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In this study we used a combination of measures including regional cerebral blood flow (rCBF) and heart rate variability (HRV) to investigate brain–heart correlates of longitudinal baseline changes of chronic low back pain (cLBP) after osteopathic manipulative treatment (OMT). Thirty-two right-handed patients were randomised and divided into 4 weekly session of OMT (N = 16) or Sham (N = 16). Participants aged 42.3 ± 7.3 (M/F: 20/12) with cLBP (duration: 14.6 ± 8.0 m). At the end of the study, patients receiving OMT showed decreased baseline rCBF within several regions belonging to the pain matrix (left posterior insula, left anterior cingulate cortex, left thalamus), sensory regions (left superior parietal lobe), middle frontal lobe and left cuneus. Conversely, rCBF was increased in right anterior insula, bilateral striatum, left posterior cingulate cortex, right prefrontal cortex, left cerebellum and right ventroposterior lateral thalamus in the OMT group as compared with Sham. OMT showed a statistically significant negative correlation between baseline High Frequency HRV changes and rCBF changes at T2 in the left posterior insula and bilateral lentiform nucleus. The same brain regions showed a positive correlation between rCBF changes and Low Frequency HRV baseline changes at T2. These findings suggest that OMT can play a significant role in regulating brain–heart interaction mechanisms.

Fepixnebart (LY3016859), a humanized immunoglobulin G4 monoclonal antibody with high binding affinity to epiregulin and tumor growth factor-α, is being developed as a novel analgesic to treat broad-spectrum chronic pain. Early phase clinical studies demonstrated fepixnebart has nonlinear pharmacokinetics in healthy subjects and patients with diabetic nephropathy. This population pharmacokinetic analysis used data from three 26-week, phase 2, proof-of-concept studies in osteoarthritis, diabetic peripheral neuropathic pain (DPNP), and chronic low back pain (CLBP) to characterize the pharmacokinetics of fepixnebart and predict its target engagement by epiregulin. Covariate relationships were also assessed. Population analysis was performed using nonlinear mixed-effects modeling software. Covariate relationships were explored graphically by plotting potential covariates versus parameters of interest. Simulated target engagement was predicted using the phase 2 dose regimen for fepixnebart (750 mg intravenous starting dose, followed by 500 mg every 2 weeks). The median simulated target engagement at 2 weeks after the last dose of fepixnebart was predicted to be 92.0%, with 90% of predictions between 86.0 and 96.2% and 68.5% of subjects predicted to exhibit target engagement exceeding 90%. The phase 2 dose regimen is adequate to test the analgesic effect of fepixnebart in patients with osteoarthritis, DPNP, and CLBP. In the final model, female sex and higher glomerular filtration rate were associated with higher clearance, female sex was associated with larger volume of distribution of the central compartment (V ) than male sex, and DPNP was associated with lower V than CLBP. There were no significant effects on the concentration of fepixnebart at which its effect on epiregulin is half-maximal (EC ). ClinicalTrials.gov: NCT04529096, NCT04476108, and NCT04456686.

Fulranumab is an investigational, fully human recombinant monoclonal antibody (IgG2) that neutralizes the biological actions of human nerve growth factor. Low back pain is a common cause of noncancer chronic pain and represents one of the most significant socioeconomic health-related problems in developed countries. This randomized, double-blind, placebo-controlled study was conducted to evaluate the analgesic effect of fulranumab in patients with moderate-to-severe chronic low back pain. Patients (aged 18–80 years) were randomized to receive subcutaneous injections every 4 weeks in 1 of 5 parallel treatment groups: placebo or fulranumab 1mg (1mgQ4wk), 3mg (3mgQ4wk), 3mg after a 6mg loading dose (6mgLD+3mgQ4wk), or 10mg (10mgQ4wk) every 4 weeks. A total of 385 patients (median age, 53 years; women, 54%) received at least 1 injection of study medication. No statistically significant differences were observed in improvement of pain intensity scores between the fulranumab treatment regimens and the placebo group at week 12 (primary end point; mean [SD], placebo: −2.0 [2.17], 1mgQ4wk: −1.9 [2.14], 3mgQ4wk: −2.2 [1.89], 6mgLD+3mgQ4wk: −2.0 [1.72] and 10mgQ4wk: −2.1 [2.18]). Results for secondary efficacy parameters (change in the Oswestry Disability Index, Brief Pain Inventory–Short Form, and Patient Global Assessment scales) were consistent with the primary outcome. A placebo effect was observed; the overall percentage of patients with treatment-emergent adverse events (TEAEs) was similar between the placebo (76%) and fulranumab treatment groups (77%–90%). Across all phases, the most common TEAEs in at least 10% of patients (combined fulranumab group vs placebo) were arthralgia (15% vs 12%), back pain (15% vs 18%), upper respiratory tract infection (15% vs 8%), paresthesia (14% vs 8%), diarrhea (12% vs 4%), headache (12% vs 8%), hypoesthesia (11% vs 5%), pain in extremity (11% vs 8%), sinusitis (10% vs 5%), and nasopharyngitis (10% vs 9%). Across all phases, neurologic TEAEs were less frequent in the placebo group (14%) versus the fulranumab treatment groups (25%). In the posttreatment phase, 8 patients had joint replacement operations, which were considered a result of normal progression of osteoarthritis. One case in the 10-mg group was determined to be rapid progession of osteoarthritis and was considered to be possibly related to study drug. Fulranumab did not demonstrate efficacy compared with placebo in patients with chronic low back pain but was generally well-tolerated. ClinicalTrials.gov identifier: NCT00973024.

