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Molecular identification of bulbospinal ON neurons by GPER which drives pain and morphine tolerance.
The rostral ventromedial medulla (RVM) exerts bi-directional descending modulation of pain, attributable to the activity of electrophysiologically-identified pro-nociceptive ON and anti-nociceptive OFF neurons. Here we report that GABAergic ON neurons specifically express G protein-coupled estrogen receptor (GPER). GPER+ neurons exhibited characteristic ON-like responses upon peripheral nociceptive stimulation. Optogenetic activation of GPER+ neurons facilitated, whilst their ablation abrogated pain. Furthermore, activation of GPER caused depolarization of ON cells, potentiated pain and ameliorated morphine analgesia through desensitizing μ-type opioid receptor (MOR)-mediated activation of potassium currents. In contrast, genetic ablation or pharmacological blockade of GPER attenuated pain, enhanced morphine analgesia and delayed the development of morphine tolerance in diverse preclinical pain models. Our data strongly support GPER as a marker for GABAergic ON cells and also illuminate the mechanisms underlying hormonal regulation of pain and analgesia, highlighting GPER as a promising target for the treatment of pain and opioid tolerance.
Learn More >Peripheral nerve injury sensitizes a complex network of spinal cord dorsal horn (DH) neurons to produce allodynia and neuropathic pain. The identification of a druggable target within this network has remained elusive, but a promising candidate is the neuropeptide Y (NPY) Y1 receptor-expressing interneuron (Y1-IN) population. We report that spared nerve injury (SNI) enhanced the excitability of Y1-INs and elicited allodynia (mechanical and cold hypersensitivity) and affective pain. Similarly, chemogenetic or optogenetic activation of Y1-INs in uninjured mice elicited behavioral signs of spontaneous, allodynic, and affective pain. SNI-induced allodynia was reduced by chemogenetic inhibition of Y1-INs, or intrathecal administration of a Y1-selective agonist. Conditional deletion of in DH neurons, but not peripheral afferent neurons prevented the anti-hyperalgesic effects of the intrathecal Y1 agonist. We conclude that spinal Y1-INs are necessary and sufficient for the behavioral symptoms of neuropathic pain and represent a promising target for future pharmacotherapeutic development of Y1 agonists.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a challenging condition to treat, and arises due to severe, dose-limiting toxicity of chemotherapeutic drugs such as paclitaxel. This often results in debilitating sensory and motor deficits that are not effectively prevented or alleviated by existing therapeutic interventions. Recent studies have demonstrated the therapeutic effects of Meteorin, a neurotrophic factor, in reversing neuropathic pain in rodent models of peripheral nerve injury induced by physical trauma. Here, we sought to investigate the potential antinociceptive effects of recombinant mouse Meteorin (rmMeteorin) using a paclitaxel-induced peripheral neuropathy model in male and female mice. Paclitaxel treatment (4 × 4mg/kg, i.p.) induced hind paw mechanical hypersensitivity by day 8 after treatment. Thereafter, in a reversal dosing paradigm, five repeated injections of rmMeteorin (0.5 and 1.8mg/kg s.c. respectively) administered over 9 days produced a significant and long-lasting attenuation of mechanical hypersensitivity in both sexes. Additionally, administration of rmMeteorin (0.5 and 1.8mg/kg), initiated before and during paclitaxel treatment (prevention dosing paradigm), reduced the establishment of hind paw mechanical hypersensitivity. Repeated systemic administration of rmMeteorin in both dosing paradigms decreased histochemical signs of satellite glial cell reactivity as measured by glutamine synthetase and connexin 43 protein expression in the DRG. Additionally, in the prevention administration paradigm rmMeteorin had a protective effect against paclitaxel-induced loss of intraepidermal nerve fibers. Our findings indicate that rmMeteorin has a robust and sustained antinociceptive effect in the paclitaxel-induced peripheral neuropathy model and the development of recombinant human Meteorin could be a novel and effective therapeutic for CIPN treatment. Perspective: Chemotherapy neuropathy is a major clinical problem that decreases quality of life for cancer patients and survivors. Our experiments demonstrate that Meteorin treatment alleviates pain-related behaviors, and signs of neurotoxicity in a mouse model of paclitaxel neuropathy.
