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Itch is a cutaneous sensation that is critical in driving scratching behavior. The long-standing question of whether there are specific neurons for itch modulation inside the brain remains unanswered. Here, we report a subpopulation of itch-specific neurons in the ventrolateral orbital cortex (VLO) that is distinct from the pain-related neurons. Using a Tet-Off cellular labeling system, we showed that local inhibition or activation of these itch-specific neurons in the VLO significantly suppressed or enhanced itch-induced scratching, respectively, whereas the intervention did not significantly affect pain. Conversely, suppression or activation of pain-specific neurons in the VLO significantly affected pain but not itch. Moreover, fiber photometry and immunofluorescence verified that these itch- and pain-specific neurons are distinct in their functional activity and histological location. In addition, the downstream targets of itch- and pain-specific neurons were different. Together, the present study uncovers an important subpopulation of neurons in the VLO that specifically modulates itch processing.
Learn More >Human epidemiological studies suggest that chronic pain can increase mortality risk. We investigated whether this was true in mice, so that underlying mechanisms might be identified. At 10 weeks of age, C57BL/6 mice of both sexes received sham or spared nerve injury (SNI) surgeries producing neuropathic pain. Mice were weighed monthly, tested behaviorally for mechanical and cold sensitivity and guarding behavior every three months post-surgery, and otherwise left undisturbed in their cages until death by natural causes. Evidence of pain over the lifespan displayed a strikingly sex-specific pattern. Male mice displayed largely stable mechanical and cold hypersensitivity and guarding at 6-30 months post-SNI. In contrast, female mice displayed a biphasic temporal pattern of mechanical hypersensitivity and guarding behavior, with a complete resolution of SNI-induced pain behavior at 6-9 months post-SNI followed by the return of pain thereafter. Mouse lifespan was not significantly altered by SNI in either sex, nor was frailty as assessed by cage inspection in the last six months of life. However, in male mice with SNI, we observe a significant correlation between average lifetime mechanical hypersensitivity and lifespan, such that death occurred sooner in male mice exhibiting more evidence of chronic pain. This relationship was not observed in female SNI mice nor in sham-operated mice of either sex. This experiment is the first to investigate pain behavior over an entire lifetime, and suggests that biology of relevance to human chronic pain is being ignored by the very short timespans of most extant preclinical pain research.
Learn More >Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the NRF2 antioxidant transcriptional network is as analgesic as inhibiting TRPA1, in part by reversing the underlying oxidative stress. Using a transcriptome-guided drug discovery strategy, we identify two NRF2 network modulators as potential treatments. One of these candidates, exemestane, is already FDA-approved and may thus be a promising alternative treatment for trigeminal neuropathic pain.
Learn More >The effects of altered neural processing, defined as altering neural networks responsible for perceptions of pain and function, on chronic pain remains unclear.
Learn More >Temporal patterns of stimulation represent a novel dimension for improving the efficacy of spinal cord stimulation to treat chronic neuropathic pain.
Learn More >Patient and stakeholder engagements in research have increasingly gained attention in healthcare and healthcare-related research. A common and rigorous approach to establish research priorities based on input from people and stakeholders is the James Lind Alliance Priority Setting Partnership (JLA-PSP). The aim of this study was to establish research priorities for chronic musculoskeletal (MSK) pain by engaging with people living with chronic MSK pain, relatives to people living with chronic MSK pain, healthcare professionals (HCP), and researchers working with chronic MSK pain.
Learn More >To calibrate or not to calibrate? This question is raised by almost everyone designing an experimental pain study with supra-threshold stimulation. The dilemma is whether to individualize stimulus intensity to the pain threshold / supra-threshold pain level of each participant or whether to provide the noxious stimulus at a fixed intensity so that everyone receives the identical input. Each approach has unique pros and cons which need to be considered to i) accurately design an experiment, ii) enhance statistical inference in the given data and, iii) reduce bias and the influence of confounding factors in the individual study e.g., body composition, differences in energy absorption and previous experience. Individualization requires calibration, a procedure already irritating the pain system but allowing to match the pain level across individuals. It leads to a higher variability of the stimulus intensity, thereby influencing the encoding of "noxiousness" reaching the central nervous system. Results might be less influenced by statistical phenomena such as ceiling/floor effects and the approach does not seem to rise ethical concerns. On the other hand, applying a fixed (standardized) intensity reduces the problem of intensity encoding leading to a large between-subjects variability in pain responses. Fixed stimulation intensities do not require pre-exposure. It can be proposed that one method is not preferable over another, however the choice depends on the study aim and the desired level of external validity. This paper discusses considerations for choosing the best approach for experimental pain studies and provides recommendations for different study designs.
Learn More >Rheumatoid arthritis (RA) severely threatens human health by causing inflammation, swelling, and pain in the joints and resulting in persistent synovitis and irreversible joint disability. In the development of RA, pro-inflammatory M1 macrophages, which express high levels of reactive oxygen species (ROS) and nitric oxide (NO), induce synovial inflammation and bone erosion. Eliminating ROS and NO in the inflamed joints is a potential RA therapeutic approach, which can drive the transition of pro-inflammatory M1 macrophages to the anti-inflammatory M2 phenotype. Taking advantage of the intrinsic ROS- and NO-scavenging capability of DNA molecules, herein, we report the development of folic acid-modified triangular DNA origami nanostructures (FA-tDONs) for targeted RA treatment. FA-tDONs could efficiently scavenge ROS and NO and actively target M1 macrophages, facilitating the M1-to-M2 transition and the recovery of associated cytokines and biomarkers to the normal level. The therapeutic efficacy of FA-tDONs was examined in the RA mouse model. As validated by appearance, histological, and serum examinations, FA-tDONs treatment effectively alleviated synovial infiltration and cartilage damage, attenuating disease progression. This study demonstrated the usage of DNA origami for RA treatment and suggested its potential in other antioxidant therapies.
Learn More >Pain is an alarm mechanism to prevent body damage in response to noxious stimuli. The NGF/TrkA axis plays an essential role as pain mediator and several clinical trials using antibodies against NGF have been yielded promising results, but side effects have precluded their clinical approval. A better understanding of the mechanism of NGF/TrkA-mediated nociception is needed. Here, we find that ARMS/Kidins220, a scaffold protein for Trk receptors, is a modulator of nociception. Male mice, with ARMS/Kidins220 reduction exclusively in TrkA-expressing cells, displayed hyperalgesia to heat, inflammatory and capsaicin stimuli, but not to cold or mechanical stimuli. Simultaneous deletion of BDNF reversed the effects of ARMS/Kidins220 knock-down alone. Mechanistically, ARMS/Kidins220 levels are reduced in vitro and in vivo in response to capsaicin through calpains, and this reduction leads to enhanced regulated BDNF secretion from DRGs. Altogether, these data indicate that ARMS/Kidins220 protein levels have a role as a pain modulator in the NGF/TrkA axis regulating BDNF secretion.
Learn More >The pathophysiology of primary Burning mouth syndrome (BMS) remains controversial. Targeted analyses or "omics" approach of saliva provide diagnostic or pathophysiological biomarkers. This pilot study's primary objective was to explore the pathophysiology of BMS through a comparative analysis of the salivary metabolome among 26 BMS female cases and 25 age and sex matched controls. Secondary objectives included comparative analyses of inflammatory cytokines, neuro-inflammation markers and steroid hormones among cases and controls, and among BMS patients according to their clinical characteristics. Salivary metabolome, neuro-inflammatory markers, cytokines and steroids were respectively analysed by liquid chromatography coupled to mass sperctrometry, ELISA and protease activity assay, and multiparametric Luminex method. Among the 166 detected metabolites, univariate analysis did not find any discriminant metabolite between groups. Supervised multivariate analysis divided patients into two groups with an accuracy of 60% but did not allow significant discrimination (permutation test, p=0.35). Among the metabolites contributing to the model, three belonging to the tyrosine pathway (L-dopa, L-tyrosine and tyramine) were involved in the discrimination between cases and controls, and among BMS patients according to their levels of pain. Among the detectable molecules, levels of cytokines, steroid hormones and neuro-inflammatory markers did not differ between cases and controls and were not associated with characteristics of BMS patients. These results do not support the involvement of steroid hormones, inflammatory cytokines or inflammatory neurogenic mediators in the pathophysiology of pain in BMS, whereas the observed shift in tyrosine metabolism may indicate an adaptative response to chronic pain or an impaired dopaminergic transmission.
Learn More >Pain is a common problem among children, particularly those with pediatric chronic diseases. Multi-faceted assessment of pain can improve communication about pain and help clinicians characterize, differentiate, and treat a patient's unique experience of pain. Pain quality is an important domain of pain, describing the subjective sensory experiences associated with pain as well as the affective experiences of pain. The aim of the current study was to quantitatively evaluate the measurement properties of the 59 PROMIS pediatric pain quality candidate items developed as part of the NIH's PROMIS initiative with input from children and adolescents with chronic pain. Participants included N = 448 pediatric patients between 8 and 18 years of age with chronic health conditions with a prominent component of chronic, or recurrent pain, including juvenile fibromyalgia (JFM), juvenile idiopathic arthritis (JIA), and sickle cell disease (SCD). A confirmatory factor analysis revealed a unidimensional model fit the data best, with 56 of the 59 items demonstrating good psychometric properties for inclusion in the final measure. Additionally, a consensus-building method was used to establish two versions of a short form measure – one with 8 items focused primarily on the sensory pain qualities and one with 8 items focused on affective pain qualities. The final measure shows good reliability and validity and is recommended for use in research and clinical care with pediatric populations.
Learn More >The potential consequences of the number of chronic pain sites (referred to multisite chronic pain) on the risk of cardiovascular diseases (CVDs) remain unclear. We attempted to investigate the causality of multisite chronic pain with CVDs and its possible causal mediators. Using summary genome-wide association statistics, two-sample Mendelian randomization (MR) analyses were undertaken to assess whether multisite chronic pain has a causal effect on the three CVDs including coronary artery disease, atrial fibrillation, and stroke. We then conducted MR mediation analyses to establish whether body mass index (BMI), smoking, and depression causally mediate any association. Genetic liability to multisite chronic pain was associated with increased risk of coronary artery disease (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.19 to 1.95 per one increase in the number of pain locations), but not with atrial fibrillation or stroke. We also found positive causal effects of multisite chronic pain on BMI, smoking, and depression, and causal effects of BMI, smoking, and depression on coronary artery disease. In multivariable MR analyses, the excess risk of coronary artery disease was attenuated after adjusting for BMI (OR 1.43, 95% CI 1.05 to 1.93), smoking (OR 1.49, 95% CI 1.11 to 2.00), depression (OR 1.44, 95% CI 1.03 to 2.01), and three risk factors combined (OR 1.34, 95% CI 0.88 to 2.05). Our findings demonstrated that multisite chronic pain led to higher risk of coronary artery disease, which is partly mediated through BMI, smoking, and depression.
Learn More >The rostral anterior cingulate cortex (rACC) has been found to be an important brain region in mediating visceral hypersensitivity. However, the underlying mechanisms remain unclear. This study aimed to explore the role of astrocytes in the maintenance of visceral hypersensitivity induced by chronic water avoidance stress (WAS) as well as the potential signaling pathway that activates astrocytes in the rACC. We found that ACC-reactive astrogliosis resulted in the overexpression of c-fos, TSP-1, and BDNF in stress-related visceral hypersensitivity rats. Visceral hypersensitivity was reversed by pharmacological inhibition of astrocytic activation after WAS, as were the overexpression of c-fos, TSP-1 and BDNF. Activation of the astrocytic Gi-pathway increased the visceral sensitivity and expression of c-fos, TSP-1, and BDNF. Visceral hypersensitivity was also ameliorated by the pharmacological inhibition of ERK and STAT1 phosphorylation after WAS. Furthermore, inhibition of the ERK-STAT1 cascade reduced astrocytic activation. These findings suggest that astrocytic ERK/STAT1 signaling in the rACC contributes to the maintenance of stress-related visceral hypersensitivity. PERSPECTIVE: Visceral hypersensitivity is a key factor in the pathophysiology of irritable bowel syndrome. This study highlights the important role of astrocytic ERK/STAT1 signaling in activating astrocytes in the rostral anterior cingulate cortex, which contributes to visceral hypersensitivity.
