Pain is a complex sensory and emotional experience that severely affects an individual's quality of life and health status. Steroid hormones, as important regulatory substances in the human body, are extensively involved in various physiological and pathological processes. In recent years, remarkable progress has been made in the research of steroid hormones in the field of pain. They play a crucial role in the occurrence, development, and treatment of pain. This review comprehensively elaborates on the roles and therapeutic mechanisms of steroid hormones in pain, explores the performances of glucocorticoids, mineralocorticoids, sex hormones, etc. in different pain models, as well as the molecular mechanisms by which they regulate pain through genomic and non-genomic effects, aiming to provide a theoretical basis for the clinical treatment of pain.

Animal-derived traditional Chinese medicines have a long-standing history in Chinese medicine, which exhibit unique efficacy due to similar structure and function with human tissue. As the major types of constituents that accounted for a relatively high proportion of animal-derived TCMs, peptides with molecular weight between 100 Da and hundreds of thousands of kDa have caught wide attention due to their outstanding bioavailability and excellent specificity.

This review aims to comprehensively delve into the up-to-date research progress in their pharmacology, mechanism, sequence composition, and therapeutic application, laying a solid foundation for future clinical treatment and scientific research.

Relevant information on the peptides from animal-derived TCMs was collected from scientific literature databases including PubMed, CNKI, literature sources (Ph.D. and M.Sc. dissertations), and Web of Science by using the keywords "Peptides", "Animal", and "TCMs" for gradual screening in the past 30 years.

To date, the peptides from 27 kinds of animal-derived TCMs have been systematically combed. Their pharmacological activity and underlying mechanisms on multiple systems (nervous, circulatory, skeletal, and immune), as well as anti-tumor, antioxidative, and antimicrobial effects, have been sorted out. Besides, the potential safety issues and deficiencies (low bioavailability, imperfect quality management, and toxicity of raw materials) have also been pointed out.

Comprehensive analysis showed that low development and resource waste accompanied by the inadequate report about the pharmacological activity of most peptides from animal-derived TCMs make it have good research prospects. Although a breakthrough in the field of healthcare products has been made, the development potential for clinical products that bring surprising turnaround will be obtained if the above-mentioned confusions and current needs (improve identification technology and design reasonable dosage forms) are implemented.

This study aims to evaluate the analgesic and anxiolytic effects of citronellal (CTL) in Swiss mice using two new sensitive and economic mouse models along with possible molecular mechanisms through in silico studies. For this, we employed marble displacement and spiked-field apparatus to check the anxiolytic and analgesic effects, respectively. In silico studies were done against cyclooxygenase (COX) enzymes and GABAA receptor subunits. Findings suggest that the test sample CTL significantly reduced the number of marbles displaces (NMD), square crosses (NSC), paw massages (NPM), and escaping attempts (NEA) in animals than the control group. CTL exhibited better effects in the perforated-field study compared to the reference drug diclofenac sodium. In both cases, CTL (200 mg/kg) significantly reduced the test parameters when combined with the standard drugs (diazepam or diclofenac sodium). In in silico studies, CTL showed binding affinities of - 5.5, - 5.2, - 4.8, and - 4.8 kcal/mol with the COX1, COX2, and GABAA receptors (α2 and α3 subunits), respectively. Taken together, CTL may exert anxiolytic- analgesic-like effects on mice, possibly through the GABAA receptor and COXs interaction pathways. These new tools might be used to check the anxiolytic and analgesic properties of a wide variety of test substances.

The accumulation of heavy metals in surface soil raises significant environmental and public health concerns around the world. This study aimed to examine the relationship between exposure to heavy metals in surface soil and the risk of pain among residents.

Using national data on eight heavy metals (arsenic, cadmium, chromium, copper, lead, mercury, nickel and zinc) in China's surface soil and a population cohort from 2011 to 2018, we analyzed pain occurrences in various body locations. Logistic regression models were used to assess the association between exposure to heavy metal in soil and pain, as adjusting for gender, age, education level, body mass index, living region, and lifestyle. The study included 13,178 individuals.

Higher exposure to soil arsenic was found to be associated with increased risk of shoulders [adjusted odds ratio (99.99% CI), 1.49 (1.01, 2.19)], wrists [1.68 (1.06, 2.64)] and ankles pain [1.58 (1.01, 2.50)]. No association was found between the remaining seven heavy metals and different types of body pain.

Our results indicate that higher soil arsenic exposure is associated with an increased risk of pain in specific body regions. This study is the first examining the associations between multiple heavy metals in surface soil and the risks of pain in different body sites. Our findings provide new insights into the health risks of soil heavy metal exposure.

Acupoint massage is a non-invasive traditional therapy that has demonstrated reliable clinical outcomes in pain management, mental health relief, sleep disorder regulation, gastrointestinal treatment, and as an adjunct therapy for cancer. Its convenience and cost-effectiveness further enhance its appeal. However, the existing English literature lacks a systematic review that encompasses the various forms of acupoint massage. The acupoint massage forms adaptability is particularly notable when considering the diverse conditions, it addresses, as well as its applicability across different age groups and gender differences. Providing a comprehensive understanding, it is crucial to outline common practices and explore specific applications in key areas. The comprehensive understanding can create opportunities for effective collaboration between preclinical and clinical studies. Defining and categorizing different forms of acupoint massage is essential, alongside investigating the neural circuits involved in touch sensation. Future efforts should enhance collaboration with modern biology, facilitating the transition from empirical to evidence-based practice. This review summarizes forms, applications, and mechanisms of mainstream acupoint massage and provides insights for future research and applications, promoting deeper integration into healthcare.

Opioids have constituted an essential element of general anesthesia for a considerable length of time. However, with the increase in opioid misuse and associated postoperative adverse effects, studies related to opioid-free anesthesia (OFA) have emerged, which pose a challenge in identifying key research directions. Accordingly, the objective of this study was to provide a review of the relevant literature in the field of OFA over the past 2 decades, with the goal of identifying the prevailing trends and research Frontiers.

A systematic review of the publications on OFA was conducted using the Web of Science Core Collection database, with the objective of identifying relevant publications between the years 2005 and 2024. The bibliometric analysis was conducted using CiteSpace (version 6.1. R6), VOSviewer (version 1.6.19), and R (version4.4.2).