Learn More >pioids are commonly used for treating chronic pain. However, with continued use, they may induce tolerance and/or hyperalgesia, which limits therapeutic efficacy. The human mechanisms of opioid-induced tolerance and hyperalgesia are significantly understudied, in part, because current models cannot fully recapitulate human pathology. Here, we engineered novel human spinal microphysiological systems (MPSs) integrated with plug-and-play neural activity sensing for modeling human nociception and opioid-induced tolerance. Each spinal MPS consists of a flattened human spinal cord organoid derived from human stem cells and a 3D printed organoid holder device for plug-and-play neural activity measurement. We found that the flattened organoid design of MPSs not only reduces hypoxia and necrosis in the organoids, but also promotes their neuron maturation, neural activity, and functional development. We further demonstrated that prolonged opioid exposure resulted in neurochemical correlates of opioid tolerance and hyperalgesia, as measured by altered neural activity, and downregulation of μ-opioid receptor expression of human spinal MPSs. The MPSs are scalable, cost-effective, easy-to-use, and compatible with commonly-used well-plates, thus allowing plug-and-play measurements of neural activity. We believe the MPSs hold a promising translational potential for studying human pain etiology, screening new treatments, and validating novel therapeutics for human pain medicine.
Learn More >Chronic pain prevalence among US adults increased between 2010 and 2019. Yet little is known about trends in the use of prescription opioids and nonpharmacologic alternatives in treating pain.
Learn More >We have made great strides in understanding how the human brain constructs the multidimensional experience of pain – both acute and chronic – over the past few decades. Pain wears many guises, but at its core, it hurts. How is this core component of pain represented in the brain, and how can we target it for relief?
Learn More >Acid-sensing ion channels (ASICs) play a critical role in nociception in human sensory neurons. Four genes ( and ) encoding multiple subunits through alternative splicing have been identified in humans. Real time-PCR experiments showed strong expression of three subunits , , and in human dorsal root ganglia; however, their detailed expression pattern in different neuronal populations has not been investigated yet. In the current study, using an hybridization approach (RNAscope), we examined the presence of , , and mRNA in three subpopulations of human dorsal root ganglia neurons. Our results revealed that and were present in the vast majority of dorsal root ganglia neurons, while was only expressed in less than half of dorsal root ganglia neurons. The distribution pattern of the three subunits was the same across the three populations of dorsal root ganglia neurons examined, including neurons expressing the REarranged during Transfection (RET) receptor tyrosine kinase, calcitonin gene-related peptide, and a subpopulation of nociceptors expressing Transient Receptor Potential Cation Channel Subfamily V Member 1. These results strongly contrast the expression pattern of in mice since our previous study demonstrated differential distribution of among the various subpopulation of dorsal root ganglia neurons. Given the distinct acid-sensitivity and activity dynamics among different ASIC channels, the expression differences between human and rodents should be taken under consideration when evaluating the translational potential and efficiency of drugs targeting ASICs in rodent studies.
Learn More >Opioid drugs influence multiple brain circuits in parallel to produce analgesia as well as side effects, including respiratory depression. At present, we do not have real-time clinical biomarkers of these brain effects. Here, we describe the results of an experiment to characterize the electroencephalographic signatures of fentanyl in humans. We find that increasing concentrations of fentanyl induce a frontal theta band (4 to 8 Hz) signature distinct from slow-delta oscillations related to sleep and sedation. We also report that respiratory depression, quantified by decline in an index of instantaneous minute ventilation, occurs at ≈1700-fold lower concentrations than those that produce sedation as measured by reaction time. The electroencephalogram biomarker we describe could facilitate real-time monitoring of opioid drug effects and enable more precise and personalized opioid administration.
Learn More >To develop and validate updated classification criteria for giant cell arteritis (GCA).
Learn More >This study probes into the function and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived exosomes loaded with miR-150-5p in mechanical allodynia.
Learn More >To develop and validate updated classification criteria for giant cell arteritis (GCA).
Learn More >The collection of increasing amounts of data in health care has become relevant for pain therapy and research. This poses problems for analyses with classical approaches, which is why artificial intelligence (AI) and machine learning (ML) methods are being included into pain research. The current literature on AI and ML in the context of pain research was automatically searched and manually curated. Common machine learning methods and pain settings covered were evaluated. Further focus was on the origin of the publication and technical details, such as the included sample sizes of the studies analyzed with ML. Machine learning was identified in 475 publications from 18 countries, with 79% of the studies published since 2019. Most addressed pain conditions included low back pain, musculoskeletal disorders, osteoarthritis, neuropathic pain, and inflammatory pain. Most used ML algorithms included random forests and support vector machines; however, deep learning was used when medical images were involved in the diagnosis of painful conditions. Cohort sizes ranged from 11 to 2,164,872, with a mode at n = 100; however, deep learning required larger data sets often only available from medical images. Artificial intelligence and ML, in particular, are increasingly being applied to pain-related data. This report presents application examples and highlights advantages and limitations, such as the ability to process complex data, sometimes, but not always, at the cost of big data requirements or black-box decisions.