Background. Chronic pain is associated with increased morbidity and mortality, predominated by cardiovascular disease and cancer. Investigating related risk factor measures may elucidate the biological burden of chronic pain. Objectives. We hypothesized that chronic pain severity would be positively associated with the risk factor composite. Methods. Data from 12,982 participants in the 6th Tromsø study were analyzed. Questionnaires included demographics, health behaviors, medical comorbidities, and chronic pain symptoms. The risk factor composite was comprised of body mass index, fibrinogen, C-reactive protein, and triglycerides. Chronic pain severity was characterized by frequency, intensity, time/duration, and total number of pain sites. Results. Individuals with chronic pain had a greater risk factor composite than individuals without chronic pain controlling for covariates and after excluding inflammation-related health conditions ( p < 0.001 ). A significant “dose-response” relationship was demonstrated with pain severity ( p < 0.001 ). In individuals with chronic pain, the risk factor composite varied by health behavior, exercise, lower levels and smoking, and higher levels. Discussion. The risk factor composite was higher in individuals with chronic pain, greater with increasing pain severity, and influenced by health behaviors. Conclusions. Identification of a biological composite sensitive to pain severity and adaptive/maladaptive behaviors would have significant clinical and research utility.

Chronic pain affects millions of people worldwide. A new study presents a promising therapeutic strategy in which Toll-like receptor (TLR) 5 stimulation enables the analgesic compound, QX-314, to specifically enter and silence large fiber sensory neurons, which convey pain in the setting of injury.

Trapezius myalgia is the most common type of chronic neck pain. While physical exercise reduces pain and improves muscle function, the underlying mechanisms remain unclear. Nitric oxide (NO) signaling is important in modulating cellular function, and a dysfunctional neuronal NO synthase (nNOS) may contribute to an ineffective muscle function. This study investigated nNOS expression and localization in chronically painful muscle. Forty-one women clinically diagnosed with trapezius myalgia (MYA) and 18 healthy controls (CON) were included in the case-control study. Subsequently, MYA were randomly assigned to either 10 weeks of specific strength training (SST, n = 18 ), general fitness training (GFT, n = 15 ), or health information (REF, n = 8 ). Distribution of fiber type, cross-sectional area, and sarcolemmal nNOS expression did not differ between MYA and CON. However, MYA showed increased sarcoplasmic nNOS localization (18.8 ± 12 versus 12.8 ± 8%, P = 0.049 ) compared with CON. SST resulted in a decrease of sarcoplasm-localized nNOS following training (before 18.1 ± 12 versus after 12.0 ± 12%; P = 0 ,027). We demonstrate that myalgic muscle displays altered nNOS localization and that 10 weeks of strength training normalize these disruptions, which supports previous findings of impaired muscle oxygenation during work tasks and reduced pain following exercise.

Astrocytes are critical for maintaining the homeostasis of the CNS. Increasing evidence suggests that a number of neurological and neuropsychiatric disorders, including chronic pain, may result from astrocyte ‘gliopathy’. Indeed, in recent years there has been substantial progress in our understanding of how astrocytes can regulate nociceptive synaptic transmission via neuronal–glial and glial–glial cell interactions, as well as the involvement of spinal and supraspinal astrocytes in the modulation of pain signalling and the maintenance of neuropathic pain. A role of astrocytes in the pathogenesis of chronic itch is also emerging. These developments suggest that targeting the specific pathways that are responsible for astrogliopathy may represent a novel approach to develop therapies for chronic pain and chronic itch.