Learn More >Adolescent alcohol use can permanently alter brain function and lead to poor health outcomes in adulthood. Emerging evidence suggests that alcohol use can predispose individuals to pain disorders or exacerbate existing pain conditions, but the underlying neural mechanisms are currently unknown. Here we report that mice exposed to adolescent intermittent access to ethanol (AIE) exhibit increased pain sensitivity and depressive-like behaviors that persist for several weeks after alcohol cessation and are accompanied by elevated CD68 expression in microglia and reduced numbers of serotonin (5-HT)-expressing neurons in the dorsal raphe nucleus (DRN). 5-HT expression was also reduced in the thalamus, anterior cingulate cortex (ACC) and amygdala as well as the lumbar dorsal horn of the spinal cord. We then found that chronic minocycline administration after AIE alleviated hyperalgesia and social deficits, while chemogenetic activation of microglia in the DRN of ethanol-naïve mice reproduced the effects of AIE on pain and social behavior. Chemogenetic activation of microglia also reduced tryptophan hydroxylase 2 (Tph2) expression and was negatively correlated with the number of 5-HT-immunoreactive cells in the DRN. Taken together, these results indicate that microglial activation in the DRN may be a primary driver of pain, negative affect, and 5-HT depletion after AIE.
Learn More >The perception of noxious environmental stimuli by nociceptive sensory neurons is an essential mechanism for the prevention of tissue damage. Etv4 is a transcriptional factor expressed in most nociceptors in dorsal root ganglia (DRG) during the embryonic development. However, its physiological role remains unclear. Here, we show that Etv4 ablation results in defects in the development of the peripheral peptidergic projections in vivo and deficits in axonal elongation and growth cone morphology in cultured sensory neurons in response to NGF. From a mechanistic point of view, our findings reveal that NGF regulates Etv4-dependent gene expression of molecules involved in extracellular matrix (ECM) remodeling. Etv4-null mice were less sensitive to noxious heat stimuli and chemical pain and this behavioral phenotype correlates with a significant reduction in the expression of the pain-transducing ion channel TRPV1 in mutant mice. Together, our data demonstrate that Etv4 is required for the correct innervation and function of peptidergic sensory neurons, regulating a transcriptional program that involves molecules associated to axonal growth and pain transduction.
Learn More >Peripheral nerves and Schwann cells have to sustain constant mechanical constraints, caused by developmental growth as well as stretches associated with movements of the limbs and mechanical compressions from daily activities. In Schwann cells, signaling molecules sensitive to stiffness or stretch of the extracellular matrix, such as YAP/TAZ, have been shown to be critical for Schwann cell development and peripheral nerve regeneration. YAP/TAZ have also been suggested to contribute to tumorigenesis, neuropathic pain, and inherited disorders. Yet, the role of mechanosensitive ion channels in myelinating Schwann cells is vastly unexplored. Here we comprehensively assessed the expression of mechanosensitive ion channels in Schwann cells and identified that PIEZO1 and PIEZO2 are among the most abundant mechanosensitive ion channels expressed by Schwann cells. Using classic genetic ablation studies, we show that PIEZO1 is a transient inhibitor of radial and longitudinal myelination in Schwann cells. Contrastingly, we show that PIEZO2 may be required for myelin formation, as the absence of PIEZO2 in Schwann cells delays myelin formation. We found an epistatic relationship between PIEZO1 and PIEZO2, at both the morphological and molecular levels. Finally, we show that PIEZO1 channels affect the regulation of YAP/TAZ activation in Schwann cells. Overall, we present here the first demonstration that PIEZO1 and PIEZO2 contribute to mechanosensation in Schwann cells as well myelin development in the peripheral nervous system.
Learn More >Pain is a common outcome after lower extremity fracture requiring surgical fixation (LEF). Although psychosocial characteristics have meaningful associations with adverse outcomes, no studies have evaluated how psychosocial characteristics throughout recovery are associated with pain outcomes. The primary purpose of this study was to determine whether psychosocial characteristics are early risk factors for pain outcomes in patients following LEF who have no history of chronic pain.
Learn More >Despite well-documented pain disparities among adults from non-White and Hispanic groups, less is known about pain disparities in non-White and Hispanic pediatric populations.
Learn More >The public health crisis of chronic pain has only increased in recognition since the Institute of Medicine's (IOM) Relieving Pain in America (2011) called for a cultural transformation in the way pain is viewed, treated, and put forward specific recommendations for action. The National Pain Strategy (NPS) provides a roadmap for putting these recommendations into practice. We implemented a program that placed nurses and behavioral specialists at the head of an interdisciplinary team utilizing best practices. In this program, nurses enacted the NPS recommendations to advance care for patients with persistent pain on long-term opioid treatment. This program promoted professional growth in nurses along with fostering success for patients. Compared with patients receiving usual care, patients in the program achieved greater reductions in pain severity, pain-related disability, and pain-related functional interference and reported greater satisfaction with pain-related care and primary care services. This article will detail the NPS-aligned practice approaches these nurses and their teams used, describe the training for the nurses, and speak to opportunities to enhance the nurse's capacity for this role in hopes of providing a model for the future implementation of an NPS-based approach by nurses.
Learn More >This study investigated clinician experience of patient use of metaphors in chronic pain communication.
Learn More >Assessment of the severity of pruritus is difficult in cats, because they manifest discomfort by increased licking, increased scratching or both.
Learn More >This study aims to evaluate the effectiveness of neural mobilization (NM) in the management of sensory dysfunction and nerve degeneration related to experimental painful diabetic neuropathy (PDN).
Learn More >This systematic review, meta-analysis and meta-regression investigated the effects of individualized interventions, based on exercise alone or combined with psychological treatment, on pain intensity and disability in patients with chronic non-specific low-back-pain. Databases were searched up to 31 January 2022 and to retrieve respective randomized controlled trials of individualized/personalized/stratified exercise interventions with or without psychological treatment compared to any control. Fifty-eight studies (n = 10084) were included. At short-term follow-up (12 weeks), low-certainty evidence for pain intensity (SMD -0.28 [95%CI -0.42 to -0.14]) and very low-certainty evidence for disability (-0.17 [-0.31 to -0.02]) indicates effects of individualized versus active exercises, and very low-certainty evidence for pain intensity (-0.40; [-0.58 to -0.22])), but not (low-certainty evidence) for disability (-0.18; [-0.22 to 0.01]) compared to passive controls. At long-term follow-up (1 year), moderate-certainty evidence for pain intensity (-0.14 [-0.22 to -0.07]) and disability (-0.20 [-0.30 to -0.10]) indicates effects versus passive controls. Sensitivity analyses indicates that the effects on pain, but not on disability (always short-term and versus active treatments) were robust. Pain reduction caused by individualized exercise treatments in combination with psychological interventions (in particular behavioral-cognitive therapies) (-0.28 [-0.42 to -0.14], low certainty) is of clinical importance. Certainty of evidence was downgraded mainly due to evidence of risk of bias, publication bias and inconsistency that could not be explained. Individualized exercise can treat pain and disability in chronic non-specific low-back-pain. The effects at short term are of clinical importance (relative differences versus active 38% and versus passive interventions 77%), especially in regard to the little extra effort to individualize exercise. Sub-group analysis suggests a combination of individualized exercise (especially motor-control based treatments) with behavioral therapy interventions to booster effects. PROSPERO registration: CRD42021247331.
Learn More >Chronic pain is highly prevalent in older adults and is associated with poor functional outcomes. Further, opioid analgesics are commonly utilized for the treatment of pain in older adults despite well-described adverse effects. Importantly, both chronic pain and opioid analgesics have been linked with impairments in cognitive function, though data are limited. In this manuscript we summarize the evidence and critical knowledge gaps regarding the relationships between pain, opioid analgesics, and cognition in older adults. Further, we provide a conceptual framework to guide future research in the development, implementation, and evaluation of strategies to optimize analgesic outcomes in older adults while minimizing deleterious effects on cognition.
Learn More >Physical activity can improve function in patients with chronic pain, however, adherence is low, in part due to inconsistent activity patterns. Smart wearable activity trackers, such as Fitbits, may help promote activity. In our program for chronic pain, we examined: (1) Fitbit activity patterns (i.e., step count, moderate-to-vigorous physical activity (MVPA), sedentary behavior), and (2) whether achievement of weekly, individualized Fitbit step goals was associated with functional outcomes. We conducted a secondary analysis of Fitbit data from our 10-week mind-body activity program for chronic pain (GetActive-Fitbit arm, N = 41). Participants self-reported emotional and physical function and completed performance-based and accelerometer-based assessments. From week 1 to week 10, 30% of participants increased >800 steps; 32.5% increased MVPA; and 30% decreased sedentary behavior. Only step count significantly changed across time with mean steps peaking at week 8 (M = +1897.60, SE = 467.67). Fitbit step goal achievement was associated with improvements in anxiety (ß = -.35, CI [-2.80, -0.43]), self-reported physical function (ß = -.34, CI [-5.17, 8.05]), and performance-based physical function (ß = .29, CI [-71.93, 28.38]), but not accelerometer-based physical function or depression. Adhering to individualized Fitbit step goals in the context of a mind-body activity program may improve anxiety and self-reported and performance-based physical function. Perspective: We examine Fitbit activity patterns and the association between quota-based pacing and functional outcomes within a mind-body activity program for adults with chronic pain. Complementing quota-based pacing and coping skills with Fitbits may be a useful approach to promote activity engagement and behavior change among chronic pain populations.
Learn More >While chemokines were originally described for their ability to induce cell migration, many studies show how these proteins also take part in many other cell functions, acting as adaptable messengers in the communication between a diversity of cell types. In the nervous system, chemokines participate both in physiological and pathological processes, and while their expression is often described on glial and immune cells, growing evidence describes the expression of chemokines and their receptors in neurons, highlighting their potential in auto- and paracrine signalling. In this study we analysed the role of nociception in the neuronal chemokinome, and in turn their role in axonal growth. We found that stimulating TRPV1 nociceptors induces a transient increase in CCL21. Interestingly we also found that CCL21 enhances neurite growth of large diameter proprioceptors . Consistent with this, we show that proprioceptors express the CCL21 receptor CCR7, and a CCR7 neutralizing antibody dose-dependently attenuates CCL21-induced neurite outgrowth. Mechanistically, we found that CCL21 binds locally to its receptor CCR7 at the growth cone, activating the downstream MEK-ERK pathway, that in turn activates N-WASP, triggering actin filament ramification in the growth cone, resulting in increased axonal growth.
Learn More >Histone lysine crotonylation (KCR), a novel epigenetic modification, is important in regulating a broad spectrum of biological processes and various diseases. However, whether KCR is involved in neuropathic pain remains to be elucidated. We found KCR occurs in macrophages, sensory neurons, and satellite glial cells of trigeminal ganglia (TG), neurons, astrocytes, and microglia of the medulla oblongata. KCR in TG was detected mainly in small and medium sensory neurons, to a lesser extent in large neurons. Peripheral nerve injury elevated KCR levels in macrophages in the trigeminal and dorsal root ganglia and microglia in the medulla oblongata but reduced KCR levels in sensory neurons. Inhibition of histone crotonyltransferases (p300) by intra-TG or intrathecal administration of C646 significantly alleviated partial infraorbital nerve transection (pIONT)- or spinal nerve ligation (SNL)-induced mechanical allodynia and thermal hyperalgesia. Intra-TG or intrathecal administration of Crotonyl coenzyme A trilithium salt to upregulate KCR dose-dependently induced mechanical allodynia and thermal hyperalgesia in mice. Mechanismly, inhibition of p300 alleviated pIONT-induced macrophage activation and reduced the expression of pain-related inflammatory cytokines , and chemokines and . Correspondingly, exogenous crotonyl-CoA induced macrophage activation and the expression of , , , and in TG, which C646 can repress. These findings suggest that might be functionally involved in neuropathic pain and neuroinflammation regulation.