Learn More >Laparoscopic TAPP/TEP approaches are well-established options for the cure of inguinal hernias. As in the open approach, mesh fixation and poor-quality biologic response represent controversial questions and are a source of concerns. Furthermore, hernia defect patency represents another problem which seems not well acknowledged among surgeons. These problems are considered the cause of frequent intra and postoperative complications. To overcome these concerns, recently a different concept of cure has emerged. Based on a newly developed dynamic responsive 3D scaffold named ProFlor, a permanent hernia defect obliteration has been finalized. Following its inherent centrifugal expansion due to its dynamic responsivity, this hernia device is positioned fixation free within the defect and induces a probiotic biological response allowing for the re-establishment of the degenerated inguinal barrier. A laparoscopic approach with the 3D scaffold has been tested on 71 patients to demonstrate its effectiveness in reducing intra and postoperative complications. The operated patients presented with bilateral and/or recurrent inguinal hernia. Overall, 122 hernia defects were obliterated with 119 dynamic responsive scaffolds. The procedures were carried out from January 2018 to January 2022 with a defined protocol and detailed procedural steps. The laparoscopic technique with the 3D hernia scaffold allowed for fixation free placement, permanent defect obliteration and dynamically induced regenerative effects. The technique proved effective in reducing intra and postoperative complications. In particular, early postoperative pain and discomfort significantly decreased. No chronic pain and no recurrences were reported during follow up. The results achieved with the described laparoscopic technique seem to embody an innovative concept for inguinal hernia repair. Fixation free, dynamic responsive, permanent defect obliteration, histologically proven regenerative effects are the distinctive features of this 3D scaffold. It seems to embody a more physiological and pathogenetically coherent concept of cure, thus improving treatment results of this widespread disease.
Learn More >Through 2018, three calcitonin gene-related peptide pathway-targeted monoclonal antibodies (CGRP mAbs) had received US Food and Drug Administration (FDA) approval for migraine prevention: erenumab, fremanezumab, and galcanezumab.
Learn More >Clinical studies have demonstrated that decreasing linoleic acid (LA) while increasing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in diets evokes an analgesic effect in headache sufferers. We utilized a rat chronic monoarthritis model to determine if these analgesic effects can be reproduced in rats and to and further probe potential analgesic mechanisms. We fed 8 rats a control diet (with fatty acid levels similar to standard US diets) and 8 rats a low LA diet with added EPA and DHA (H3L6 diet) and after 10 weeks, performed a unilateral intraarticular injection of Complete's Freund Adjuvant (CFA). We evaluated thermal and mechanical sensitivity as well as hind paw weight bearing prior to and at 4 and 20 days post CFA injection. At 28 days post CFA injection rats were euthanized and tissue collected. H3L6 diet fed rats had higher concentrations of EPA and DHA, as well as higher concentrations of oxidized lipids derived from these fatty acids, in hind paw and plasma, compared to control fed rats. LA and oxidized LA metabolites were lower in the plasma and hind paw of H3L6 compared to control fed rats. Diet did not affect thermal or mechanical sensitivity, nor did it affect hind paw weight bearing. In conclusion, the H3L6 diet evoked biochemical changes in rats but did not impact pain related behavioral measures in this chronic monoarthritis model.
Learn More >Neuroinflammation in the peripheral nervous system has been linked to cancer metastasis-induced bone pain. The stimulator of interferon genes (STING), an innate immune sensor for cytosolic DNA, plays an important role in inflammation and cancer metastasis and is reported to be a critical regulator of nociception. Here, we examined the role of STING in primary nociceptive neurons and chronic pain to determine if it could be a new target for treating bone cancer pain (BCP).
Learn More >Early diagnosis and treatment of endometriosis affecting adolescent women are important in preventing chronic pain. Our aim was to analyze the clinical characteristics and severity of symptoms in adolescent patients with endometriosis compared to older patients.