In conclusion, 477 publications were included in this study. The number of annual publications in this field has exhibited a steady increase over the past 2 decades. The United States and its institutions were found to be the most central. Forget, Patrice, and BELOEIL H were identified as the most prolific and highly cited authors, respectively. The journal with the highest number of publications was BMC Anesthesiology. The most frequently cited journal was Anesthesia and Analgesia, followed by Anesthesiology. In addition, keyword burst, keywords co-occurrence, and analysis of cited references indicate that recent studies have focused on: opioid consumption, pain, and postoperative nausea and vomiting (PONV). Meanwhile, analysis of keyword clusters and keywords timeline view showed that the main research frontiers are sevoflurane anesthesia, plane block, multimodal anesthesia, opioid-sparing anesthesia.

Our results show that the current trends and directions of research focus on opioid consumption, pain, and PONV. Frontiers for future research are expected to include research areas related to sevoflurane anesthesia, plane block, multimodal anesthesia, opioid-sparing anesthesia.

The complex nature of pain pathophysiology complicates the establishment of objective diagnostic criteria and targeted treatments. The heterogeneous manifestations of pain stemming from various primary diseases contribute to the complexity and diversity of underlying mechanisms, leading to challenges in treatment efficacy and undesirable side effects. Recent evidence suggests the presence of apoptotic cells at injury sites, the distal dorsal root ganglia (DRG), spinal cord, and certain brain regions, indicating a potential link between the ineffective clearance of dead cells and debris and pain persistence. This review highlights recent research findings indicating that efferocytosis plays a significant yet often overlooked role in lesion expansion while also representing a potentially reversible impairment that could be targeted therapeutically to mitigate chronic pain progression. We examine recent advances into how efferocytosis, a process by which phagocytes clear apoptotic cells without triggering inflammation, influences pain initiation and intensity in both human diseases and animal models. This review summarizes that efferocytosis contributes to pain progression from the perspective of defective and inefficient efferocytosis and its subsequent secondary necrocytosis, cascade inflammatory response, and the shift of phenotypic plasticity and metabolism. Additionally, we investigate the roles of newly discovered genetic alterations or modifications in biological signaling pathways in pain development and chronicity, providing insights into innovative treatment strategies that modulate efferocytosis, which are promising candidates and potential avenues for further research in pain management and prevention.

BackgroundNeck and shoulder exercises are recommended to improve Neck and Shoulder Pain (NSP). However, it is unclear why exercises for the neck and shoulder improve NSP, and methods for evaluating the effects of these exercises have not been clear.ObjectiveThe purpose of this study was to investigate time-dependent changes in stiffness of the neck extensor muscles due to prolonged sitting and the effect of exercise.MethodsTwenty-five healthy adult women sat with their hands on a desk for 90 min looking at a computer screen and then performed neck and shoulder exercise. Shear wave velocities (SWV) of the neck extensor muscles (the upper trapezius, levator scapulae, rhomboid major, and splenius capitis muscles) were measured at 0, 30, 60, and 90 min after the start of sitting and after the exercise. At the same time, changes in NSP were recorded.ResultsDuring prolonged sitting, SWV in the upper trapezius increased significantly with time (p < 0.001). Neck and shoulder exercise significantly decreased SWV and NSP (p < 0.001).ConclusionsThe results of this study revealed objective changes in neck muscle stiffness by prolonged sitting. Neck and shoulder exercise may reduce muscle stiffness and contribute to relieve NSP.

The cerebrospinal fluid-contacting nucleus(CSF-contacting nucleus) is a pair of unique nuclei in the brain parenchyma which has long been demonstrated to play an important role in pain signal processing. However, the mechanisms by which the CSF-contacting nucleus intervenes in pain is unclear. The NRG1-ErbB4 signaling plays an important role in the nervous system and has been shown to be involved in the regulation of pain. Whether there is an involvement of NRG1-ErbB4 signaling in the regulation of pain in the CSF-contacting nucleus is currently unknown. Here, our works showed that c-Fos expression in the CSF-contacting nucleus was increased in response to incisional pain. The activation of the CSF-contacting nucleus by chemogenetics could induce thermal hyperalgesia in naive mice without effecting the pain in mice suffering from incision pain. The inhibition of the CSF-contacting nucleus alleviated incision pain, but had no effect on the pain response in naive mice. With immunofluorescence staining and Western blot, the NRG1-ErbB4 signaling in the CSF-contacting nucleus showed upregulated during the acute pain phase. And, activating NRG1-ErbB4 signaling in the CSF-contacting nucleus specifically by intracranial injection of drugs, the naïve mice displayed thermal hyperalgesia while inhibiting this signaling by intracranial injection could reverse the hyperalgesia caused by CSF-contacting nucleus activation, and execute an analgesic effect during the painful phase in mice. Our study suggested that the CSF-contacting nucleus plays a regulatory role in thermal pain in mice via NRG1-ErbB4 signaling.

Regardless of their cause, persistent physical symptoms are distressing somatic complaints that occur on most days for at least several months. They are common in patients with somatic diseases, functional somatic disorders, mental disorders, and undiagnosed medical conditions and are often associated with significant impairment and medical costs. Despite their prevalence and impact, persistent physical symptoms are often overlooked in medical care. This Personal View stresses the importance of recognising persistent physical symptoms as a European health issue. It advocates improvements in research, clinical management, public health, and policy. Efforts should prioritise integrating models of symptom perception and biopsychosocial perspectives into medical care and education, fostering interdisciplinary collaboration, and developing standardised guidelines to enhance patient care, reduce stigma, and improve clinical outcomes. Increased research funding can accelerate progress in understanding and effectively managing persistent physical symptoms. Addressing these priorities will support patients and healthcare professionals, ensuring adequate care and a higher quality of life for affected individuals.

Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin-sensitive ion channel implicated in pain sensation. While TRPV1 potentiation in hyperalgesia development has been extensively investigated, its functional decline during pain relief remains largely unexplored. Here, by molecular, electrophysiological and in vivo evidence, we reveal that S-palmitoylation fine-tunes TRPV1 function by promoting its degradation via the lysosome pathway thereby facilitating inflammatory pain relief. The palmitoyl acyltransferase ZDHHC4 is identified to physically interact with TRPV1 and to catalyze S-palmitoylation at the cysteine residues C157, C362, C390, and C715 of the channel. Furthermore, we show that TRPV1 palmitoylation is counterbalanced by the depalmitoylase acyl-protein thioesterase 1 (APT1), thereby reinstating pain sensation. These findings provide important mechanistic insights into the relief phase of inflammatory pain.