Learn More >Chronic musculoskeletal pain (CMP) is the most common type of chronic pain, defined as persistent or recurrent pain condition deriving from musculoskeletal structures such as muscles, joints or bones that lasts for more than 3 months. CMP is multifactorial and severely affects people's quality of life. CMP may be influenced by a number of factors, including contextual factors, the presence of comorbidities, arthritis coping efficacy and access to CMP care. To deepen the comprehensive understanding of CMP, this narrative review provides the latest literature on disease classification, clinical diagnosis, treatment and basic research. In terms of the classification of the disease, here we introduce the 11th edition of the International Classification of Diseases (IDC-11), in which CMP is divided into chronic primary musculoskeletal pain and chronic secondary musculoskeletal pain. In the clinical diagnosis section, the progress of central sensitization in the diagnosis of CMP will also be summarized. In addition, we summarize some recent advances in clinical treatment and basic research.
Learn More >Although activation of microglial cells is critical in developing brain disorders, their role in anxiety-like behaviors in pain is still vague. This study indicates that alteration of microglia's neuronal spine engulfment capacity in ventral zona incerta (ZI ) leads to significant pain and anxiety-like behaviors in mice 1-day post-injection of Complete Freud's Adjuvant (CFA1D). Performing whole-cell patch-clamp recordings in GABAergic neurons in the ZI (ZI ) in brain slices, we observed decreased activity in ZIv and reduced frequency of the miniature excitatory postsynaptic currents (mEPSCs) in ZI of CFA1D mice compared with the saline1D mice. Besides, chemogenetic activation of ZI significantly relieved pain and anxiety-like behaviors in CFA1D mice. Conversely, in naïve mice, chemogenetic inhibition of ZI induced pain and anxiety-like behaviors. Interestingly, we found changes in the density and morphology of ZI and increased microglial engulfment of spines in ZI of CFA1D mice. Furthermore, pain sensitization and anxiety-like behaviors were reversed when the ZI of CFA1D-treated mice were chemically inhibited by intra-ZI minocycline injection, accompanied by the recovery of decreased ZI excitability. Conclusively, our results provide novel insights that dysregulation of microglial engulfment capacity encodes maladaptation of ZI , thus promoting the development of anxiety-like behaviors in acute pain.
Learn More >Screening serum biomarkers for acute and subacute pain is important for precise pain management. This study aimed to examine serum levels of angiogenic factors in patients with acute and subacute pain as potential biomarkers. Serum samples were collected from 12 healthy controls, 20 patients with postherpetic neuralgia (PHN), 4 with low back pain (LBP), and 1 with trigeminal neuralgia (TN). Pain intensity in these patients was evaluated using the visual analog scale (VAS). The serum concentrations of 11 angiogenic biomarkers were examined by Milliplex Map Human Angiogenesis Magnetic Bead Panel 2. The pain assessment from VAS showed that all patients showed moderate and severe pain. Among 11 angiogenic factors, osteopontin (OPN), thrombospondin-2 (TSP-2), soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1), soluble urokinase-type plasminogen activator receptor (suPAR), and soluble epidermal growth factor receptors (sErbB2) were up-regulated and soluble interleukin-6 receptor α (sIL-6Rα) were down-regulated in patients with pain compared to the healthy participants (all -values were < 0.005). Moreover, a linear regression model showed that the serum OPN concentration was correlated with pain intensity in patients with PHN ( = 0.03). There was no significant difference between the serum concentration of soluble epidermal growth factor receptors, sErbB3, soluble AXL, tenascin, and soluble neuropilin-1 in patients with acute and subacute pain and that of healthy controls. The results of this study provided new valuable insights into our understanding of angiogenic factors that may contribute to as mechanistic biomarkers of pain, and reveal the pathophysiological mechanism of pain. www.chictr.org.cn, identifier ChiCTR2200061775.
Learn More >Accurate specification of the drugs' solubility is known as an important activity to appropriately manage the supercritical impregnation process. Over the last decades, the application of supercritical fluids (SCFs), mainly CO, has found great interest as a promising solution to dominate the limitations of traditional methods including high toxicity, difficulty of control, high expense and low stability. Oxaprozin is an efficient off-patent nonsteroidal anti-inflammatory drug (NSAID), which is being extensively used for the pain management of patients suffering from chronic musculoskeletal disorders such as rheumatoid arthritis. In this paper, the prominent purpose of the authors is to predict and consequently optimize the solubility of Oxaprozin inside the COSCF. To do this, the authors employed two basic models and improved them with the Adaboost ensemble method. The base models include Gaussian process regression (GPR) and decision tree (DT). We optimized and evaluated the hyper-parameters of them using standard metrics. Boosted DT has an MAE error rate, an R2-score, and an MAPE of 6.806E-05, 0.980, and 4.511E-01, respectively. Also, boosted GPR has an R2-score of 0.998 and its MAPE error is 3.929E-02, and with MAE it has an error rate of 5.024E-06. So, boosted GPR was chosen as the best model, and the best values were: (T = 3.38E + 02, P = 4.0E + 02, Solubility = 0.001241).
Learn More >These days, many efforts have been made to increase and develop the solubility and bioavailability of novel therapeutic medicines. One of the most believable approaches is the operation of supercritical carbon dioxide fluid (SC-CO). This operation has been used as a unique method in pharmacology due to the brilliant positive points such as colorless nature, cost-effectives, and environmentally friendly. This research project is aimed to mathematically calculate the solubility of Oxaprozin in SC-CO through artificial intelligence. Oxaprozin is a nonsteroidal anti-inflammatory drug which is useful in arthritis disease to improve swelling and pain. Oxaprozin is a type of BCS class II (Biopharmaceutical Classification) drug with low solubility and bioavailability. Here in order to optimize and improve the solubility of Oxaprozin, three ensemble decision tree-based models including random forest (RF), Extremely random trees (ET), and gradient boosting (GB) are considered. 32 data vectors are used for this modeling, moreover, temperature and pressure as inputs, and drug solubility as output. Using the MSE metric, ET, RF, and GB illustrated error rates of 6.29E-09, 9.71E-09, and 3.78E-11. Then, using the R-squared metric, they demonstrated results including 0.999, 0.984, and 0.999, respectively. GB is selected as the best fitted model with the optimal values including 33.15 (K) for the temperature, 380.4 (bar) for the pressure and 0.001242 (mole fraction) as optimized value for the solubility.
Learn More >There have been a few studies regarding the pre-attack symptoms (PAS) and pre-episode symptoms (PES) of cluster headache (CH), but none have been conducted in the Chinese population. The purpose of this study was to identify the prevalence and features of PAS and PES in Chinese patients, as well as to investigate their relationships with pertinent factors.
Learn More >Arginine vasopressin (AVP) is a hypothalamic neurosecretory hormone well known as an antidiuretic, and recently reported to be involved in pain modulation. The expression kinetics of AVP and its potential involvement in the descending pain modulation system (DPMS) in neuropathic pain (NP) remains unclear. We investigated AVP expression and its effects on mechanical and thermal nociceptive thresholds using a unilateral spinal nerve ligation (SNL) model. All rats with SNL developed NP. Intensities of enhanced green fluorescent protein (eGFP) in the supraoptic and paraventricular nuclei, median eminence, and posterior pituitary were significantly increased at 7 and 14 days post-SNL in AVP-eGFP rats. In situ hybridisation histochemistry revealed significantly increased AVP mRNA expression at 14 days post-SNL compared with the sham control group. The chemogenetic activation of AVP neurones significantly attenuated mechanical and thermal hyperalgesia with elevated plasma AVP concentration. These analgesic effects were suppressed by pre-administration with V1a receptor antagonist. AVP neurones increased the neuronal activity of serotonergic dorsal raphe, noradrenergic locus coeruleus, and inhibitory interneurones in the spinal dorsal horn. These results suggest that the hypothalamo-neurohypophysial system of AVP is upregulated in NP and activated endogenous AVP exerts analgesic effects via the V1a receptors. AVP neurones may activate the DPMS.
Learn More >Temporal summation of second pain (TSSP) has been suggested as a psychophysical index for central sensitization, one of the critical mechanisms in the chronification of pain. However, there is no gold standard for protocols to measure TSSP. The purpose was to establish the stimulus intensity for measuring TSSP. Female patients with chronic myofascial temporomandibular disorders pain (n = 16) and healthy female volunteers with no pain (n = 15) participated. Pain thresholds (PT °C) were measured, and repetitive heat stimuli at three stimulus intensities (PT °C, PT + 1 °C, PT + 2 °C) were applied. TSSP parameters were quantified as TSSP magnitude (TSm) and TSSP frequency (TSf). In healthy female volunteers, pain ratings significantly decreased at PT °C (p < 0.050), besides TSm and TSf at PT + 2 °C were significantly higher than those at PT °C (p < 0.025). In chronic pain patients, pain ratings significantly increased at PT + 1 °C and PT + 2 °C (p < 0.050). At PT + 2 °C, TSm and TSf in chronic pain patients were significantly higher than those in healthy volunteers (p < 0.050). It could be helpful to measure TSSP with the stimulus intensity adjusted individually to the patient's pain thresholds + 2 °C for assessing central sensitization.
Learn More >Headache is the most frequent symptom of cerebral venous thrombosis (CVT) but there is limited information about the frequency and phenotype of headache, weeks to months after cerebral venous thrombosis (post-cerebral venous thrombosis headache, post cerebral venous thrombosis headache).
Learn More >This systematic review and meta-analysis investigated the effect of phonophoresis when various gel types were used. Medline (using PubMed), EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were used to search for relevant studies from the date of their inception to June 28, 2021. We included studies that were randomized controlled trials (RCTs), included patients with a diagnosis of knee osteoarthritis, included treatment with either phonophoresis or therapeutic ultrasound with placebo gel, and reported clinical and functional outcomes. Continuous variables are expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Statistical analysis was performed using RevMan 5.3 software. We initially retrieved 2176 studies and finally analyzed nine RCTs including 423 patients. The intervention group significantly outperformed the control group in pain scores with NSAID gel (SMD = - 0.53, 95% CI [- 1.02, - 0.05], I = 73%) and in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) function score with corticosteroid gel (SMD = - 0.96, 95% CI [- 1.47, - 0.44], I = 20%). Phonophoresis alleviated pain and improved functional performance. Because of some limitations of this study, additional high-quality, large-scale RCTs are required to confirm the benefits.
Learn More >Safe and non-invasive on-demand relief is a crucial and effective treatment for postoperative pain because it considers variable timing and intensity of anesthetics. Ultrasound modulation is a promising technique for this treatment because it allows convenient timed and non-invasive controlled drug release. Here, we created an ultrasound-triggered lidocaine (Lido) release platform using an amino acid hydrogel functioning as three-dimensional (3D) scaffold material (Lido-PPIX@ER hydrogel). It allows control of the timing, intensity and duration of lidocaine (Lido) to relieve postoperative pain. The hydrogel releases Lido due to the elevated reactive oxygen species (ROS) levels generated by PPIX under ultrasound triggering. The Lido-PPIX@ER hydrogel under individualized ultrasound triggering released lidocaine and provided effective analgesia for more than 72 h. The withdrawal threshold was higher than that in the control group at all time points measured. The hydrogel showed repeatable and adjustable ultrasound-triggered nerve blocks , the duration of which depended on the extent and intensity of insonation. On histopathology, no systemic effect or tissue reaction was observed in the ultrasound-triggered Lido-PPIX@ER hydrogel-treated group. The Lido-PPIX@ER hydrogel with individualized (highly variable) ultrasound triggering is a convenient and effective method that offers timed and spatiotemporally controlled Lido release to manage postoperative pain. This article presents the delivery system for a new effective strategy to reduce pain, remotely control pain, and offer timed and spatiotemporally controlled release of Lido to manage postoperative pain.