Pain affects millions worldwide, posing significant challenges in diagnosis and treatment. Despite advances in understanding pain mechanisms, there remains a critical need for validated biomarkers to enhance diagnosis, prognostication, and personalized therapy. This review synthesizes recent advancements in identifying and validating acute and chronic pain biomarkers, including imaging, molecular, sensory, and neurophysiological approaches. We emphasize the emergence of composite, multimodal strategies that integrate psychosocial factors to improve the precision and applicability of biomarkers in chronic pain management. Neuroimaging techniques like MRI and positron emission tomography provide insights into structural and functional abnormalities related to pain, while electrophysiological methods like electroencepholography and magnetoencepholography assess dysfunctional processing in the pain neuroaxis. Molecular biomarkers, including cytokines, proteomics, and metabolites, offer diagnostic and prognostic potential, though extensive validation is needed. Integrating these biomarkers with psychosocial factors into clinical practice can revolutionize pain management by enabling personalized treatment strategies, improving patient outcomes, and potentially reducing healthcare costs. Future directions include the development of composite biomarker signatures, advances in artificial intelligence, and biomarker signature integration into clinical decision support systems. Rigorous validation and standardization efforts are also necessary to ensure these biomarkers are clinically useful. Large-scale collaborative research will be vital to driving progress in this field and implementing these biomarkers in clinical practice. This comprehensive review highlights the potential of biomarkers to transform acute and chronic pain management, offering hope for improved diagnosis, treatment personalization, and patient outcomes.

Interactions between central glial cells and neurons in the pain circuitry are critical contributors to the pathogenesis of chronic pain. In the central nervous system (CNS), two major glial cell types predominate: astrocytes and microglia. Injuries or pathological conditions which evoke pain are concurrently associated with the presence of a reactive microglia or astrocyte state, which is characterized by a variety of changes in the morphological, molecular, and functional properties of these cells. In this review, we highlight the changes that reactive microglia and astrocytes undergo following painful injuries and insults and discuss the critical and interactive role these two cell types play in the initiation and maintenance of chronic pain. Additionally, we focus on several crucial mechanisms by which microglia and astrocytes contribute to chronic pain and provide commentary on the therapeutic promise of targeting these pathways. In particular, we discuss how the inflammasome in activated microglia drives maturation and release of key pro-inflammatory cytokines, which drive pain through neuronal- and glial regulations. Moreover, we highlight several potentially-druggable hemichannels and proteases produced by reactive microglia and astrocytes in pain states and discuss how these pathways regulate distinct phases during pain pathogenesis. We also review two emerging areas in chronic pain research: 1) sexually dimorphic glial cell signaling and 2) the role of oligodendrocytes. Finally, we highlight important considerations for potential pain therapeutics targeting glial cell mediators as well as questions that remain in our conceptual understanding of glial cell activation in pain states.

The dorsal medial prefrontal cortex (dmPFC) has been recognized as a key cortical area for nociceptive modulation. However, the underlying neural pathway and the function of specific cell types remain largely unclear. Here, we show that lesions in the dmPFC induced an algesic and anxious state. Using multiple tracing methods including a rabies-based transsynaptic tracing method, we outlined an excitatory descending neural pathway from the dmPFC to the ventrolateral periaqueductal gray (vlPAG). Specific activation of the dmPFC/vlPAG neural pathway by optogenetic manipulation produced analgesic and antianxiety effects in a mouse model of chronic pain. Inhibitory neurons in the dmPFC were specifically activated using a chemogenetic approach, which logically produced an algesic and anxious state under both normal and chronic pain conditions. Antagonists of the GABAA receptor (GABAAR) or mGluR1 were applied to the dmPFC, which produced analgesic and antianxiety effects. In summary, the results of our study suggest that the dmPFC/vlPAG neural pathway might participate in the maintenance of pain thresholds and antianxiety behaviors under normal conditions, while silencing or suppressing the dmPFC/vlPAG pathway might be involved in the initial stages and maintenance of chronic pain and the emergence of anxiety-like behaviors.