Pain assessment in patients with temporomandibular joint (TMJ) disorders during physiotherapy is a challenging yet desired task. Our study addresses two issues. First, we compare the pain perception in patients with TMJ disorders and a control group. The hand dynamometer is verified as an alternate pain self-report device in the second stage. For the dynamometer validation, we employed a cuff-pressure test to induce pain of various intensities. In the second stage, physiological signals (electrodermal activity and blood volume pulse) have been acquired during the physiotherapy in a control group and patients suffering from TMJ disorder. The linear mixed-effects modeling is carried out to find differences in pain and no pain states, considering subjects' health condition. The main result of the present pilot study is that physiological reactions to painful physiotherapy do not differ between patients with chronic pain and the control group. This finding concludes that studies on TMJ disorder procedures may also be performed on healthy subjects.

Chronic pain (CP) affects over 30 % of the global population, imposing significant financial burdens on individuals and society. However, existing treatments for CP offer limited efficacy and troublesome side effects, primarily owing to a lack of knowledge of its precise underlying mechanism. Pathological stimuli disrupt the intricate process of protein folding and endoplasmic reticulum (ER) homeostasis. This disruption leads to the accumulation of misfolded or unfolded proteins in the ER, generating a condition termed ER stress. Emerging data have indicated that ER stress, occurring in the peripheral and central nervous systems, contributes to the development and maintenance of CP. This review aimed to comprehensively explore the intersection of ER stress and CP within the lower and upper nervous systems and highlight the cell-specific contributions of the unfolded protein response in different CP types. We provide a comprehensive synthesis of evidence from animal models, examining neuronal and non-neuronal mechanisms and discuss the damaging ER stress-linked inflammation, autophagy, oxidative stress, and apoptosis, which collectively drive disease progression and contribute to a neurotoxic environment. However, the mechanisms through which ER stress influences the most advanced centre-of-pain projections in the brain remain unclear. Further investigation in this area is crucial to elucidate the relationship between ER stress and CP and facilitate the development of novel therapeutic drugs for this intractable dilemma.

Abscisic acid (ABA), a phytohormone traditionally recognized for its role in plant stress responses, has recently emerged as a significant player in mammalian defense mechanisms. Like plants, various mammalian cell types synthesize ABA in response to specific health challenges, although the precise pathways remain not fully elucidated. ABA is associated with the regulation of inflammation and insulin signaling, prompting extensive research into its potential as a therapeutic agent for various diseases. ABA exerts its effects through its receptors, particularly PPAR-γ and LANCL-2, which serve as signaling hubs regulating numerous pathways. Through these interactions, ABA profoundly impacts mammalian health, and new ABA targets continue to be identified. Numerous studies in animal models demonstrate ABA's benefit in managing conditions such as neurological and psychiatric disorders, cancer, and malaria infections, all of which involve significant inflammatory dysregulation. In this manuscript we review the studies covering ABA synthesis and release in cell cultures, the signaling pathways regulated by ABA, and how these impact health in preclinical models. Furthermore, we highlight recent research suggesting that measuring ABA levels in human body fluids could serve as a useful biomarker for pathological conditions, providing insights into disease progression and treatment efficacy. This comprehensive review outlines the current understanding of ABA in mammalian pathophysiology, identifying gaps in knowledge, particularly concerning ABA biosynthesis and metabolism in mammals. In addition, this study emphasizes the need for clinical trials to validate the effectiveness of ABA-based therapies and its reliability as a biomarker for various diseases.

This study aims to determine the usage pattern, effectiveness and safety of oral tramadol 75 mg and dexketoprofen trometamol 25 mg fixed-dose combination (TRAM/DKP FDC) in the short-term treatment of moderate-to-severe acute pain in real-world clinical practice in Asia.

Real-world, prospective, multicentre, observational, phase IV study.

13 tertiary-care hospital sites across the Philippines, Thailand, Malaysia and Singapore.

Adult patients aged 18-80 years prescribed TRAM/DKP FDC for the short-term (up to 5 days) treatment of moderate-to-severe acute pain.

Primary endpoints were the proportion of patients prescribed TRAM/DKP FDC with different types of postsurgical and non-surgical treatments, and the average dosing frequency and duration of TRAM/DKP FDC treatment. Secondary endpoints were the proportion of patients achieving ≥30% pain reduction at 8 hours post the first dose (pain severity was assessed using the 11-point Numeric Pain Rating Scale); patient satisfaction at the end of treatment (based on a 5-point Patient Global Evaluation Scale (PGE)) and safety including the incidence of adverse drug reactions (ADRs).

Among 599 patients (median age 44 years, 61.3% female) enrolled in this study, 68.61% (n=411) were postsurgical and 31.39% (n=188) were non-surgical patients. TRAM/DKP FDC was prescribed in a diverse group of postsurgical patients (eg, orthopaedic, general and cancer surgery) as well as in non-surgical conditions (eg, lower back pain and musculoskeletal pain). In the majority of patients, TRAM/DKP FDC was prescribed every 8 hours (65.94%) and for 5 days (78.80%). There was a significant reduction in pain intensity throughout the study and 65% of patients achieved ≥30% pain reduction from baseline at 8 hours post the first dose of TRAM/DKP FDC on day 1. 95.69% of patients were satisfied with the treatment (rated good, very good and excellent on the PGE scale). Overall, 13.9% of patients reported ADRs; most were mild to moderate in severity. The most common ADRs were nausea, vomiting and dizziness.

This study showed that TRAM/DKP FDC was used in diverse types of postsurgical and non-surgical patients in the real-world setting in Asia. It effectively reduced pain and was well tolerated with a high level of patient satisfaction.