Learn More >Chronic pain has been associated with changes in pain-related brain structure and function, including advanced brain aging. Non-pharmacological pain management is central to effective pain management. However, it is currently unknown how use of non-pharmacological pain management is associated with pain-related brain changes. The objective of the current study was to examine the association between brain-predicted age difference and use of non-pharmacological pain management (NPM) in a sample of middle-aged and older adults with and without chronic knee pain across two time points. One-hundred and 12 adults (mean age = 57.9 ± 8.2 years) completed sociodemographic measures, clinical pain measures, structural T1-weighted brain magnetic resonance imaging, and self-reported non-pharmacological pain management. Using a validated approach, we estimated a brain-predicted age difference (brain-PAD) biomarker, calculated as brain-predicted age minus chronological age, and the change in brain-PAD across 2 years. Repeated measures analysis of covariance was conducted to determine associations of non-pharmacological pain management and brain-PAD, adjusting for age, sex, study site, and clinical pain. There was a significant timepain/NPM interaction effect in brain-PAD ( < 0.05). Tests of simple main effects indicated that those persistently using NPM had a "younger" brain-PAD over time, suggesting a potential protective factor in persistent NPM use. Future studies are warranted to determine the influence of NPM in brain aging and pain-related neurological changes.
Learn More >Neuroinflammation plays a vital role in the development of neuropathic pain and is mediated mainly by microglia. Suppressing microglial M1-polarization attenuates neuropathic pain. Recently, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a key mediator of inflammation and shows potential in modulating microglial polarization. In this study, we evaluated whether cGAS-STING is a potential therapeutic target. Spared nerve injury (SNI) surgery was conducted in adult male rats to establish a neuropathic pain model. We showed that SNI promoted microglial M1-polarization and induced cGAS-STING pathway activation in the spinal cord. Double-label immunofluorescence assays showed that cGAS-STING activation mainly occurred in neurons and microglia but not astrocytes. We further conducted in vitro experiments using BV-2 microglial cells. The results showed that LPS-induced microglial M1-polarization was accompanied by cGAS-STING pathway activation, but cGAS-STING inhibition by antagonists suppressed LPS-induced microglial M1-polarization. In vivo, we also showed that a cGAS antagonist and a STING antagonist suppressed the microglial M1-polarization and ameliorated the mechanical allodynia induced by SNI. These findings suggested that the cGAS-STING pathway might be a potential therapeutic target for treating neuropathic pain. However, further research is warranted to verify our findings in female rodents.
Learn More >General fatigue, sleep-related fatigue, and cognitive fatigue are prevalent and disruptive in adults with chronic musculoskeletal (MSK) pain, but little is known about these fatigue subtypes in pediatric musculoskeletal pain.
Learn More >In the central nervous system, post-inhibitory rebound firing (RF) may mediate overactivity of neurons under pathophysiological condition. RF is also observed in dorsal root ganglion (IRA) neurons. However, the functional significance of RF in primary sensory neurons has remained unknown. After peripheral sensory nerve/neuron injury, DRG neurons exhibit hyperexcitability. Therefore, RF may play a role in neuropathic pain.
Learn More >Although patients' complaints suggest polyneuropathy (PNP) and neuropathic pain, routine investigations do not always support the diagnosis. Assessing two-point-pain discrimination thresholds (2ptDT) and quantify body representation disturbances might be useful to close this diagnostic gap.
Learn More >We aimed to quantify patient preferences for efficacy, safety and convenience features of atopic dermatitis (AD) treatments.
Learn More >Genicular nerve radiofrequency ablation (GNRFA) is a minimally invasive intervention for patients with chronic knee pain (CKP) not responding to conservative treatments. Few investigations have compared treatment outcomes of cooled-RFA (c-RFA) and thermal-RFA (t-RFA), two common approaches of GNRFA. This study aims to investigate and compare outcomes, including probability of treatment success, between c-RFA and t-RFA in patients with CKP.
Learn More >To describe the prevalence and characteristics of spinal cord injury (SCI) related pain during initial inpatient rehabilitation and to investigate relationships with demographic and lesion characteristics.
Learn More >Music is increasingly being recognised as an adjuvant treatment for pain management. Music can help to decrease the experience of both chronic and experimental pain. Cognitive agency has been identified as a specific mechanism that may mediate the analgesic benefits of music engagement however, it is unclear if this specific mechanism translates to acute pain. Previous attempts to understand the cognitive mechanisms that underpin music analgesia have been predominantly lab-based, limiting the extent to which observed effects may apply to participants' everyday lives. Addressing these gaps, in naturalistic settings, the present study examined the degree to which cognitive agency (i.e., perceived choice in music), music features (i.e., complexity), and individual levels of musical sophistication were related to perceived pain. In an online global experiment, using a randomised between groups experimental design with two levels for choice (no choice and perceived choice) and two levels for music (high and low complexity), a sample of 286 adults experiencing acute pain reported their pain intensity and pain unpleasantness pre- and post-music listening. A bespoke piece of music was co-created with a commercial artist to enable the manipulation of music complexity while controlling for familiarity, while facilitating an authentic music listening experience. Overall, findings demonstrated that increased perceived control over music is associated with analgesic benefits, and that perceived choice is more important than music complexity. Highlighting the importance of listener engagement, people who reported higher levels of active engagement experienced greater decreases of pain intensity in the perceived choice condition, than those who reported lower levels of active engagement. These findings have implications for both research and practice, emphasising the importance of facilitating freedom of choice, and sustained engagement with music throughout music listening interventions.
Learn More >Symptoms of people who have systemic sclerosis (SSc) are heterogeneous and difficult to address clinically. Because diverse symptoms often co-occur and may share common underlying mechanisms, identifying symptoms that cluster together may better target treatment approaches. We sought to identify and characterize patient subgroups based on symptom experience.
Learn More >To investigate the auditory features of patients with vestibular migraine (VM) and to analyze the possible relevant factors of hearing loss.
Learn More >This narrative review highlights the interventional musculoskeletal techniques that have evolved in recent years.
Learn More >Psoriatic arthritis (PsA) is a chronic inflammatory disease that reduces quality of life. This study assessed the effects of risankizumab (RZB) on the achievement of minimal clinically important differences (MCID) in patient-reported outcomes (PROs).
Learn More >Migraine is deemed a neurovascular disorder and there is growing evidence on the increased risk of cardiovascular disease, especially ischemic stroke, in patients with migraine. However the risk of peripheral artery disease (PAD) and stroke in migraineurs and the association between migraineurs with or without aura is still under debate. Our study aimed to identify the risk of PAD and stroke in migraineurs with or without aura. This was a population-based cohort study utilizing Taiwan Longitudinal Health Insurance Database (LHID2010). Patients with coding of migraine from 2002 to 2011 were enrolled and those with established cardiovascular disease defined as myocardial infarction, stroke, PAD, venous thromboembolism, atrial fibrillation and heart failure diagnosis before the index date were excluded. Participants were categorized into migraine group, migraine without aura group, and migraine with aura group respectively. The subjects in the three groups were propensity score-matched randomly to their counterparts without migraine. The study outcome was PAD and stroke. The Cox proportional hazard model was used to estimate the hazard ratios with 95% confidence interval (CI) for the association between migraine and the incident events of disease, after controlling for related variables. The migraine, migraine without aura, and migraine with aura group included 5,173 patients, 942 patients and 479 patients respectively after propensity score-matching. The migraine group had an increased risk of PAD [adjusted hazard ratio (aHR): 1.93; 95% confidence interval (CI): 1.45-2.57; p < 0.001] and stroke (aHR: 1.55; 95% CI: 1.35-1.77; p < 0.001) compared to their non-migraine controls. Both the groups of migraine without aura and with aura had an increased risk of stroke (aHR: 1.49, 95% CI: 1.11-2.00; p = 0.008; aHR: 1.63, 95% CI: 1.10-2.43; p = 0.016). With regards to the outcome of PAD, the group of migraine with aura had a trend of an increased risk but did not reach statistical significance (aHR: 1.95, 95% CI: 0.86-4.40; p = 0.108). Migraineurs without established cardiovascular disease had a significantly increased risk of PAD and stroke, and the risk of stroke persists in migraineurs with or without aura, with an increased trend of PAD in migraineurs with aura. Our study result should remind clinical physicians of the risk of PAD in the future among migraineurs even without established cardiovascular disease currently, and screening for PAD and stroke may be needed in caring patients with migraine.
Learn More >δ-Opioid receptors (DORs, encoded by the Oprd1 gene) are expressed throughout the peripheral and central nervous system, and DOR stimulation reduces nociception. Previous studies suggest DORs promote the development of analgesic tolerance of μ-opioid receptor (MOR) agonists. It is uncertain whether DORs expressed in primary sensory neurons are involved in regulating chronic pain and MOR agonist-induced tolerance. In this study, we generated Oprd1 conditional knockout (Oprd1-cKO) mice by crossing Advillin-Cre mice with Oprd1-floxed mice. DOR expression in the dorsal root ganglion was diminished in Oprd1-cKO mice. Systemic or intrathecal injection of the DOR agonist SNC-80 produced analgesia in wild-type (WT), but not Oprd1-cKO, mice. In contrast, intracerebroventricular injection of SNC-80 produced a similar analgesic effect in WT and Oprd1-cKO mice. However, morphine-induced analgesia, hyperalgesia, or analgesic tolerance did not differ between WT and Oprd1-cKO mice. Compared with WT mice, Oprd1-cKO mice showed increased mechanical and heat hypersensitivity after nerve injury or tissue inflammation. Furthermore, blocking DORs with naltrindole increased nociceptive sensitivity induced by nerve injury or tissue inflammation in WT, but not Oprd1-cKO, mice. In addition, naltrindole potentiated glutamatergic input from primary afferents to spinal dorsal horn neurons increased by nerve injury or CFA in WT mice; this effect was absent in Oprd1-cKO mice. Our findings indicate that DORs in primary sensory neurons are critically involved in the analgesic effect of DOR agonists but not morphine-induced analgesic tolerance. Presynaptic DORs at primary afferent central terminals constitutively inhibit inflammatory and neuropathic pain by restraining glutamatergic input to spinal dorsal horn neurons.
Learn More >As a traditional Chinese therapy, acupuncture is proposed worldwide as a treatment for pain and other health problems, but the findings of acupuncture analgesia have been inconsistent due to its variable modalities of therapeutic intervention.
Learn More >Allergic conjunctivitis is highly prevalent and affects up to one third of the general population. The current understanding of the pathophysiology and therapeutic strategies center around the type 2 inflammatory pathway. However, there is an increasing body of evidence that suggests neurogenic mechanisms also play a role in allergic inflammation, with a substantial proportion of allergic conjunctivitis patients experiencing both ocular itch and pain.
Learn More >Cerebrospinal fluid (CSF) shunting is widely used in refractory idiopathic intracranial hypotension (IIH). Although multiple reviews have assessed its efficacy compared with other surgical treatments, there is no detailed analysis that evaluates the clinical outcomes after CSF shunting.