Learn More >Endometriosis is a chronic inflammatory disease that can have serious physical and emotional consequences for patients in terms of pain, quality of life, and infertility. Despite affecting about 10% of women, the pathophysiology and economic impact of the disease are not fully understood. This study aimed to review and summarize research articles quantifying the direct and indirect costs of endometriosis in the context of current national and international treatment guidelines. A search including the terms 'endometriosis' AND 'costs' OR 'cost of illness' OR 'cost analysis' OR 'economic burden' was performed, focusing on studies published between January 2000 and May 2022. Total costs, costs of primary and secondary care, productivity losses, and indirect costs were reported. The medical costs of endometriosis were principally registered in secondary care settings, where surgery was the main cost driver. There was considerable variability of populations and study settings, with the overall direct medical cost range of endometriosis from US$1459 to US$20,239 (2022) per patient per year. An increasing trend has been reported in secondary care costs over time; however, not enough data were available at this time to evaluate inpatient and outpatient costs versus treatment strategies. Similarly, further research is required to evaluate the costs and potential savings associated with new therapies. Numerous studies have evaluated the indirect costs of endometriosis in recent years, finding costs between US$4572 and US$14,079 (2022). Currently, limited data are available on the economic burden of the disease at the patient level.
Learn More >Patients with persistent and severe dry eye disease (DED) have corneal hypersensitivity, resulting in ocular pain, and diquafosol sodium, a potent P2Y receptor agonist, is commonly used to improve the resultant tear film stability. This study determined the effects of diquafosol instillation on the suppression of trigeminal subnucleus caudalis (Vc) neuronal activity and ocular pain by enhancing tear film stability in the model for chronic DED. The effects of diquafosol on the ocular surface were assessed by the topical application for 28 days, starting from the 14th day since unilateral exorbital gland removal (chronic DED). Loss of tear volume secretion in chronic DED rats was significantly reversed by diquafosol instillation after 28 days, compared with saline treatment. The number of eyeblinks and pERK-IR neurons in the superficial laminae of Vc following hypertonic saline administration to the ocular surface was lower in diquafosol-treated chronic DED rats than in saline-treated rats. The neuronal activity evoked by hypertonic saline and mechanical stimulation along with the spontaneous neuronal activity in the superficial laminae of the Vc were suppressed in diquafosol-treated chronic DED rats. These findings suggest that ocular surface instillation of diquafosol for 28 days attenuates the neuronal hyperactivity in the Vc and the ocular pain that often occurs in chronic DED.
Learn More >Neuropathic pain (NP) is the cardinal symptom of neural injury, and its underlying molecular mechanism needs further investigation. Complements, especially complement 3 (C3), are involved in the pathophysiology of many neurological disorders, while the specific role of C3 in NP is still obscure. In this study, we found that both C3 and its receptor C3aR were upregulated in the spinal dorsal horn in a rat chronic constriction injury (CCI) model. In addition, C3 was mainly detected in astrocytes, while C3aR was expressed in microglia and neuron. Intrathecal injection of C3 antibody and C3aR antagonist alleviated NP in CCI model together with reduced M1 polarization of microglia. Our finding suggested that blockade of the C3/C3aR pathway might be a novel strategy for NP.
Learn More >The purpose of this study was to perform a systematic review of the available literature on morphological and functional brain changes measured by modern neuroimaging techniques in patients suffering from chronic cancer-related pain. A systematic search was conducted in PubMed, Embase, and Web of Science using different keyword combinations. In addition, a hand search was performed on the reference lists and several databases to retrieve supplementary primary studies. Eligible articles were assessed for methodological quality and risk of bias and reviewed by two independent researchers. The search yielded only four studies, three of which used MRI and one PET-CT. None of the studies measured longitudinal morphological (i.e., gray or white matter) changes. All studies investigated functional brain changes and found differences in specific brain regions and networks between patients with chronic cancer-related pain and pain-free cancer patients or healthy volunteers. Some of these alterations were found in brain networks that also show changes in non-cancer populations with chronic pain (e.g., the default mode network and salience network). However, specific findings were inconsistent, and there was substantial variation in imaging methodology, analysis, sample size, and study quality. There is a striking lack of research on morphological brain changes in patients with chronic cancer-related pain. Moreover, only a few studies investigated functional brain changes. In the retrieved studies, there is some evidence that alterations occur in brain networks also involved in other chronic non-cancer pain syndromes. However, the low sample sizes of the studies, finding inconsistencies, and methodological heterogeneity do not allow for robust conclusions.