Despite wide endorsement of a biopsychosocial framework for pain, social aspects of pain remain rarely addressed in the context of pain prevention and management. In this review, we aim to 1) examine the broad scope of social determinants and consequences of pain and their interactions across multiple levels of organization, and 2) provide a framework synthesizing existing concepts and potential areas for future work on social aspects of pain, drawing upon socioecological, intersectional, and life course approaches. Integrating interdisciplinary theory and evidence, we outline pathways through which multilevel social factors and pain may affect each other over time. We also provide a brief summary of intrapersonal aspects of pain, which are thought to operate at the interface between individuals and the social context. Progressing from micro- to macrolevel factors, we illustrate how social determinants of pain can directly or indirectly contribute to pain experiences, expression, risk, prognosis, and impact across populations. We consider 1) at the interpersonal level, the roles of social comparison, social relatedness, social support, social exclusion, empathy, and interpersonal conflict; 2) at the group or community level, the roles of intimacy groups, task groups, social categories, and loose associations; and 3) at the societal level, the roles of political, economic, and cultural systems, as well as their policies and practices. We present examples of multilevel consequences of pain across these levels and discuss opportunities to reduce the burden and inequities of pain by expanding multilevel social approaches in pain research and practice. PERSPECTIVE: Despite wide endorsement of a biopsychosocial framework for pain, social aspects of pain are often unclearly defined, hindering their use in pain prevention, management, and research. We summarize the scope of social aspects of pain and provide a framework synthesizing existing concepts and potential areas for future work.

Pain is a common symptom of many clinical diseases; it adversely affects patients' physical and mental health, reduces their quality of life, and heavily burdens patients and society. Pain treatment is one of the most difficult problems today. There is an urgent need to explore the potential factors involved in the pathogenesis of pain to improve its diagnosis and treatment rate. Piezo1/2, a newly identified mechanosensitive ion channel opens in response to mechanical stimuli and plays a critical role in regulating pain-related diseases. Inhibition or downregulation of Piezo1/2 alleviates disease-induced pain. Therefore, in this study, we comprehensively discussed the biology of this gene, focusing on its potential relevance in pain-related diseases, and explored the pharmacological effects of drugs using this gene for the treatment of pain.

Retrospective review of prospectively collected data.

To determine the impact of preoperative symptom duration on postoperative functional outcomes after cervical disc replacement (CDR) for radiculopathy.

CDR has emerged as a reliable and efficacious treatment option for degenerative cervical spine pathologies. The relationship between preoperative symptom duration and outcomes after CDR is not well established.

Patients with radiculopathy without myelopathy who underwent primary 1- or 2-level CDRs were included and divided into shorter (<6 mo) and prolonged (≥6 mo) cohorts based on preoperative symptom duration. Patient-reported outcome measures (PROMs) included neck disability index (NDI), visual analog scale (VAS) neck and arm. Changes in PROM scores and minimal clinically important difference (MCID) rates were calculated. Analyses were conducted on the early (within 3 mo) and late (6 mo-2 y) postoperative periods.

A total of 201 patients (43.6±8.7 y, 33.3% female) were included. In both early and late postoperative periods, the shorter preoperative symptom duration cohort experienced significantly greater change from preoperative PROM scores compared with the prolonged symptom duration cohort for NDI, VAS-Neck, and VAS-Arm. The shorter symptom duration cohort achieved MCID in the early postoperative period at a significantly higher rate for NDI (78.9% vs. 54.9%, P =0.001), VAS-Neck (87.0% vs. 56.0%, P <0.001), and VAS-Arm (90.5% vs. 70.7%, P =0.002). Prolonged preoperative symptom duration (≥6 mo) was identified as an independent risk factor for failure to achieve MCID at the latest timepoint for NDI (OR: 2.9, 95% CI: 1.2-6.9, P =0.016), VAS-Neck (OR: 9.8, 95% CI: 3.7-26.0, P <0.001), and VAS-Arm (OR: 7.5, 95% CI: 2.5-22.5, P <0.001).

Our study demonstrates improved patient-reported outcomes for those with shorter preoperative symptom duration undergoing CDR for radiculopathy, suggesting delayed surgical intervention may result in poorer outcomes and greater postoperative disability.

Level III.

Individuals with elevated psychopathic traits exhibit decision-making deficits linked to a failure to learn from negative outcomes. We investigated how reduced pain sensitivity affects reinforcement-based decision-making in individuals with varying levels of psychopathic traits, as measured by the Self-Report Psychopathy Scale-Short Form. Using computational modelling, we estimated the latent cognitive processes in a community non-offender sample (n = 111) that completed a task with choices leading to painful and non-painful outcomes. Higher psychopathic traits were associated with reduced pain sensitivity and disturbances in reinforcement learning from painful outcomes. In a Structural Equation Model, a superordinate psychopathy factor was associated with a faster return to original stimulus-outcome associations as pain tolerance increased. This provides evidence directly linking reduced pain sensitivity and learning from painful outcomes with elevated psychopathic traits. Our results offer insights into the computational mechanisms of maladaptive decision-making in psychopathy and antisocial behavior.

Ion channels play an important role in mediating pain through signal transduction, regulation, and control of responses, particularly in neuropathic pain. Transient receptor potential channel superfamily plays an important role in cation permeability and cellular signaling. Transient receptor potential channel Melastatin 2 (TRPM2) subfamily regulates Ca2+ concentration in response to various chemicals and signals from the surrounding environment. TRPM2 has a role in several physiological functions such as cellular osmosis, temperature sensing, cellular proliferation, as well as the manifestation of many disease processes such as pain process, cancer, apoptosis, endothelial dysfunction, angiogenesis, renal and lung fibrosis, and cerebral ischemic stroke. Toll-like Receptor 4 (TLR4) is a critical initiator of the immune response to inflammatory stimuli, particularly those triggered by Lipopolysaccharide (LPS). It activates downstream pathways leading to the production of oxidative molecules and inflammatory cytokines, which are modulated by basal and store-operated calcium ion signaling. The cytokine production and release cause an imbalance of antioxidant enzymes and redox potential in the Endoplasmic Reticulum and mitochondria due to oxidative stress, which results from TLR-4 activation and consequently induces the production of inflammatory cytokines in neuronal cells, exacerbating the pain process. Very few studies have reported the role of TRPM2 and its association with Toll-like receptors in the context of neuropathic pain. However, the molecular mechanism underlying the interaction between TRPM2 and TLR-4 and the quantum of impact in acute and chronic neuropathic pain remains unclear. Understanding the link between TLR-4 and TRPM2 will provide more insights into pain regulation mechanisms for the development of new therapeutic molecules to address neuropathic pain.