Learn More >Headache is among the most frequent symptoms persisting or newly developing after coronavirus disease 2019 (COVID-19) as part of the so-called long COVID syndrome. The knowledge on long COVID headache is still limited, however growing evidence is defining the features of this novel condition, in particular regarding clinical characteristics, some pathophysiological mechanisms and first treatment recommendations. Long COVID headache can present in the form of worsening of a preexisting primary headache, or, more specifically, in the form of a new (intermittent or daily) headache starting during the acute infection or after a delay. It often presents together with other long COVID symptoms, most frequently with hyposmia. It can manifest with a migrainous or, more frequently, with a tension-type-like phenotype. Persistent activation of the immune system and trigeminovascular activation are thought to play a role. As there are virtually no treatment studies, treatment currently is largely guided by the existing guidelines for primary headaches with the corresponding phenotype. The present report, a collaborative work of the international group of the Junior Editorial Board of The Journal of Headache and Pain aims to summarize the most recent evidence about long COVID headache and suggests approaches to the diagnosis and treatment of this disorder.
Learn More >There is a lack of data on SARS-CoV-2 vaccination safety in children and young people (CYP) with rheumatic and musculoskeletal diseases (RMDs). Current vaccination guidance is based on data from adults with RMDs or CYP without RMDs.
Learn More >Elevated depressive symptoms are observed in a significant number of youth with inflammatory bowel disease (IBD) and have been linked to illness stigma and social isolation. Body image dissatisfaction is an understudied variable in the pediatric IBD literature that may be related to both stigma and social difficulties. It is suspected that, due to the stigmatizing nature of IBD, some youth may feel self-conscious about their body image, which contributes to decreased feelings of social belongingness and ultimately depressive symptoms. The current study tested an illness stigma→ body image dissatisfaction→ thwarted belongingness→ depressive symptoms serial mediation model, in which IBD stigma was hypothesized to indirectly influence youth depressive symptoms through the sequential effects of stigma on body image dissatisfaction and thwarted social belongingness.
Learn More >Central sensitisation contributes to patient variability when treating pain in endometriosis. Targeting this process may alleviate hyperalgesia and allodynia in women refractory to current treatments. Thus far, there has been no review of targeted treatments for central sensitisation in women with endometriosis. Therefore, this review aims to identify and summarise the findings of studies regarding the availability and efficacy of targeted treatments for central sensitisation in women with endometriosis.
Learn More >Prescription-related opioid misuse, especially in chronic pain populations, is an ongoing problem and is related to increased mortality. The purpose of this study was to assess the utility of two restructured scales of the MMPI-2-RF: the Personality Psychopathology Five (PSY-5-RF) and the Higher-Order Scales to determine which of their subscales may be beneficial for identifying the risk of opioid misuse in a chronic pain population. A sample of 136 patients with chronic disabling occupational musculoskeletal disorders completed the MMPI-2-RF and the Current Opioid Misuse Measure (COMM) upon admission to a functional restoration program. The PSY-5-RF and H-O subscales were correlated with the baseline COMM scores. Correlation analyses, ROC curve analyses, and multiple binary logistic regression models were developed to determine which subscales were most associated with elevated COMM scores. The results of the regression analyses suggest that Scale elevations on two of the PSY-5-RF Scales and two Higher-Order Scales of the MMPI-2-RF demonstrated significant associations with elevated COMM scores, thus exhibiting the utility of these subscales in identifying the risk of opioid misuse among chronic pain patients. These findings are clinically meaningful in underscoring the importance of identifying specific personality traits as potential predictors of opioid misuse, and identifying those at risk through careful screening. Clinical implications based on each of the PSY-5-RF and H-O scales significantly associated with elevated COMM scores are discussed.
Learn More >Primary headache is a very common and disabling disease. The burden of pain and recurrent attacks may lead to a poor quality of life, anxiety and depression. An increased risk of low functioning and curricular performances in young patients with primary headache has been described. The mechanisms underlying the relationship between migraine and poor school achievement may be various and could be a reflection of weak cognitive skills. Data concerning the cognitive functioning in the free pain interval in pediatric age are under-investigated and results are far from conclusive. The present review article suggests that, though considered a benign disease, pediatric migraine may be associated to altered neuropsychological functioning in the interictal phase. Although children and adolescents with migraine generally have a normal intelligence, they may show a not homogeneous cognitive profile, characterized by possible difficulties in verbal skills, in particular comprehension abilities. Pediatric primary headache may present altered neuropsychological functioning involving attentional resources, processing speed and memory, particularly verbal memory. Given the impact that this disease can have on school performance and the tendency to persist from childhood to adulthood, a cognitive screening in young patients affected by primary headache is pivotal. Additional neuropsychological research using more homogenous methods is needed.
Learn More >In 2018, the Food and Drug Administration (FDA) approval of anti-calcitonin gene-related peptide (CGRP) therapies for the treatment of migraine represented a milestone for the management of the disease in adults. On the contrary, the novelties in the field of pediatric migraine are inserted in a different scenario and still concern: (1) diagnostic criteria of the international classification of headache disorders-3 (ICHD-3) that show numerous limits of applicability in the developmental age; (2) the release of the results of the Childhood and Adolescent Migraine Prevention (CHAMP) study that raised doubts about the usefulness of traditional drugs for the treatment of pediatric migraine; (3) the Coronavirus disease 2019 (COVID-19) pandemic has put the spotlight on the importance of managing the psychological factors associated with the disease. In this mini review we discuss the most relevant news in pediatric migraine over the last 5 years.
Learn More >Since December 2019, the time when the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was spotted, numerous review studies have been published on COVID-19 and its neuro invasion. A growing number of studies have reported headaches as a common neurological manifestation of COVID-19. Although several hypotheses have been proposed regarding the association between headache and the coronavirus, no solid evidence has been presented for the mechanism and features of headache in COVID-19. Headache also is a common complaint with the omicron variant of the virus. COVID-19 vaccination also is a cause of new-onset headaches or aggravation of the previous headache in migraine or tension headache sufferers. In this review study, the types of headaches reported in previous studies and their possible pathogenic mechanisms are outlined. To accomplish this objective, various types of headaches are classified and their patterns are discussed according to ICHD-3 diagnostic criteria, including, headaches attributed to systemic viral infection, viral meningitis or encephalitis, non-infectious inflammatory intracranial disease, hypoxia and/or hypercapnia, cranial or cervical vascular disorder, increased cerebrospinal fluid (CSF) pressure, refractive error, external-compression headache, and cough headache. Then, their pathogeneses are categorized into three main categories, direct trigeminal involvement, vascular invasion, and inflammatory mediators. Furthermore, persistent headache after recovery and the predictors of intensity is further investigated. Post-vaccination headache is also discussed in this review.
Learn More >Low-intensity shockwave therapy (LiST) has been applied in the clinical treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), but few studies have focused on the prediction of its therapeutic effect before treatment.
Learn More >Irritable bowel syndrome (IBS) is a chronic disease leading to abdominal pain that is often related to psychological distress. The aim of the study was to investigate the temporal relationships between abdominal pain and psychological variables in patients with IBS.
Learn More >Understanding mechanisms that underly the transition from acute to chronic pain and identifying potential targets for preventing or minimizing this progression have specific relevance for chronic postsurgical pain (CPSP). Though it is clear that multiple psychosocial, family, and environmental factors may influence CPSP, this review will focus on parallels between clinical observations and translational laboratory studies investigating the acute and long-term effects of surgical injury on nociceptive pathways. This includes data related to alterations in sensitivity at different points along nociceptive pathways from the periphery to the brain; age- and sex-dependent mechanisms underlying the transition from acute to persistent pain; potential targets for preventive interventions; and the impact of prior surgical injury. Ongoing preclinical studies evaluating age- and sex-dependent mechanisms will also inform comparative efficacy and preclinical safety assessments of potential preventive pharmacological interventions aimed at reducing the risk of CPSP. In future clinical studies, more detailed and longitudinal peri-operative phenotyping with patient- and parent-reported chronic pain core outcomes, alongside more specialized evaluations of somatosensory function, modulation, and circuitry, may enhance understanding of individual variability in postsurgical pain trajectories and improve recognition and management of CPSP.
Learn More >Accessibility of treatment with monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) signaling pathway is impeded by regulatory restrictions. Affected individuals may seek out other services including non-pharmacological therapies. Thus, we found it timely to ascertain the use of non-pharmacological therapies in individuals with treatment-resistant migraine eligible for and naïve to treatment with CGRP-signaling targeting monoclonal antibodies.
Learn More >Psychological acceptance has emerged as an important construct to explain low psychological distress in different clinical samples. However, the incremental validity of psychological acceptance to explain adjustment to medical conditions over other related and well-established constructs, such as coping, is relatively unclear. This study explored whether psychological acceptance significantly contributes to explain adjustment above and beyond coping in females with endometriosis. A total of 169 females ( = 34.95 years; = 6.07 years) with endometriosis and pain symptoms completed the Acceptance and Action Questionnaire-II, the Brief-COPE, the Hospital Anxiety and Depression Scale, the Psychological Wellbeing Scale, and the Endometriosis Health Profile-5. We conducted Hierarchical Regression Analyses to determine the contribution of psychological acceptance to explaining adjustment. The results showed that the contribution of psychological acceptance ranged from 11 to 20% when controlling for coping, while coping explained from 1 to 8% when the model was reversed. The findings suggest that psychological acceptance is a more useful construct than coping for predicting PD and other psychological outcomes in females with endometriosis.
Learn More >The cerebellum is associated with the biology of migraine in a variety of ways. Clinically, symptoms such as fatigue, motor weakness, vertigo, dizziness, difficulty concentrating and finding words, nausea, and visual disturbances are common in different types of migraine. The neural basis of these symptoms is complex, not completely known, and likely involve activation of both specific and shared circuits throughout the brain. Posterior circulation stroke, or neurosurgical removal of posterior fossa tumors, as well as anatomical tract tracing in animals, provided the first insights to theorize about cerebellar functions. Nowadays, with the addition of functional imaging, much progress has been done on cerebellar structure and function in health and disease, and, as a consequence, the theories refined. Accordingly, the cerebellum may be useful but not necessary for the execution of motor, sensory or cognitive tasks, but, rather, would participate as an efficiency facilitator of neurologic functions by improving speed and skill in performance of tasks produced by the cerebral area to which it is reciprocally connected. At the subcortical level, critical regions in these processes are the basal ganglia and thalamic nuclei. Altogether, a modulatory role of the cerebellum over multiple brain regions appears compelling, mainly by considering the complexity of its reciprocal connections to common neural networks involved in motor, vestibular, cognitive, affective, sensory, and autonomic processing-all functions affected at different phases and degrees across the migraine spectrum. Despite the many associations between cerebellum and migraine, it is not known whether this structure contributes to migraine initiation, symptoms generation or headache. Specific cerebellar dysfunction genetically driven excitatory/inhibitory imbalances, oligemia and/or increased risk to white matter lesions has been proposed as a critical contributor to migraine pathogenesis. Therefore, given that neural projections and functions of many brainstem, midbrain and forebrain areas are shared between the cerebellum and migraine trigeminovascular pathways, this review will provide a synopsis on cerebellar structure and function, its role in trigeminal pain, and an updated overview of relevant clinical and preclinical literature on the potential role of cerebellar networks in migraine pathophysiology.
Learn More >The restricted duration is a fundamental drawback of traditional local anesthetics during postoperative pain from a single injection. Therefore, an injectable local anesthetic that produces repeatable on-demand nerve blocks would be ideal.
Learn More >Polyunsaturated fatty acids (PUFAs) play a role in pain regulation. This study sought to determine whether free PUFAs found in red blood cells also play a role in nociceptive processing. We examined associations between circulating PUFAs and nociceptive thresholds to noxious mechanical stimuli. We also determined whether nociceptive thresholds were associated with nociplastic pain conditions.