Learn More >This manuscript uses the perspectives and insights that emerged from the Analgesic Museum conference held virtually on March 11, 2022 as a mechanism for considering the role museums and artists can play in the public health effort to reduce the burden of persistent pain. One hundred and fifty-seven individuals from 22 countries registered for the Analgesic Museum conference. The event explored the intersection of art and pain management practices with presentations centered on three domains of interest: exhibition development, arts experiences and practices, and research and creative scholarship.
Learn More >Psoriasis impacts various aspects of patients' health-related quality of life and is associated with sleep problems. However, research discussing the associations between interleukin-17 blockage therapies and sleep problems in patients with psoriasis is insufficient. We aimed to assess the effectiveness of brodalumab in alleviating sleep problems in real-life patients with plaque psoriasis. This analysis was part of the single-arm, open-label, multicenter, prospective, cohort study, ProLOGUE (study period October 2017-March 2020), which involved Japanese patients with plaque psoriasis. Assessments included correlation of Medical Outcomes Study Sleep Scale-Revised (MOS Sleep-R) scores (Sleep Problems Index-II [SPI-II] and MOS Sleep-R subscale scores) with multiple patient-reported outcome scores and the Psoriasis Area and Severity Index (PASI) at baseline. Additionally, change from baseline in MOS Sleep-R scores was assessed at weeks 12 and 48 of brodalumab treatment. Seventy-three patients were enrolled (male 82.2%, median age 54.0 years). At baseline, the SPI-II score correlated with the Patient Health Questionnaire-8 score (Spearman correlation coefficient [ρ] = -0.474) and weakly correlated with the Itch Numeric Rating Scale (NRS; ρ = -0.366), Skin Pain NRS (ρ = -0.275), and all Treatment Satisfaction Questionnaire for Medication-9 domain scores (ρ = 0.270, ρ = 0.303, and ρ = 0.322 for effectiveness, convenience, and global satisfaction, respectively) but did not correlate with the PASI score. The SPI-II score and MOS Sleep-R subscale scores, except the Snoring score (p = 0.0319), did not significantly change from baseline to week 12 of brodalumab treatment. In conclusion, treatment with brodalumab did not improve overall sleep problems in real-life patients with plaque psoriasis, suggesting that sleep problems require attention in daily clinical practice (Japan Registry of Clinical Trials identifier, jRCTs031180037).
Learn More >Metformin is the first-line oral treatment for type 2 diabetes mellitus and is prescribed to more than 150 million people worldwide. Metformin's effect as a glucose-lowering drug is well documented but the precise mechanism of action is unknown. A recent finding of an association between paternal metformin treatment and increased numbers of genital birth defects in sons and a tendency towards a skewed secondary sex ratio with less male offspring prompted us to focus on other evidence of reproductive side effects of this drug. Metformin in humans is documented to reduce the circulating level of testosterone in both men and women. In experimental animal models, metformin exposure induced sex-specific reproductive changes in adult rat male offspring with reduced fertility manifested as a 30% decrease in litter size and metformin exposure to fish, induced intersex documented in testicular tissue. Metformin is excreted unchanged into urine and feces and is present in wastewater and even in the effluent of wastewater treatment plants from where it spreads to rivers, lakes, and drinking water. It is documented to be present in numerous freshwater samples throughout the world – and even in drinking water. We here present the hypothesis that metformin needs to be considered a potential reproductive toxicant for humans, and probably also for wildlife. There is an urgent need for studies exploring the association between metformin exposure and reproductive outcomes in humans, experimental animals, and aquatic wildlife.
Learn More >Fibromyalgia is a heterogenous primary pain syndrome whose severity has been associated with descending pain modulatory system (DPMS) function and functional connectivity (FC) between pain processing areas. The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism has been linked to vulnerability to chronic pain. In this cross-sectional imaging genetics study, we investigated fibromyalgia, the relationship between BDNF Val66Met heterozygous genotypes (Val/Met), and the functional connectivity (FC) response pattern to acute pain stimulus in the motor (MC) and prefrontal (PFC) cortex assessed by near-infrared spectroscopy (fNIRS) before and after a cold pressor test utilizing water (0-1 °C). Also, we assessed the relationship between this genotype with the DPMS function and quality of life. We included 42 women (Val/Val = 30; Val/Met = 12) with fibromyalgia, ages 18-65. The MANCOVA comparing Val/Met to Val/Val genotypes showed higher ΔFC between left(l)-PFC-l-MC (β = 0.357, p = 0.048), l-PFC-right(r)-PFC (β = 0.249, p = 0.012), l-PFC-r-MC (β = 0.226, p = 0.022), and l-MC-r-PFC (β = 0.260, p = 0.016). Val/Met genotypes showed higher efficiency of the DPMS and lower disability due to pain. Here we show that fibromyalgia patients carrying the Val/Met BDNF genotype presented an increased ΔFC across MC and PFC in response to acute pain associated with differences in acute pain perception and fibromyalgia symptoms.