Pain is essential for survival, but individual responses to painful stimuli vary, representing a complex interplay between sensory, cognitive, and affective factors. Individual differences in personality traits and in pain perception covary but it is unclear which traits play the most significant role in understanding the pain experience and whether this depends on pain modality. A systematic search identified 1534 records (CINAHL, MEDLINE, PsycInfo, PubMed and Web of Science), of which 22 were retained and included in a systematic review. Only studies from the pressure pain domain (n=6) could be compared in a formal meta-analysis to evaluate the relationship between Big Five traits and experimental pain. Pressure pain tolerance correlated positively with Extraversion and negatively with Neuroticism with a trivial effect size (<0.1). While these findings suggest personality might be only weakly related to pain in healthy individuals, we emphasize the need to consider standardization, biases, and adequate sample sizes in future research, as well as additional factors that might affect experimental pain sensitivity.

Congenital insensitivity to pain (CIP) is a rare condition where individuals are born with an inability to perceive pain. This can lead to various complications in the skin, skeletal system, and other bodily systems. Chronic osteomyelitis is one of the possible manifestations of CIP, which can be difficult to diagnose and treat due to the lack of pain as a diagnostic criterion.

A 5-year-old boy with CIP developed chronic osteomyelitis in his right leg, presented with fever, claudication, swelling, and local heat for 2 months. He had a history of CIP since birth, diagnosed at 18 months of age. He also had a family history of CIP. He had previously suffered a shoulder fracture and had taken asthma medication for 1 year. He had experienced tonsillitis 2 months ago. On examination, he had hepatomegaly, enlarged lymph nodes in the groin, and a minor swelling on the right knee. He had an audible snapping sound during knee flexion. Blood tests showed increased inflammatory markers. Imaging studies confirmed presence of osteomyelitis, and bone biopsy revealed infection with Staphylococcus aureus. Treatment included vancomycin and cefotaxime.

Genetic factors behind CIP were discussed, highlighting challenges in diagnosis. Manifestations of CIP, diverse and age-related, include orthopaedic issues, ophthalmological effects, and thermoregulation disturbances. The patient's case is presented with unique features, necessitating a comprehensive diagnostic approach.

This case highlights the challenges faced in diagnosing osteomyelitis among CIP patients and emphasizes the need for other diagnostic criteria apart from pain.

Postoperative ophthalmic pain not only induces anxiety and depression among patients, but also prolongs the recovery cycle. However, the management of postoperative pain in ophthalmology is still not standardized. The effectiveness of acupuncture in treating postoperative pain has been validated based on numerous clinical trials and meta-analysis. Our study is to conduct the first data mining analysis to identify the most effective acupoints selection and combinations for treating postoperative ophthalmic pain, inform.

We will search bibliographic databases from inception to November 2023. Clinical trials evaluating the effectiveness of acupuncture therapy in the management of postoperative ophthalmic pain will be selected. Reviews, protocols, animal studies, case reports, systematic evaluations and Meta-analyses will be excluded. Primary outcome indicators will be clinical outcomes related to postoperative ophthalmic pain. Descriptive statistics will be performed in Excel 2019. Association rule analysis will be performed in SPSS Modeler 18.0. Exploratory factor analysis and cluster analysis will be performed in SPSS Statistics 25.0.

This study will investigate the most effective point selection and combination of acupuncture points for the treatment of postoperative ophthalmic pain.

Our findings will provide evidence for the effectiveness and potential therapeutic prescription of acupuncture for postoperative ophthalmologic pain, helping clinicians and patients work together to make more informed decisions.

Forehead aesthetic injections are a well-known source of discomfort, and many analgesic non-invasive techniques have been proposed to ameliorate pain. However, no study has compared all these techniques for aesthetic purposes. Therefore, this study aimed to compare the effectiveness of topical cream anesthesia, vibratory stimulus, cryotherapy, pressure, and even no intervention, on pain during and immediately after injection, when considering aesthetic injections in the forehead.

Seventy patients were selected and had their foreheads divided into 5 parts, which received four different analgesic techniques, and one control zone was added. A numeric rating scale was used to assess pain, two direct questions were asked to evaluate patients' preference and discomfort with the techniques, and the adverse events were quantified. The injections were performed in the same sequence, with three minutes of rest between them and in a single session. Comparisons among analgesic methods for pain relief were performed by the one-way analysis of variance (ANOVA), considering a significance level of 5%.

No significant differences were found among the analgesic methods, and between the methods and the control zone, both during and immediately after the injections (p > 0.05). The preferred method for pain relief was the use of topical anesthetic cream (47%), while the most uncomfortable technique was manual distraction (pressure) (36%). Only one patient reported an adverse event.

No analgesic method to diminish pain was superior to the others or was better than no method. Nevertheless, the topical anesthetic cream was the preferred technique, causing less discomfort.

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Concerns related to pain from intravitreal injections are one of the key factors mentioned by patients when asked about therapy. In this systematic review and network meta-analysis, we evaluate the literature of comparative clinical trials on the relationship between needle gauge size and pain experience during intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy.

We searched 12 literature databases on 14 October 2023 for comparative studies of gauge sizes for intravitreal anti-VEGF injections. The primary outcome of interest was the reported pain experience immediately after the injection. All outcomes of pain were transformed into standardized effect sizes using Cohen's d. Using a network meta-analysis approach, we were able to compare all gauge sizes and rank them according to the reported pain experience.

We identified nine eligible studies with data on a total of 998 patients and 1004 eyes. Needle sizes studied were 26-gauge, 27-gauge, 29-gauge, 30-gauge, 32-gauge, 33-gauge, and 34-gauge. A complete network was present, which allowed for a network meta-analysis. We used the thickest (26-gauge) needle as the reference group and observed a clear trend of lower pain experience with thinner gauge sizes (d: -0.4, d: -2.7, d: -3.8, d: -4.8, d: -4.5, and d: -5.3; respectively, for 27-gauge, 29-gauge, 30-gauge, 32-gauge, 33-gauge, and 34-gauge).