Learn More >TREK2 is a member of the 2-pore domain family of K+ channels (K2P) preferentially expressed by unmyelinated, slow-conducting and non-peptidergic isolectin B4-binding (IB4+) primary sensory neurons of the dorsal root ganglia (DRG). IB4+ neurons depend on the glial-derived neurotrophic factor (GDNF) family of ligands (GFL's) to maintain their phenotype. In our previous work, we demonstrated that 7 days after spinal nerve axotomy (SNA) of the L5 DRG, TREK2 moves away from the cell membrane resulting in a more depolarised resting membrane potential (Em). Given that axotomy deprives DRG neurons from peripherally-derived GFL's, we hypothesized that they might control the expression of TREK2. Using a combination of immunohistochemistry, immunocytochemistry, western blotting, in vivo pharmacological manipulation and behavioral tests we examined the ability of the GFL's (GDNF, neurturin and artemin) and their selective receptors (GFRα1, GFRα2 and GFRα3) to regulate the expression and function of TREK2 in the DRG. We found that TREK2 correlated strongly with the three receptors normally and ipsilaterally for all GFR's after SNA. GDNF, but not NGF, neurturin or artemin up-regulated the expression of TREK2 in cultured DRG neurons. In vivo continuous, subcutaneous administration of GDNF restored the subcellular distribution of TREK2 ipsilaterally and reversed mechanical and cold allodynia 7 days after SNA. This is the first demonstration that GDNF controls the expression of a K2P channel in nociceptors. As TREK2 controls the Em of C-nociceptors affecting their excitability, our finding has therapeutic potential in the treatment of chronic pain.
Learn More >Cannabinoid Receptor 2 (CB2) is a G protein-coupled receptor (GPCR) with considerable, though as yet unrealised, therapeutic potential. Promising preclinical data supports the applicability of CB2 activation in autoimmune and inflammatory diseases, pain, neurodegeneration, and osteoporosis. A diverse pharmacopoeia of cannabinoid ligands is available, which has led to considerable advancements in the understanding of CB2 function and extensive preclinical evaluation. However, until recently, most CB2 ligands were highly lipophilic and as such not optimal for clinical application due to unfavourable physicochemical properties. A number of strategies have been applied to develop CB2 ligands to achieve closer to 'drug-like' properties and a few such compounds have now undergone clinical trial. We review the current state of CB2 ligand development and progress in optimising physicochemical properties, understanding advanced molecular pharmacology such as functional selectivity, and clinical evaluation of CB2-targeting compounds.
Learn More >The benefits of preventive treatment on the effectiveness of migraine management have rarely been examined. This post hoc analysis investigated the impact of eptinezumab on the optimization of acute medication effectiveness using the 4-item Migraine Treatment Optimization Questionnaire (mTOQ-4) to measure acute medication optimization over 4 weeks post-infusion.
Learn More >While most individuals physically injured at work will make a complete medical recovery, a portion of workers will experience persistent pain following their injury. This study estimated persistent pain prevalence and its association with health and return-to-work outcomes 18 months following the incidence of a disabling work-related injury.
Learn More >The COVID-19 pandemic resulted in a novel challenge for healthcare delivery and implementation in the United States (US) in 2020 and beyond. Telemedicine arose as a significant and effective medium for safe and efficacious physician-patient interactions. Prior to the COVID-19 pandemic, telemedicine while available, had infrequently been utilized in pain medicine practices due to difficulties with reimbursement, the learning curve associated with new technology usage, and the need for new logistical systems in place to implement telemedicine effectively. Given the unique constraints on the healthcare system during the COVID-19 pandemic, the ubiquitous utilization of telemedicine among pain medicine physicians increased, giving insight into potential future roles for the technology beyond the pandemic.
Learn More >The most common presentation of cluneal neuropathy is ipsilateral low back and gluteal pain. Cluneal neuralgia has been described historically in surgical contexts, with much of the description and treatment related to entrapment and decompression, respectively. Treatment options for addressing axial low back pain have evolved with advancements in the field of interventional pain medicine, though clinical results remain inconsistent. Recent attention has turned toward peripheral nerve stimulation. Nonsurgical interventions targeting the superior and medial cluneal nerve branches have been performed in cases of low back and buttock pain, but there is no known review of the resulting evidence to support these practices.
Learn More >Postoperative pain management in breast surgery and video-assisted thoracic surgeries (VATS) remains challenging. Oral or intravenous infusion of opioids were early treatments, but they can result in gastrointestinal reactions, respiratory inhibition, and other adverse reactions. In recent years, various regional block techniques have been employed for postoperative analgesia of these surgeries. However, a pair-wise meta-analysis cannot comprehensively rank and evaluate the analgesic effects and adverse events of various regional blocks.
Learn More >The previous research showed contradictions in the relationships between psychological flexibility processes and functioning. This meta-analysis is the first to provide a comprehensive meta-analysis of the associations between six core processes of psychological flexibility and functioning among chronic pain patients. Four databases were searched (PsycINFO; PubMed; CINAHL; Web of Science) along with reference lists. Thirty-six cross-sectional studies were included (7,812 chronic pain patients). A three-level meta-analytic model was used to examine the associations. The publication bias was assessed with the Egger test, funnel plot, and -curve analysis. Significant associations were found between functioning and six processes of psychological flexibility (i.e., acceptance, defusion, present moment, committed action, self as context, and values). Except for the relationship between defusion and functioning, the relationships between the other five psychological flexibility processes and functioning were all moderated by domains of functioning. No moderators were found regarding age, percentage of females, country, or type of instrument used to measure functioning. These findings may carry significant implications for chronic pain patients and clinical workers. It might be more effective to focus on functioning-related psychological flexibility processes rather than all therapy packages if the relationships between functioning and specific processes of psychological flexibility were better informed. Limitations were also discussed.
Learn More >Hospitalization is the primary driver of inflammatory bowel disease (IBD)-related healthcare costs and morbidity. Traditional prediction models have poor performance at identifying patients at highest risk of unplanned healthcare utilization. Identification of patients who are high-need and high-cost (HNHC) could reduce unplanned healthcare utilization and healthcare costs.
Learn More >To establish the prevalence of long-term and serious harms of medical cannabis for chronic pain.
Learn More >The purpose of this study is to analyze and visualize the research trends on acupuncture therapy for postoperative pain over the past 20 years to identify hotspots and frontiers, and provide new research ideas.
Learn More >Immunoglobulins (IG) are widely used for the treatment of a variety of immune-mediated diseases. The exact mechanism of action remains unknown, but IG modulate the expression and function of Fc receptors, interfere with complement activation and production of cytokines, neutralize pathogenic autoantibodies, and affect the activation and effector functions of B and T lymphocytes. Immunoglobulins are usually delivered intravenously, and are effective in ameliorating motor symptoms, and/or preventing disease progression in immune-mediated neuropathies, including Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.
Learn More >In recent decades, an area of active research has supported the notion that progesterone promotes a wide range of remarkable protective actions in experimental models of nervous system trauma or disease, and has also provided a strong basis for considering this steroid as a promising molecule for modulating the complex maladaptive changes that lead to neuropathic pain, especially after spinal cord injury. In this review, we intend to give the readers a brief appraisal of the main mechanisms underlying the increased excitability of the spinal circuit in the pain pathway after trauma, with particular emphasis on those mediated by the activation of resident glial cells, the subsequent release of proinflammatory cytokines and their impact on N-methyl-D-aspartate receptor function. We then summarize the available preclinical data pointing to progesterone as a valuable repurposing molecule for blocking critical cellular and molecular events that occur in the dorsal horn of the injured spinal cord and are related to the development of chronic pain. Since the treatment and management of neuropathic pain after spinal injury remains challenging, the potential therapeutic value of progesterone opens new traslational perspectives to prevent central pain.
Learn More >Observational findings achieved that gut microbes mediate human metabolic health and disease risk. The types of intestinal microorganisms depend on the intake of food and drugs and are also related to their metabolic level and genetic factors. Recent studies have shown that chronic inflammatory pain is closely related to intestinal microbial homeostasis. Compared with the normal intestinal flora, the composition of intestinal flora in patients with chronic inflammatory pain had significant changes in , , , etc. At the same time, short-chain fatty acids and amino acids, the metabolites of intestinal microorganisms, can regulate neural signal molecules and signaling pathways, thus affecting the development trend of chronic inflammatory pain. Glucocorticoids and non-steroidal anti-inflammatory drugs in the treatment of chronic inflammatory pain, the main mechanism is to affect the secretion of inflammatory factors and the abundance of intestinal bacteria. This article reviews the relationship between intestinal microorganisms and their metabolites on chronic inflammatory pain and the possible mechanism.
Learn More >To evaluate a dermatologist-centred screening tool followed by a structured rheumatological examination including MRI of sacroiliac joints and spine for the recognition of psoriatic arthritis with axial involvement (axPsA).
Learn More >Nonsurgical Treatment of Neuralgia and Cervicogenic Headache: A Systematic Review and Meta-analysis.
Extracranial compression of peripheral sensory nerves is one of many origins of chronic headaches. Identifying these patients can be difficult, and they are often diagnosed with neuralgia or cervicogenic headache. The recent literature provides the outcomes of surgical decompression in patients with these headaches. This study aimed to give an overview of the current literature on the nonsurgical treatment options and to evaluate the effectiveness of these treatments in patients with neuralgia and cervicogenic headache.
Learn More >The purposes of this study are to explore (1) whether comorbid depressive symptoms in patients with chronic back pain (CBP) affect the pain matrix. And (2) whether the interaction of depression and CBP exacerbates impaired brain function.
Learn More >Compare through case-control studies, the salivary characteristics of patients with and without BMS.
Learn More >The pathophysiology of migraine remains to be elucidated. We have recently shown that interictal migraineurs exhibit reduced fractional anisotropy (FA) in the root entry zone of the trigeminal nerve when compared to controls, but it is not known if this altered nerve anatomy is associated with changes within the brainstem or higher cortical brain regions. Diffusion tensor imaging of the brain was used to calculate regional measures of structure, including mean diffusivity (MD), axial diffusivity (AX) and radial diffusivity (RD) in addition to voxel-based morphometry of T1-weighted anatomical images. Linear relationships between trigeminal nerve anatomy (FA) and MD throughout the brainstem and/or higher cortical regions were determined in both controls ( = 31, brainstem; = 38, wholebrain) and interictal migraineurs ( = 32, brainstem; = 38, wholebrain). Additionally, within the same brain areas, relationships of AX and RD with nerve FA were determined. We found that in both interictal migraine and control participants, decreasing trigeminal nerve FA was associated with significantly increased MD in brainstem regions including the spinal trigeminal nucleus and midbrain periaqueductal gray matter (PAG), and in higher brain regions such as the hypothalamus, insula, posterior cingulate, primary somatosensory and primary visual (V1) cortices. Whereas, both control and migraineur groups individually displayed significant inverse correlations between nerve FA and MD, in migraineurs this pattern was disrupted in the areas of the PAG and V1, with only the control group displaying a significant linear relationship (PAG controls = -0.58, = 0.003; migraineurs = -0.25, = 0.17 and V1 controls = -0.52, = 0.002; migraineurs = -0.10, = 0.55). Contrastingly, we found no gray matter volume changes in brainstem or wholebrain areas. These data show that overall, trigeminal nerve anatomy is significantly related to regional brain structure in both controls and migraineurs. Importantly, the PAG showed a disruption of this relationship in migraineurs suggesting that the anatomy and possibly the function of the PAG is uniquely altered in episodic migraine, which may contribute to altered orofacial pain processing in migraine.
Learn More >To investigate the effect of prolonged low-level laser therapy application combined with exercise on pain and disability in patients with osteoarthritis of the knee.