Learn More >Glial cells, such as microglia and astrocytes, in the trigeminal spinal subnucleus caudalis (Vc) are activated after trigeminal nerve injury and interact with Vc neurons to contribute to orofacial neuropathic pain. Complement C1q released from microglia has been reported to activate astrocytes and causes orofacial mechanical allodynia. However, how C1q-induced phenotypic alterations in Vc astrocytes are involved in orofacial pain remains to be elucidated. Intracisternal administration of C1q caused mechanical allodynia in the whisker pad skin and concurrent significant upregulation of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 in the Vc. Immunohistochemical analyses clarified that C1q induces a significant increase in the cytokine interleukin (IL)-1β, predominantly in Vc astrocytes and partially in Vc microglia. The number of c-Fos-positive neurons in the Vc increased significantly in response to C1q. IL-1 receptor antagonist (IL-1Ra) was used to analyze the involvement of IL-1β in C1q-induced mechanical allodynia. Intracisternal administration of IL-1Ra ameliorated C1q-induced orofacial mechanical allodynia. The present findings suggest that IL-1β released from activated astrocytes and microglia in the Vc mediates C1q-induced orofacial pain.
Learn More >Osteoarthritis (OA) is a complex chronic inflammatory disease characterized by articular degeneration and pain. Recent studies have identified interleukin 6 (IL-6) as a potential mediator leading to OA, but the therapeutic effects of inhibiting IL-6 signaling in intreating OA need to be further clarified. Here, we identified the intracellular signal transduction induced by recombinant IL-6 and focused on the impact of tyrphostin AG490 (a JAK2 inhibitor) on cartilage degeneration and OA pain. We found that IL-6 increased the inflammatory cytokines production and hypertrophic markers expression of primary mouse chondrocytes by activating JAK2/STAT3. Meanwhile, tyrphostin AG490 significantly attenuated articular degeneration and osteophyte formation in experimental mice with anterior cruciate ligament transection (ACLT) surgery. In vivo electrophysiological experiments showed that articular stimulation of IL-6 induced spinal hyperexcitability, which was prevented by coinjection of tyrphostin AG490. Specifically, compared with DMSO-treated ACLT mice, tyrphostin AG490 improved ambulate activity of mice and abolished the enhancement of serum bradykinin induced by IL-6. Together, we suggest that tyrphostin AG490 protected against progression of OA and improved OA prognosis by reducing cartilage degeneration and arthritis pain. Our findings provide further evidence for targeting IL-6 signaling in the treatment of OA.
Learn More >measures such as disability-adjusted life years (DALY) are becoming increasingly important for the standardized assessment of the burden of disease due to death and disability. The BURDEN 2020 pilot project was designed as an independent burden-ofdisease study for Germany, which was based on nationwide data, but which also yielded regional estimates.
Learn More >An estimated 5.5 million people in England have high-impact chronic pain, which is severe pain associated with significant disability. Current models of healthcare often fail to address their broad range of symptoms and address their complex non-medical needs.
Learn More >Lumbar disc herniation is seen in 5-15% of patients with lumbar back pain and is the most common spine disorder demanding surgical correction. Spinal surgery is one of the most effective management for these patients. However, current surgical techniques still present complications such as chronic pain in 10-40% of all patients who underwent lumbar surgery, which has a significant impact on patients' quality of life. Research studies have shown that transcutaneous electrical acupoint stimulation (TEAS) may reduce the cumulative dosage of intraoperative anesthetics as well as postoperative pain medications in these patients.
Learn More >A biopsychosocial rehabilitation is recommended for chronic nonspecific low back pain (CNLBP); however, its effectiveness compared to the traditional supervised exercise therapy of CNLBP treatment is still unclear.