A gauge size of 30 or thinner may minimize patient discomfort related to intravitreal anti-VEGF therapy.

To analyze the associations between pain and physical performance in different aging contexts.

Data from 1725 older adults from Canada, Brazil, Colombia, and Albania from the 2014 wave of the IMIAS were used to assess the associations between Back Pain (BP) or Lower Limb Pain (LLP) and physical performance by the Short Physical Performance Battery (SPPB). Three binary logistic regression models adjusted for sex, age, study site, education, income sufficiency, BMI, depressive symptoms, and chronic conditions were used to estimate the associations between LLP or BP and SPPB. The SPPB was classified into good performance (8 points or more) and poor physical performance (< 8 points).

The mean age of the older men was 71.2 (± 3.0) and the mean age of the women was 71.2 (± 2.8) years. Older men (72.8%, p < 0.05) and women (86.1%, p-value < 0.05) from Albania had the highest frequencies of self-reported general pain. Older women in Colombia had the highest frequencies of LLP or BP (33.5%, p-value < 0.05). In the fully adjusted logistic regression model, LLP or BP was significantly associated with poor SPPB (OR = 0.48, 0.35 to 0.66 95% CI, p < 0.01).

Pain symptoms are associated with reduced physical performance in older people, even when adjusted for other clinical and sociodemographic factors. Protocols for aiming to increase the level of physical activity to manage pain should be incorporated into health care strategies.

Pain is a major clinical challenge, and understanding the pathophysiology is critical for optimal management. The autonomic nervous system reacts to pain stimuli, and autonomic dysfunction may predict pain sensation. The most used assessment of autonomic function is based on electrocardiographic measures, and the ability of such measures to predict pain was investigated.

English articles indexed in PubMed and EMBASE were reviewed for eligibility and included when they reported electrocardiographic-derived measures' ability to predict pain response. The quality in prognostic studies (QUIPS) tool was used to assess the quality of the included articles.

The search revealed 15 publications, five on experimental pain, five on postoperative pain, and five on longitudinal clinical pain changes, investigating a total of 1069 patients. All studies used electrocardiographically derived parameters to predict pain assessed with pain thresholds using quantitative sensory testing or different scales. Across all study modalities, electrocardiographic measures were able to predict pain. Higher parasympathetic activity predicted decreased experimental, postoperative, and long-term pain in most cases while changes in sympathetic activity did not consistently predict pain.

Most studies demonstrated that parasympathetic activity could predict acute and chronic pain intensity. In the clinic, this may be used to identify which patients need more intensive care to prevent, for example postoperative pain and develop personalized chronic pain management.

Pain is a debilitating problem, and the ability to predict occurrence and severity would be a useful clinical tool. Basal autonomic tone has been suggested to influence pain perception. This systematic review investigated electrocardiographic-derived autonomic tone and found that increased parasympathetic tone could predict pain reduction in different types of pain.

The prevalence of pain comorbid and anxiety/depression in clinical observations has been high, and the number of related publications has increased in recent years. Nevertheless, few studies have used bibliometric methods to analyze the scientific research on comorbid pain and depression/anxiety. The aim of this study was to systematically examine the trends in global scientific research on comorbid pain and depression/anxiety from 2012 to 2022.

Papers published between 2012 and 2022 were identified in the Web of Science database. Publications that examined comorbid pain and depression/anxiety were included. The language was limited to English. CiteSpace, Excel and VOSviewer were used to analyze the volume of publications, countries, institutions, authors, cocited authors, and keywords.

A total of 30,290 papers met the inclusion criteria of the study. Using CiteSpace, VOSviewer and Excel, the results showed that the United States (10,614 publications), Harvard University (1195 publications), and Jensen, Mark P. (77 publications) were the most productive country, institution, and author, respectively. The hotspots and frontiers were "relationship between depression and pain", "gender differences in pain and depression/anxiety domains", "study of specific pain types with depression/anxiety", "treatment of pain combined with anxiety/depression", and "effects of COVID-19 on patients with pain combined with depression/anxiety".

These findings indicate a growing interest in the field of comorbid pain and depression/anxiety. The research has been broad and deep, but there is still much room for growth. Furthermore, there is a need for more mature global collaborative networks as well as more high-quality research results in the future.

Pain can be defined as an unpleasant sensory and emotional experience caused by either actual or potential tissue damage or even resemble that unpleasant experience. For years, science has sought to find treatment alternatives, with minimal side effects, to relieve pain. However, the currently available pharmacological options on the market show significant adverse events. Therefore, the search for a safer and highly efficient analgesic treatment has become a priority. Stem cells (SCs) are non-specialized cells with a high capacity for replication, self-renewal, and a wide range of differentiation possibilities. In this review, we provide evidence that the immune and neuromodulatory properties of SCs can be a valuable tool in the search for ideal treatment strategies for different types of pain. With the advantage of multiple administration routes and dosages, therapies based on SCs for pain relief have demonstrated meaningful results with few downsides. Nonetheless, there are still more questions than answers when it comes to the mechanisms and pathways of pain targeted by SCs. Thus, this is an evolving field that merits further investigation towards the development of SC-based analgesic therapies, and this review will approach all of these aspects.

Pain is a multifaceted process that encompasses unpleasant sensory and emotional experiences. The essence of the pain process is aversion, or perceived negative emotion. Central sensitization plays a significant role in initiating and perpetuating of chronic pain. Melzack proposed the concept of the "pain matrix", in which brain regions associated with pain form an interconnected network, rather than being controlled by a singular brain region. This review aims to investigate distinct brain regions involved in pain and their interconnections. In addition, it also sheds light on the reciprocal connectivity between the ascending and descending pathways that participate in pain modulation. We review the involvement of various brain areas during pain and focus on understanding the connections among them, which can contribute to a better understanding of pain mechanisms and provide opportunities for further research on therapies for improved pain management.

Regardless of the etiology, if pain persists chronically, it can detrimentally impact multiple aspects of a patient's well-being. Both physical and psychological effects are significant in many chronic pain patients. In this regard, psychological consequences can alter a patient's quality of life, functionality, and social functioning. Opioids have been the long-established gold standard for acute pain treatment in settings such as the postoperative period. An alternative to opioids in pain management has been highly sought after. Through a non-selective mechanism, cebranopadol is a first-in-class oral drug which combines agonism of the mu and nociceptin opioid peptide (NOP) receptors to provide improved analgesia, while reducing the occurrence of many typically opioid side effects. This manuscript is a narrative review of the possible use of cebranopadol in pain management.

