource for comparative sensory neuroscience and inform translational interpretation of pain and itch therapeutics across species.

Pain and symptoms of depression and anxiety (here, psychological distress) are frequently reported by people with HIV. Although pain is widely acknowledged to contribute to distress, distress may also contribute to pain and its persistence. Facilitation of nociceptive signalling is one pathway by which distress could exacerbate pain. The current study investigated the relationships between symptoms of depression and anxiety, secondary hyperalgesia (SH), and persistent pain in people with HIV, reporting pain (n=19) or no pain (n=26). We hypothesised that self-reported distress would be positively associated with the surface area (primary measure) and magnitude (secondary measure) of induced SH, and that participants reporting persistent pain would display greater induced SH than those reporting no pain. We found that distress was positively associated with the surface area (p=0.02) and the magnitude (p=0.01) of induced SH. However, participants with persistent pain showed no difference in the surface area of SH compared to pain-free participants (p=0.87), and those with pain displayed a marginally lower magnitude of SH (p=0.05). These findings position SH as a potentially useful mechanistic outcome for interventions that aim to address pain by reducing symptoms of depression and anxiety. PerspectiveSymptoms of depression and anxiety were positively associated with induced secondary hyperalgesia in people with suppressed HIV.

ImportanceChronic pain (CP) is a major public health problem in the US. The COVID-19 pandemic led to widespread disruptions in the US and it is important to monitor changes in pain during and after the pandemic. ObjectiveTo determine prevalence of chronic pain (CP) and high-impact chronic pain (HICP) before, during, and after the COVID-19 pandemic and identify potential contributing factors. MethodsWe analyze a nationally representative sample of 88,469 community-dwelling Americans aged 18 and older from three cross-sectional waves of the National Health Interview Survey before (2019), during (2021), and after (2023) the COVID-19 pandemic. Year of interview is the exposure. All regression models control for age and sex; fully controlled models include 19 additional covariates (demographics, socioeconomic status, health behaviors, health conditions, mental health, and health insurance type); analyses also explore the role of long COVID. Outcomes are CP and HICP using measures proposed by the US National Pain Strategy; we also present findings for six site-specific pain measures. ResultsBetween 2019 and 2023, CP and HICP prevalence increased by 18% and 13%, respectively. Specifically, CP prevalence was 20.6% (95%CI: 19.9-21.2%) in 2019, 20.9%(20.3-21.6%) in 2021, and 24.3% (23.7-25.0%) in 2023. HICP prevalence declined from 7.5% (7.1-7.8%) in 2019 to 6.9% (6.6-7.3%) in 2021, before rising sharply to 8.5% (8.1-8.9%) in 2023. The increases occurred in all examined body sites except for tooth/jaw pain, and in all major population groups. Approximately 13% of the increase in CP and HICP was attributable to long COVID. Conclusions and RelevancePain among US adults was high before and during the pandemic but has surged substantially since. In 2023, an unprecedented 60 million Americans had chronic pain and 21 million had high-impact chronic pain.

The extracellular matrix (ECM) is a dynamic structure composed of a large number of molecules that can be divided into six different categories and are collectively called the matrisome. The ECM plays pivotal roles in physiological and pathological processes in many tissues, including the nervous system. Intriguingly, alterations in ECM molecules/pathways are often associated with painful human conditions and murine experimental pain models. Nevertheless, mechanistic insight into the interplay of normal or defective ECM and pain is largely lacking. To expand the knowledge on ECM composition and synthesis in the peripheral nervous system, we used a transcriptomal approach to investigate the expression and cellular origin of matrisome genes in murine and human dorsal root ganglia (DRG), containing the cell bodies of sensory neurons. Bulk RNA sequencing data showed that over 60% of all matrisome genes were expressed in both murine and human DRG, with proportionally more core matrisome genes (glycoproteins, collagens, and proteoglycans) expressed compared to matrisome-associated genes (ECM-affiliated genes, ECM regulators and secreted factors). Examination of the cellular origin of matrisome expression by single cell RNA sequencing on murine DRG revealed that core matrisome genes, especially collagens, were expressed by vascular leptomeningeal-like (fibroblast) cell types whereas matrisome-associated genes were mainly expressed by neuronal cell types. We analyzed cell-cell communication networks with the CellChat R package and predicted an important role for the Collagen signaling pathway in connecting vascular cell types and nociceptors in murine tissue, which we confirmed by analysis of spatial transcriptomic data from human DRG. RNAscope in situ hybridization and immunohistochemistry confirmed expression of collagens in fibroblasts surrounding nociceptors in human DRG. This study supports the idea that the DRG matrisome may contribute to neuronal signaling in both mouse and human. The identification of the cellular distribution of murine and human matrisome genes provides a framework to study the role of the ECM in peripheral nervous tissue and its effects on pain signaling. HighlightsO_LITranscriptomal analyses of mouse and human dorsal root ganglia (DRG) revealed that over 60% of matrisome genes are expressed by murine and human dorsal root ganglia (DRG), with over 85% of the genes with orthologues overlapping between both species. C_LIO_LIMatrisome-associated genes had the highest expression in both species and included conserved expression of annexins, S100 calcium binding proteins and cathepsins. C_LIO_LICollagens and collagen receptors are expressed by distinct cell types in murine and human DRG, suggesting that the collagen signaling pathway could be involved in cell-cell signaling. C_LI