Learn More >This study aims to study the effect of mindfulness-based program on the psychological, biomechanical and inflammatory domains of patients with chronic low back pain.
Learn More >The study aimed to examine the clinical and neurophysiological predictors of motor event-related desynchronization (ERD) and synchronization (ERS) in patients with chronic pain due to knee osteoarthritis (KOA).
Learn More >To examine the association between chronic spontaneous urticaria (CSU) and interstitial cystitis/bladder pain syndrome (IC/BPS).
Learn More >GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC).
Learn More >An overlap between the skin disease rosacea and the headache disease migraine has been established; however, the magnitude of this overlap and the distribution between subtypes/phenotypes remains unclear.
Learn More >To identify good practice in the community management of chronic pain, and to understand the perspective of a group of healthcare service users towards the management of chronic pain using technology during the COVID-19 pandemic.
Learn More >Migraine and dementia, two major public health challenges, are associated, but more knowledge is needed to understand their relationship. Objectives of this study were to investigate 1) the association between non-self-reported measures of migraine and dementia, and whether dementia was associated with 2) migraine without aura (MO) and with aura (MA) in combination with migraine medication use, and 3) migraine severity operationalized as the number of migraine prescriptions.
Learn More >Neuropathic pain(NP) is derived from the dysfunctions of nerve system. The current research is to explore the impact and mechanism of miR-19a-3p in neuropathic pain in rats.
Learn More >The impact of migraine without aura (MWoA) on cognitive function remains controversial, especially given the sparse literature on emotional memory.
Learn More >Neuropathic pain (NP) following a spinal cord injury (SCI) is often hard to control and therapies should be focused on the physical, psychological, behavioral, social, and environmental factors that may contribute to chronic sensory symptoms. Novel therapeutic treatments for NP management should be based on the combination of pharmacological and nonpharmacological options. Some of them are addressed in this review with a focus on mechanisms and novel treatments. Several reports demonstrated an aberrant expression of non-coding RNAs (ncRNAs) that may represent key regulatory factors with a crucial role in the pathophysiology of NP and as potential diagnostic biomarkers. This review analyses the latest evidence for cellular and molecular mechanisms associated with the role of circular RNAs (circRNAs) in the management of pain after SCI. Advantages in the use of circRNA are their stability (up to 48 h), and specificity as sponges of different miRNAs related to SCI and nerve injury. The present review discusses novel data about deregulated circRNAs (up or downregulated) that sponge miRNAs, and promote cellular and molecular interactions with mRNAs and proteins. This data support the concept that circRNAs could be considered as novel potential therapeutic targets for NP management especially after spinal cord injuries.
Learn More >Low-back pain requires comprehensive care using a biopsychosocial model. The psychologic dimension plays an important role, but the link between sagittal alignment and a given psychopathological profile is little studied. The aim of this study was to analyze the psychopathological profiles and sagittal parameters of a population with low-back pain and to assess the link.
Learn More >The primary aim of this pilot study was to test the feasibility and acceptability of a prototype of a novel digital system enabling somatosensory training at home by means of a gamified mobile application in patients with chronic pain. The secondary aims were to test the effect size of the intervention on clinical outcomes to power a subsequent randomized controlled trial. We conducted a pilot randomized controlled trial in patients with fibromyalgia. This was an 8-week crossover study, which included a 4-week somatosensory training phase (daily use with the novel digital system) and a 4-week control phase (no use of this new system) in a random order. Feasibility was tested by objectively measuring the adherence and retention rates. Acceptability and changes in pain and disability were measured through data from subjective questionnaires. Thirty-five patients completed the study. The satisfaction questionnaire indicated high training enjoyment, ease of use for daily training and interest to continue to use the intervention after the study. The adherence (93%) and retention (94%) rates were high. The effect sizes were moderate for pain intensity (0.57). The novel gamified technology for remotely delivered somatosensory training is feasible in a group of patients with fibromyalgia, and results in high engagement, satisfaction, and adherence. A subsequent clinical trial with the final version of the technology platform, including a longer training with more sensory training tasks and a bigger sample size is necessary.