In pre-clinical studies, cebranopadol was similar to morphine in its pain control efficacy. In a phase IIa trial, cebranopadol was superior to placebo in reducing pain. In a randomized clinical trial, cebranopadol was superior to morphine. Another study concluded that cebranopadol had a lower misuse potential when compared to hydromorphone. In summary, cebranopadol offers new opportunities in treating chronic moderate to severe pain, while also countering risks of addiction. Additional studies are warranted to further evaluate the safety and efficacy of cebranopadol. In this regard, cebranopadol could prove to be a promising alternative to current pain treatment options.

Chronic pain in adults is a frequent clinical symptom with a significant impact on patient well-being. Therefore, sufficient pain management is of utmost importance. While tramadol is a commonly used pain medication, the quality of evidence supporting its use has been questioned considering the observed adverse events. Our objective will be to assess the benefits and harms of tramadol compared with placebo or no intervention for chronic pain.

We will conduct a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis to assess the beneficial and harmful effects of tramadol in any dose, formulation, or duration. We will accept placebo or no intervention as control interventions. We will include adult participants with any type of chronic pain, including cancer-related pain. We will systematically search the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, and BIOSIS for relevant literature. We will follow the recommendations by Cochrane and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The risk of systematic errors ('bias') and random errors ('play of chance') will be assessed. The certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Although tramadol is often being used to manage chronic pain conditions, the beneficial and harmful effects of this intervention are unknown. The present review will systematically assess the current evidence on the benefits and harms of tramadol versus placebo or no intervention to inform clinical practice and future research.

PROSPERO CRD42019140334.

Postoperative cognitive dysfunction (POCD) is a medically induced, rapidly occurring postoperative disease, which is hard to recover and seriously threatens the quality of life, especially for elderly patients, so it is important to identify the risk factors for POCD and apply early intervention to prevent POCD. As we have known, pain can impair cognition, and many surgery patients experience different preoperative pain, but it is still unknown whether these patients are vulnerable for POCD. Here we found that chronic pain (7 days, but not 1 day acute pain) induced by Complete Freund's Adjuvant (CFA) injected in the hind paw of rats could easily induce spatial cognition and memory impairment after being exposed to sevoflurane anesthesia. Next, for the mechanisms, we focused on the Periaqueductal Gray Matter (PAG), a well-known pivotal nucleus in pain process. It was detected the existence of neural projection from ventrolateral PAG (vlPAG) to adjacent nucleus Dorsal Raphe (DR), the origin of serotonergic projection for the whole cerebrum, through virus tracing and patch clamp recordings. The Immunofluorescence staining and western blot results showed that Tryptophan Hydroxylase 2 (TPH2) for serotonin synthesis in the DR was increased significantly in the rats treated with CFA for 7 days and sevoflurane for 3 hours, while chemo-genetic inhibition of the vlPAG-DR projection induced obvious spatial learning and memory impairment. Our study suggests that preoperative chronic pain may facilitate cognitive function impairment after receiving anesthesia through the PAG-DR neural circuit, and preventative analgesia should be a considerable measure to reduce the incidence of POCD.

Bone diseases including bone defects, bone infections, osteoarthritis, and bone tumors seriously affect life quality of the patient and bring serious economic burdens to social health management, for which the current clinical treatments bear dissatisfactory therapeutic effects. Biomaterial-based strategies have been widely applied in the treatment of orthopedic diseases but are still plagued by deficient bioreactivity. With the development of nanotechnology, layered double hydroxides (LDHs) with adjustable metal ion composition and alterable interlayer structure possessing charming physicochemical characteristics, versatile bioactive properties, and excellent drug loading and delivery capabilities arise widespread attention and have achieved considerable achievements for bone disease treatment in the last decade. However, to the authors' best knowledge, no review has comprehensively summarized the advances of LDHs in treating bone disease so far. Herein, the advantages of LDHs for orthopedic disorders treatment are outlined and the corresponding state-of-the-art achievements are summarized for the first time. The potential of LDHs-based nanocomposites for extended therapeutics for bone diseases is highlighted and perspectives for LDHs-based scaffold design are proposed for facilitated clinical translation.

(1) Background: There is not much research about obesity in nursing homes although knowledge will help us to develop customized treatment plans and prevention strategies, which may help to decrease the burden for all persons involved. The objective of conducting this study was to describe the prevalence of obesity and the association between obesity and care problems in nursing home patients. (2) Methods: This study is a secondary data analysis of data collected in an annually performed cross-sectional study called "Nursing Quality Measurement 2.0". A standardized and tested questionnaire was used to collect data. (3) Results: In total, 1236 nursing home patients took part, and 16.7% of them were obese. The multivariate logistic regression analysis results show that urinary incontinence is significantly associated with the presence of obesity (OR 2.111). The other care problems of pressure injuries, fecal and double incontinence, physical restraints, falls, and pain were not associated with obesity. (4) Conclusions: The results indicate that, in the nursing home setting, healthcare staff should pay special attention to the patients' nutritional status and help patients to maintain a healthy weight and prevent a loss of muscle mass and function. Conducting more studies with larger sample sizes is recommended, as this will allow for differentiation among different obesity classes.

The Terror Management Theory (TMT) offered a great deal of generative hypotheses that have been tested in a plethora of studies. However, there is a still substantive lack of clarity about the interpretation of TMT-driven effects and their underlying neurological mechanisms. Here, we aimed to expand upon previous research by introducing two novel methodological manipulations aimed to enhance the effects of mortality salience (MS). We presented participants with the idea of the participants' romantic partner's death as well as increased the perceived threat of somatosensory stimuli. Linear mixed modelling disclosed the greater effects of MS directed at one's romantic partner on pain perception (as opposed to the participant's own mortality). The theta event-related oscillatory activity measured at the vertex of the scalp was significantly lower compared to the control condition. We suggest that MS aimed at one's romantic partner can result in increased effects on perceptual experience; however, the underlying neural activities are not reflected by a classical measure of cortical arousal.