Learn More >Natural compounds and their synthesized analogues continue to be valuable sources in the discovery and development of novel anti-inflammatory agents. AL-04 is a thiol analogue derived from a natural sesquiterpene alantolactone, that demonstrated potential anti-inflammatory activity in vitro in comparison to its parent compound. However, the anti-inflammatory mechanism of action of AL-04 has not been elucidated. In this context, we investigated the signaling pathway that primarily mediate the anti-inflammatory activity of AL-04 and its effect on principal inflammatory mediators including iNOS, COX-2 and ROS. Furthermore, the anti-inflammatory activity was investigated in vivo in carrageenan induced paw oedema model in addition to the exploration of anti-nociceptive activity and acute toxicity. The results suggested that treatment with AL-04 significantly decreased the LPS-induced upregulation of pro-inflammatory cytokines and mediators in addition to the downregulated transcription of TNF-α and IL-6 in RAW 264.7 cell line. Furthermore, mRNA and the protein expression of COX-2 and iNOS were also significantly attenuated with AL-04 at a concentration of 10 µM. Western blot studies further suggested that AL-04 downregulated LPS-stimulated NF-κB p65 expression. In addition to this the anti-inflammatory activity of AL-04 was demonstrated in carrageenan induced paw oedema model with significant inhibition of oedema in a dose-dependent manner. The anti-inflammatory activity of AL-04 was further demonstrated in balb/c mice by inhibition of leukocyte migration and vascular permeability. Besides, AL-04 also inhibited thermally and chemically induced pain in tail-flick and acetic acid induced writing assays respectively in balb/c mice suggesting the analgesic potential of the compound. Acute toxicity studies further suggested the appreciable safety of AL-04 at high dose of 2000 mg/kg with no indications of toxicity or changes in biochemical and haematological parameters. Overall, the study insinuates the anti-inflammatory potential of AL-04 and paves way for further exploration of the compound as a safer therapeutic anti-inflammatory agent.
Learn More >Although sleep quantity and quality appear to be interrelated, most previous studies have considered sleep duration and insomnia symptoms as distinct entities. We therefore examined whether there is a joint effect of sleep duration and long-term changes in insomnia symptoms on the risk of recurrent chronic spinal pain. We performed a prospective study of 8,788 participants who participated in three surveys over ∼22 years and reported chronic spinal pain at the first, second, or both surveys. Adjusted risk ratios (RRs) were calculated for the risk of recurrent spinal pain at the last survey associated with self-reported sleep duration at the first survey and changes in insomnia symptoms between the two first surveys. Compared to participants with normal sleep duration (7-9 h) and no insomnia symptoms at the two first surveys, participants with insomnia symptoms over the same period had RRs of spinal pain of 1.33 (95% CI 1.26-1.41) in the last survey if they reported normal sleep duration and 1.50 (95% CI 1.34-1.67) if they reported short sleep (≤6 h). The corresponding RRs for spinal pain for participants who improved their sleep symptoms were 1.09 (95% CI 1.00-1.19) for those with normal sleep and 1.13 (95% CI 0.88-1.45) for those with short sleep. In conclusion, people who reported insomnia symptoms over ∼10 years in combination with short sleep had a particularly increased risk of recurrent spinal pain. Improvement in insomnia symptoms was associated with a favorable prognosis.
Learn More >Transection of the supraclavicular nerve (SCN) through supraclavicular incisions can lead to debilitating neuroma formation. Targeted muscle reinnervation (TMR) proved to be an effective technique for the prevention and treatment of neuroma. In this case series, we propose the TMR of the SCN to the motor branch of the omohyoid muscle (OM) to prevent the formation of neuroma and avoid chronic pain at the supraclavicular area after thoracic outlet syndrome (TOS) procedures. A total of 10 patients underwent the procedure. Dissection of the SCN and its branches was performed through a supraclavicular incision. The branches were transected close to the clavicle. The inferior belly of the OM was identified and its motor branch isolated. Coaptation of the SCN branches with the motor branch of the OM was performed under the microscope and the wound was closed in layers. All the patients denied pain or hypersensitivity at the supraclavicular area on follow-up. In summary, the motor branch of the OM is a viable recipient for the TMR of the SCN and can prevent and treat painful neuromas at the supraclavicular area with minimal morbidity.
Learn More >Opioid-free analgesia (OFA) may mitigate opioid-related harms after outpatient general surgery; however, the comparative effectiveness of this approach should be assessed in robust randomized controlled trials (RCTs). Undertaking an RCT on OFA raises important practical concerns, including surgeon and patient hesitation regarding pain management without opioids. We conducted a qualitative study to explore patients' and clinicians' perspectives and experiences with a pilot trial focused on OFA after outpatient general surgery.
Learn More >Sigma receptors (σ R and σ R) are pharmacologically characterized membrane-bound receptors that bind a wide range of chemical compounds. Alzheimer's disease, traumatic brain injury, schizophrenia, and neuropathic pain have all been associated with abnormal σ activity. The σ receptor has recently been identified as a potential therapeutic target for inhibiting the formation of amyloid plaques. Numerous laboratories are now investigating the potential of σ ligands. Small molecule discovery is the focus of current research, with the goal of using target-based action to treat a variety of illnesses and ailments. Functionalized γ-butyrolactone and oxazolidinone-based ligands, in particular, are pharmacologically important scaffolds in drug discovery research and have been thoroughly examined for σ receptor efficacy. The purpose of this study was to evaluate the pharmacophoric features of different σ receptor ligands using techniques. This study used a library of 58 compounds having a γ-butyrolactone and oxazolidinone core. To investigate the binding characteristics of the ligands with the σ receptor, a 3D homology model was developed. To understand the binding pattern of the γ-butyrolactone and oxazolidinone based ligands, molecular docking studies were performed on both σ and σ receptors. Furthermore, MM/GBSA binding energy calculations were used to confirm the binding of ligands on the σ over σ receptor. These findings will aid in the discovery of selective σ ligands with good pharmacophoric properties and potency in the future.
Learn More >Managing postoperative pain requires an individualized approach in order to balance adequate pain control with risk of persistent opioid use and narcotic abuse associated with inappropriately outsized narcotic prescriptions. Shared decision-making has been proposed to address individual pain management needs. We report here the results of a quality improvement initiative instituting prescribing guidelines using shared decision-making and preoperative pain expectation and management education to decrease excess opioid pills after surgery and improve patient satisfaction.
Learn More >Repetitive transcranial magnetic stimulation (rTMS), a form of non-invasive brain stimulation, is a novel avenue for the management of chronic musculoskeletal pain. Despite evidence for the effectiveness of rTMS in chronic pain conditions, the clinical uptake of rTMS remains limited and little is known regarding patient perceptions of this therapeutic technique.
Learn More >Although intense pulsed light (IPL) has been commonly used in the field of medical cosmetics in recent years, the exact outcomes of IPL in the treatment of inflammatory skin diseases remain unclear. To assess the clinical evidence for the use of IPL in the treatment of various inflammatory skin diseases and propose evidence-based recommendations, we searched for relevant publications in the PubMed and Web of Science databases and provided updated information. The inflammatory skin diseases treated with IPL consisted of acne vulgaris, rosacea, psoriasis, hidradenitis suppurativa (HS), atopic dermatitis (AD), Riehl's melanosis, lupus erythematosus, cutaneous sarcoidosis, pilonidal cysts, and pigmented actinic lichen planus (PALP). The efficacy of IPL treatment for these inflammatory skin diseases was described and evaluated. Forty-two studies were included to provide this assessment. The evidence suggests that IPL can effectively and safely improve acne vulgaris and rosacea (recommendation grade B). For other described inflammatory skin diseases, IPL can be used as a tentative or supplementary treatment (recommendation grade C and D). The main complications include transitory erythema, edema, and pain, with the possibility of hyperpigmentation, blisters, and a burning sensation in some individuals.
Learn More >In recent years, a growing number of researches indicate that S100B may act in migraine, but the relationship between S100B and migraine remains controversial. Therefore, the current study aimed to perform a meta-analysis to quantitatively summarize S100B levels in migraine patients.
Learn More >Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is one of the most important natural products in the genus Due to its numerous biological effects, there has been extensive and increasing research interest in capsaicin, resulting in increased scientific publications in recent years. Therefore, an in-depth bibliometric analysis of published literature on capsaicin from 2001 to 2021 was performed to assess the global research status, thematic and emerging areas, and potential insights into future research. Furthermore, recent research advances of capsaicin and its combination therapy on human cancer as well as their potential mechanisms of action were described. In the last two decades, research outputs on capsaicin have increased by an estimated 18% per year and were dominated by research articles at 93% of the 3753 assessed literature. In addition, anti-cancer/pharmacokinetics, cytotoxicity, neurological and pain research studies were the keyword clusters generated and designated as thematic domains for capsaicin research. It was evident that the United States, China, and Japan accounted for about 42% of 3753 publications that met the inclusion criteria. Also, visibly dominant collaboration nodes and networks with most of the other identified countries were established. Assessment of the eligible literature revealed that the potential of capsaicin for mitigating cancer mainly entailed its chemo-preventive effects, which were often linked to its ability to exert multi-biological effects such as anti-mutagenic, antioxidant and anti-inflammatory activities. However, clinical studies were limited, which may be related to some of the inherent challenges associated with capsaicin in the limited clinical trials. This review presents a novel approach to visualizing information about capsaicin research and a comprehensive perspective on the therapeutic significance and applications of capsaicin in the treatment of human cancer.
Learn More >The anandamide is a relevant ligand due to its capacity of interacting with several proteins, including the T-type calcium channels, which play an important role in neuropathic pain and depression disorders. Hence, a detailed characterization of the chemical properties and conformational stability of anandamide may provide valuable information to understand its behavior in a biological context. Herein, conceptual DFT and QTAIM analyses were performed to theoretically characterize the chemical reactivity properties and the structural stability of conformations of anandamide, using the BP86/cc-pVTZ level of theory. Global reactivity description, based on conceptual DFT, indicates that the hardness increases and the electrophilicity index decreases for both, the hairpin and U-shape conformers relative to the extended conformers. Also, an increase in the chemical potential value and a decrease in the electronegativity and the electrophilicity index is observed in the ethanolamide open ring conformers in comparison with the corresponding closed ring structures. In addition, regarding the characterization of local reactivity descriptors, the maximum values of the Fukui and Parr functions indicate that the most probable location for a nucleophilic attack is either the hydroxyl oxygen located in the ethanolamide closed ring conformers or the carbonyl oxygen present in the open ring conformers. The most probable location for an electrophilic attack is in the alkyl double bond region in all anandamide conformers. According to the QTAIM results, the intramolecular hydrogen bond formation stabilizing the structure of anandamide has interaction energy values for the closed ring conformations of 12.33-12.46 kcal mol, indicating a strong interaction. Lastly, molecular docking calculations determined that a region in the pore, denominate as pore-blocking, is a probable site for the interaction of anandamide with the human Ca3.2 isoform of the T-type calcium channel family. The pore-blocking site contains hydrophobic residues where the non-polar part in the final alkyl region of anandamide established mainly alkyl-alkyl interactions, while the polar part (the ethanolamide group) interacts with the polar residue S900. The information based on conceptual DFT presented may aid in the design of drugs with similar chemical characteristics as those identified in anandamide so as to bind anandamide-interacting proteins, including the T-type calcium channels.
Learn More >At present, there are two techniques which are widely applied clinically; the midline and the paramedian. Both methods are difficult for clinicians when treating the elderly. The aim of this work is to explore the feasibility of an ultrasound-assisted modified paramedian technique for spinal anesthesia in the elderly. This would provide clinicians with a new and easy-to-operate technique.