Total knee replacement (TKR) is the gold-standard treatment for end-stage chronic osteoarthritis pain, yet many patients report chronic postoperative pain after TKR. The search for preoperative predictors for chronic postoperative pain following TKR has been studied with inconsistent findings. This study investigates the predictive value of quantitative sensory testing (QST) and PainDETECT for postoperative pain 3, 6, and 12 months post-TKR. We assessed baseline and postoperative (3- and 6-months) QST measures in 77 patients with knee OA (KOA) and 41 healthy controls, along with neuropathic pain scores in patients (PainDETECT). QST parameters included pressure pain pressure threshold (PPT), pain tolerance threshold (PTT), conditioned pain modulation (CPM), and temporal summation (TS) using cuff algometry, alongside mechanical hyperalgesia, and mechanical temporal summation to repeated pinprick stimulation. Compared to healthy controls, KOA patients at baseline demonstrated hyperalgesia to pinprick stimulation at the medial OA-affected knee and cuff pressure on the ipsilateral calf. Lower cuff algometry PTT and mechanical pinprick hyperalgesia were associated with baseline KOA pain intensity. Moreover, baseline pinprick pain hyperalgesia explained 25% of variance in pain intensity 12 months post-TKR and preoperative neuropathic pain scores also captured 30% and 20% of the variance in postoperative pain at 6- and 12-months, respectively. A decrease in mechanical pinprick hyperalgesia from before surgery to 3 months after TKR was associated with lower postoperative pain at the 12 months post-TKR follow-up, and vice-versa. Our findings suggest that preoperative pinprick hyperalgesia and PainDETECT neuropathic-like pain symptoms show predictive value for the development of chronic post-TKR pain.

BackgroundChronic pain following traumatic stress exposure (TSE) is common. Increasing evidence suggests inflammatory/immune mechanisms are induced by TSE, play a key role in the recovery process versus development of post-TSE chronic pain, and are sex specific. In this study, we tested the hypothesis that the inflammatory marker C-reactive protein (CRP) is associated with chronic pain after TSE in a sex-specific manner. MethodsWe utilized blood-plasma samples and pain questionnaire data from men (n=99) and (n=223) women enrolled in AURORA, a multi-site emergency department (ED)-based longitudinal study of TSE survivors. We measured CRP using Ella/ELISA from plasma samples collected in the ED ( peritraumatic CRP, n=322) and six months following TSE (n=322). Repeated measures mixed-effects models were used to assess the relationship between peritraumatic CRP and post-TSE chronic pain. ResultsPeritraumatic CRP levels significantly predicted post-TSE chronic pain, such that higher levels of CRP were associated with lower levels of pain over time following TSE, but only in men (men:{beta}=-0.24, p=0.037; women:{beta}=0.05, p=0.470). By six months, circulating CRP levels had decreased by more than half in men, but maintained similar levels in women (t(290)=1.926, p=0.055). More men with a decrease in CRP levels had decreasing pain over time versus women (men:83% women:65%; Z=2.21, p=0.027). ConclusionsIn men but not women, we found circulating peritraumatic CRP levels predict chronic pain outcomes following TSE and resolution of CRP levels in men over time might be associated with increased pain recovery. Further studies are needed to validate these results. SummaryPeritraumatic circulating CRP levels predicted pain recovery in men following TSE and decreases in CRP levels over time were greater in men compared to women.