Transient receptor potential (TRP) channels are sensors for a variety of cellular and environmental signals. Mammals express a total of 28 different TRP channel proteins, which can be divided into seven subfamilies based on amino acid sequence homology: TRPA (Ankyrin), TRPC (Canonical), TRPM (Melastatin), TRPML (Mucolipin), TRPN (NO-mechano-potential, NOMP), TRPP (Polycystin), TRPV (Vanilloid). They are a class of ion channels found in numerous tissues and cell types and are permeable to a wide range of cations such as Ca²⁺, Mg²⁺, Na⁺, K⁺, and others. TRP channels are responsible for various sensory responses including heat, cold, pain, stress, vision and taste and can be activated by a number of stimuli. Their predominantly location on the cell surface, their interaction with numerous physiological signaling pathways, and the unique crystal structure of TRP channels make TRPs attractive drug targets and implicate them in the treatment of a wide range of diseases. Here, we review the history of TRP channel discovery, summarize the structures and functions of the TRP ion channel family, and highlight the current understanding of the role of TRP channels in the pathogenesis of human disease. Most importantly, we describe TRP channel-related drug discovery, therapeutic interventions for diseases and the limitations of targeting TRP channels in potential clinical applications.

Brain computer interfaces (BCIs) can find applications in assistive systems for patients who experience conditions that impede their motor abilities. A BCI uses signals acquired from the brain to control external devices. As physical pain influences cortical signals, the presence of pain can negatively impact the performance of the BCI. In this work, we propose a strategy to mitigate this negative impact. Cortical signals are acquired from test subjects while they performed two mental arithmetic tasks, in the presence and the absence of painful stimuli. The task of the BCI is to reliably classify the two mental arithmetic tasks from the cortical recordings, irrespective of the presence or the absence of pain. We propose to do this classification, hierarchically, in two levels. In the first level, the data is classified into those captured in the presence and the absence of pain. Depending on the results of the classification from the first level, in the second level, the BCI performs the classification of tasks using a classifier trained either in the presence or the absence of pain. A 1-dimensional convolutional neural network (1D-CNN) is used for classification at both levels. It is observed that using this hierarchical strategy, the BCI is able to classify the tasks with an accuracy greater than 90%, irrespective of the presence or the absence of pain. Given that the presence of physical pain has shown previously to reduce the classification accuracy of a BCI to almost chance levels, this mitigation strategy will be a significant step towards enhancing the performance of BCIs when they are used in assistive systems for patients.

Chemoselective O-alkylation of 1-aryl-3-polyfluoroalkylpyrazol-5-oles under basic conditions resulted in a series of 5-alkoxypyrazoles (26 derivatives). They showed an acceptable ADME profile (in silico) and can be considered as drug-like. In experiments in vivo (CD-1 mice), it was found that the obtained compounds do not have toxic properties at a dose of more than 150 mg/kg (for most compounds at a dose of >300 mg/kg, and for lead compounds - >600 mg/kg). 22 Compounds from this series demonstrated from moderate to high analgesic effects (28-104 % at 1 h and 37-109 % at 2 h after administration) in vivo in the hot plate test (SD rats, 15 mg/kg, intraperitoneal (ip)). The lead compound was 4-([1-phenyl-3-(trifluoromethyl)pyrazol-5-yl]oxy)butan-1-ol, which not only increased the latent period in the hot plate test by 103 % at both measurement points but also showed a pronounced analgesic effect under conditions of capsaicin-induced nociception (CD-1 mice, 15 mg/kg, ip). According to molecular modeling, all synthesized compounds can interact with the TRPV1 ion channel. This biological target was confirmed in in vitro experiments on Chinese hamster ovary cells expressing rTRPV1. 5-Alkoxypyrazoles were partial agonists of the TRPV1 ion channel in various degree, and the most active was the same pyrazole as in in vivo tests.

The present research article provides data about the differences in post-traumatic stress symptoms, and defense mechanisms based on the levels of perceived stress (low, average, high), using a large national sample of 1100 Italian individuals, collected during the first wave of the COVID-19 pandemic. Participants completed an online survey through the Google Form platform, where the Ten-Item Perceived Stress Scale, Impact of Event Scale - Revised, and Forty Item Defense Style Questionnaire were included. First, the cut-offs of the perceived stress scale were calculated by determining the 25^th and 75^th percentile scores for the sample of this survey. Then, MANOVA analyses were performed, together with ANOVAs and the Bonferroni Post hoc analyses as a follow-up. The dataset (.xlsx) includes the survey scores, while the tables and figures provide the analysed data, where the differences are shown. This data article may provide useful bases for future research on perceived stress and for suggesting associated factors on which focus clinical intervention and preventive programs.

Providing cultural education to health professionals is essential in improving the quality of care and outcomes for Aboriginal and Torres Strait Islander patients. This study reports the evaluation of a novel training workshop used as an intervention to improve communication with Aboriginal and Torres Strait Islander patients of persistent pain services.

In this single-arm intervention study, health professionals undertook a one-day workshop, which included cultural capability and communication skills training based on a clinical yarning framework. The workshop was delivered across three adult persistent pain clinics in Queensland. At the end of the training, participants completed a retrospective pre/post evaluation questionnaire (5 points Likert scale, 1 = very low to 5 = very high), to rate their perceived importance of communication training, their knowledge, ability and confidence to communicate effectively. Participants also rated their satisfaction with the training and suggested improvements for future trainings.

Fifty-seven health professionals were trained (N = 57/111; 51% participation rate), 51 completed an evaluation questionnaire (n = 51/57; 90% response rate). Significant improvements in the perceived importance of communication training, knowledge, ability and confidence to effectively communicate with Aboriginal and Torres Strait Islander patients were identified (p < 0.001). The greatest increase was in the perceived confidence pre-training mean of 2.96 (SE = 0.11) to the post-training mean of 4.02 (SE = 0.09).

This patient-centred communication training, delivered through a novel model that combines cultural capability and the clinical yarning framework applied to the pain management setting, was highly acceptable and significantly improved participants' perceived competence. This method is transferrable to other health system sectors seeking to train their clinical workforce with culturally sensitive communication skills.