Learn More >Bupivacaine hydrochloride (BVC) represents an option to produce long-lasting analgesia, and complexation in cyclodextrins has shown improvements in biopharmaceutical properties. This study aimed to characterize and test the cytotoxicity and antinociceptive effects of BVC complexed in sulfobutylether-β-cyclodextrin (SBEβCD). The kinetics and stoichiometry of complexation and BVC-SBEβCD association constant were evaluated by phase solubility study and Job's plot. Evidence of the BVC-SBEβCD complex formation was obtained from scanning electron microscopy (SEM), infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). The cytotoxicity was evaluated in keratinocyte (HaCaT) and neuroblastoma (SH-SY5Y). Antinociceptive effects were registered via orofacial pain models: the formalin test, carrageenan-induced hyperalgesia, and postoperative pain (intraoral incision). The complex formation occurred at a 1:1 BVC-SBEβCD molar ratio, with a low association constant (13.2 M). SEM, DSC, and FTIR results demonstrated the host-guest interaction. The IC values determined in SH-SY5Y were 216 µM and 149 µM for BVC and BVC-SBEβCD, respectively (p < 0.05). There was no difference in HaCaT IC. In orofacial pain model, BVC-SBEβCD significantly prolonged antinociceptive effect, in about 2 h, compared to plain BVC. SBEβCD can be used as a drug delivery system for bupivacaine, whereas the complex showed long-lasting analgesic effects.
Learn More >Post-traumatic neuropathic pain is a major factor affecting the quality of life after finger trauma and is reported with considerable variance in the literature. This can partially be attributed to the different methods of determining neuropathic pain. The Douleur Neuropathique 4 (DN4) has been validated to be a reliable and non-invasive tool to assess the presence of neuropathic pain. This study investigated the prevalence of neuropathic pain after finger amputation or digital nerve repair using the DN4 questionnaire.
Learn More >Glucosylsphingosine (GS) is an endogenous sphingolipid that specifically accumulates in the skin of patients with atopic dermatitis (AD). Notably, it was recently found that GS can induce itch sensation by activating serotonin receptor 2A and TRPV4 ion channels. However, it is still uncertain whether other molecules are involved in GS-induced itch sensation. Therefore, by using the calcium imaging technique, we investigated whether serotonin receptor 2 – specifically 2A and 2B – can interact with TRPV1 and TRPA1, because these are representative ion channels in the transmission of itch. As a result, it was found that GS did not activate TRPV1 or TRPA1 per se. Moreover, cells expressing both serotonin receptor 2 and TRPV1 did not show any changes in calcium responses. However, enhanced calcium responses were observed in cells expressing serotonin receptor 2 and TRPA1, suggesting a possible interaction between these two molecules. Similar synergistic effects were also observed in cells expressing serotonin receptor 2 and TRPA1, but not TRPV1. Furthermore, a phospholipase C inhibitor (U73122) and a store-operated calcium entry blocker (SKF96365) significantly reduced GS-induced responses in cells expressing both serotonin receptor 2 and TRPA1, but not with pre-treatment with a Gβγ-complex blocker (gallein). Therefore, we propose a putative novel pathway for GS-induced itch sensation, such that serotonin receptor 2 could be coupled to TRPA1 but not TRPV1 in sensory neurons.
Learn More >To evaluate whether digital pain extent is associated with an array of psychological factors such as optimism, pessimism, expectations of recovery, pain acceptance, and pain self-efficacy beliefs as well as to analyse the association between digital pain extent and pain intensity and pain-related disability in people with chronic musculoskeletal pain.
Learn More >Patients with chronic postsurgical pain (CPSP) frequently exhibit comorbid cognitive deficits. Recent observations have emphasized the critical effects of gut microbial metabolites, like short-chain fatty acids (SCFAs), in regulating cognitive function. However, the underlying mechanisms and effective interventions remain unclear. According to hierarchical clustering and 16S rRNA analysis, over two-thirds of the CPSP rats had cognitive impairment, and the CPSP rats with cognitive impairment had an aberrant composition of gut SCFA-producing bacteria. Then, using feces microbiota transplantation, researchers identified a causal relationship between cognitive-behavioral and microbic changes. Similarly, the number of genera that generated SCFAs was decreased in the feces from recipients of cognitive impairment microbiota. Moreover, treatment with the SCFAs alleviated the cognitive-behavioral deficits in the cognitively compromised pain rats. Finally, we observed that SCFA supplementation improved histone acetylation and abnormal synaptic transmission in the medial prefrontal cortex (mPFC), hippocampal CA1, and central amygdala (CeA) area via the ACSS2 (acetyl-CoA synthetase2)-HDAC2 (histone deacetylase 2) axis. These findings link pain-related cognition dysfunction, gut microbiota, and short-chain fatty acids, shedding fresh insight into the pathogenesis and therapy of pain-associated cognition dysfunction.
Learn More >Pain is an unpleasant sensory and emotional experience. Understanding the neural mechanisms of acute and chronic pain and the brain changes affecting pain factors is important for finding pain treatment methods. The emergence and progress of non-invasive neuroimaging technology can help us better understand pain at the neural level. Recent developments in identifying brain-based biomarkers of pain through advances in advanced imaging can provide some foundations for predicting and detecting pain. For example, a neurologic pain signature (involving brain regions that receive nociceptive afferents) and a stimulus intensity-independent pain signature (involving brain regions that do not show increased activity in proportion to noxious stimulus intensity) were developed based on multivariate modeling to identify processes related to the pain experience. However, an accurate and comprehensive review of common neuroimaging techniques for evaluating pain is lacking. This paper reviews the mechanism, clinical application, reliability, strengths, and limitations of common neuroimaging techniques for assessing pain to promote our further understanding of pain.
Learn More >It has been well demonstrated that the cerebellum is associated with cognitive and affective processing as well as the traditionally conceptualized motor function. In the present chapter, we explore the behavioral and neurobiological implications of a common congenital cerebellar condition, Chiari malformation Type I, on cognitive and affective processing. We also emphasize the associations between Chiari-related chronic pain, cognitive dysfunction, and emotion dysregulation. Based on our review of the literature, we argue that chronic pain can account for a substantial amount of the cognitive dysfunction and emotion dysregulation in Chiari malformation Type I. Yet, there also exists aspects of Chiari-related cognitive dysfunction and emotion dysregulation that appear to be at least partially independent of chronic pain and more directly associated with abnormalities in cerebrospinal fluid flow dynamics and cerebro-cerebellar communication pathways.
Learn More >In the presence of neuropathic pain, other sensory qualities, such as touch or pressure, which are a sign of nerve damage, are almost always affected. However, it is unclear to which extent spinal cord stimulation (SCS) influences these simultaneously damaged sensory pathways or possibly contributes to their regeneration.
Learn More >Chronic overlapping pain conditions (COPCs) are a collection of chronic pain syndromes that often co-occur and are thought to share underlying nociplastic pathophysiology. Since they can manifest as seemingly unrelated syndromes they have historically been studied in isolation. Use of International Classification of Diseases (ICD) codes in medical records has been proposed as a means to identify and study trends in COPCs at the population level, however validated code sets are needed. Recently, a code set comprising ICD-10 codes as proxies for 11 COPCs was validated. The goal of this project was to validate a code set composed of ICD-9 codes for the identification of COPCs in administrative datasets. Data was extracted using the Electronic Medical Record Search Engine at the University of Michigan Health System from January 1st, 2011 to January 1st, 2015. The source population were patients with one of the candidate ICD-9 codes corresponding to various COPCs. Natural language searches were used as a reference standard. If code sets met a pre-specified threshold of agreement between ICD-9 codes and natural language searches (≥ 70%), they were retained and diagnostic accuracy statistics were calculated for each code set. Validated ICD-9 code sets were generated for 10 of the 11 COPCs evaluated. The majority had high levels of diagnostic accuracy, with all but one code set achieving ≥ 80% specificity, sensitivity, and predictive values. This code set may be used by pain researchers to identify COPCs using ICD-9 codes in administrative datasets.
Learn More >Lornoxicam (LOR), a BCS Ⅱ nonsteroidal anti-inflammatory drug, has been clinically utilized for moderate to severe acute pain management. However, it has poor water solubility and insufficient tabletability, leading to erratic absorption and challenge in tablet processability. This study reported a novel solid state of LOR (i.e., LOR sodium chelate monohydrate, LOR-Na·HO) with significantly improved solubility, dissolution rate and tabletability. The prepared chelate (CCDC No.: 2125157) contains LOR, Na, and HO in a molar ratio of 1:1:1, where Na ions bridged with O(5) of amide group, and N(2) of pyridine group on LOR, as well as O(4) on HO through coordination bonds. LOR-Na·HO displayed a superior dissolution rate (5∼465 folds) than commercial LOR due to its increased wettability (contact angle: 74.5° vs 85.6°) and lower solvation free energy (∼2-fold). In addition, the significant improvement in tabletability was caused by high plasticity and deformability, which was attributed to its special interlayer gliding with weak bonding interactions across layers but strong coordination bonding interactions within layers. The novel LOR-Na·HO with significantly enhanced pharmaceutical performance offers a promising strategy for further product development.
Learn More >Prior research has demonstrated the widespread presence of racial disparities in emergency department (ED) care and analgesia. We hypothesized that racial disparities continue to exist in ED analgesic prescribing patterns, time to analgesia, and time to provider in the treatment of headache.
Learn More >There are many surgical operations performed daily in operation rooms worldwide. Adequate anesthesia is needed during an operation. Besides hypnosis, adequate analgesia is critical to prevent autonomic reactions. Clinical experience and vital signs are usually used to adjust the dosage of analgesics. Analgesia nociception index (ANI), which ranges from 0 to 100, is derived from heart rate variability (HRV) via electrocardiogram (ECG) signals, for pain evaluation in a non-invasive manner. It represents parasympathetic activity. In this study, we compared the performance of multilayer perceptron (MLP) and long short-term memory (LSTM) algorithms in predicting expert assessment of pain score (EAPS) based on patient's HRV during surgery. The objective of this study was to analyze how deep learning models differed from the medical doctors' predictions of EAPS. As the input and output features of the deep learning models, the opposites of ANI and EAPS were used. This study included 80 patients who underwent operations at National Taiwan University Hospital. Using MLP and LSTM, a holdout method was first applied to 60 training patients, 10 validation patients, and 10 testing patients. As compared to the LSTM model, which had a testing mean absolute error (MAE) of 2.633 ± 0.542, the MLP model had a testing MAE of 2.490 ± 0.522, with a more appropriate shape of its prediction curves. The model based on MLP was selected as the best. Using MLP, a seven-fold cross validation method was then applied. The first fold had the lowest testing MAE of 2.460 ± 0.634, while the overall MAE for the seven-fold cross validation method was 2.848 ± 0.308. In conclusion, HRV analysis using MLP algorithm had a good correlation with EAPS; therefore, it can play role as a continuous monitor to predict intraoperative pain levels, to assist physicians in adjusting analgesic agent dosage. Further studies may consider obtaining more input features, such as photoplethysmography (PPG) and other kinds of continuous variable, to improve the prediction performance.
Learn More >Low back pain is a major cause of disability worldwide that declines the quality of life; it poses a substantial economic burden for the patient and society. Intervertebral disc (IVD) degeneration (IDD) is the main cause of low back pain, and it is also the pathological basis of several spinal degenerative diseases, such as intervertebral disc herniation and spinal stenosis. The current clinical drug treatment of IDD focuses on the symptoms and not their pathogenesis, which results in frequent recurrence and gradual aggravation. Moreover, the side effects associated with the long-term use of these drugs further limit their use. The pathological mechanism of IDD is complex, and oxidative stress and inflammation play an important role in promoting IDD. They induce the destruction of the extracellular matrix in IVD and reduce the number of living cells and functional cells, thereby destroying the function of IVD and promoting the occurrence and development of IDD. Phytochemicals from fruits, vegetables, grains, and other herbs play a protective role in the treatment of IDD as they have anti-inflammatory and antioxidant properties. This article reviews the protective effects of phytochemicals on IDD and their regulatory effects on different molecular pathways related to the pathogenesis of IDD. Moreover, the therapeutic limitations and future prospects of IDD treatment have also been reviewed. Phytochemicals are promising candidates for further development and research on IDD treatment.
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