Learn More >Physical activity, particularly walking, is commonly used for the treatment of diseases such as low back pain. In this study, the effects of walking wearing the new ToneFit Reha training belt (TFR) were compared to both Nordic walking and regular walking. The TFR is intended to intensify the effects of walking through the integration of two adjustable resistance handles.Ten patients with low back pain performed regular walking, Nordic walking and walking with the TFR in a movement laboratory. The kinematics of the trunk, upper extremities and lower extremities were measured, and the activity of the trunk and upper extremity muscles recorded. Data were analysed by repeated-measures ANOVA and paired t-test.Kinematics indicated that walking with the TFR introduces instability that was mitigated by a delayed peak trunk rotation (peak at 63.3% gait cycle, vs. 52.8% in walking (p=0.001) and 51.0% in NW (p=0.007)). Upper extremity kinematics (constrained elbow flexion, high peak shoulder abduction) showed movement patterns that need to be considered when training over a longer period. Increased muscle activity was observed especially for upper extremity muscles, when training with TFR. Overall, walking with the TFR was found to be a suitable therapy for use in a rehabilitation setting.
Learn More >Good clinical outcomes in orthopaedics are largely dictated by the biomedical model, despite mounting evidence of the role of psychosocial factors. Understanding orthopaedic providers' conceptualizations of good clinical outcomes and what facilitates and hinders them may highlight critical barriers and opportunities for training providers on biopsychosocial models of care and integrating them into practice.
Learn More >Diclofenac etalhyaluronate (DF-HA) is a recently developed analgesic conjugate of diclofenac and hyaluronic acid that has analgesic and anti-inflammatory effects on acute arthritis. In this study, we investigated its analgesic effect on osteoarthritis, using a rat model of monoiodoacetate (MIA).
Learn More >Insights into the pathophysiology of many non-immune-mediated drug reactions referred to as toxicities, sensitivities, intolerances, or pseudoallergies have resulted from research identifying the mastocyte-related G-protein-coupled receptor (GPCR) member X2 (MRGPRX2), a human mast cell receptor mediating adverse reactions without the involvement of antibody priming. Opioid-induced degranulation of mast cells, particularly morphine, provoking release of histamine and other preformed mediators and causing hemodynamic and cutaneous changes seen as flushing, headache and wheal and flare reactions in the skin, is an example of results of MRGPRX2 activation. Opioids including morphine, codeine, dextromethorphan and metazocine as well as endogenous prodynorphin opioid peptides activate MRGPRX2 at concentrations causing mast cell degranulation. Unlike the canonical opioid receptors, MRGPRX2 shows stereochemical recognition preference for dextro rather than levo opioid enantiomers. Opioid analgesic drugs (OADs) display a range of histamine-releasing potencies from the strong releaser morphine to doubtful releasers like hydromorphone and the non-releaser fentanyl. Whether there is a correlation between histamine release by individual OADs, MRGPRX2 activation, and presence or absence of adverse cutaneous effects is not known. To investigate the question, ongoing research with recently pursued methodologies and strategies employing basophil and mast cell tests resulting from MRGPRX2 insights should help to elucidate whether or not an opioid's histamine-releasing potency, and its property of provoking an adverse reaction, are each a reflection of its activation of MRGPRX2.
Learn More >The importance of pain education is widely accepted and recognized. This is a key part of educating the undergraduate and postgraduate healthcare workforce is an essential strategy for promoting effective pain practice. This study aims to evaluate the pain management module training courses for newly graduated doctors to address the knowledge gap between specialist care and primary care physicians. This was an observational study of an evaluation of a pain education project focused on neuropathic pain management core competency was provided. Multimodal teaching approaches such as didactic teaching and vignettes of cases discussion, video teaching, and learning module. A pretest survey was carried out to assess the baseline knowledge of the participants. Completion of the post-test and participant experience questionnaire were collected. Comparison of the pre-and post-test scores for all participants was undertaken using the Wilcoxon signed-ranked test with effect size calculated. The participant's experience questionnaire scores were analyzed descriptively to produce mean and standard deviations from each question. A total of 274 participants completed all of the course sections from the average of 350 eligible participants. Of 274 participants, more than half were female (64.96%), with more than half participants being General Practitioner (54.38%) followed by a neurologist (35.04%). For all sessions, a Wilcoxon signed-rank test outlined that differences between all pre-and post-test scores were significant (P < .001). There was a marked improvement in the post-test as evidenced by statistically significant increases in mean scores differences. We developed an educational training courses for physicians to address the limitation in existing medical undergraduate training of neuropathic pain management. The training led to improvement in participant's knowledge and skills with positive outcomes.
Learn More >Pediatric primary chronic pain disorders come with diagnostic uncertainty, which may obscure diagnostic expectations for referring providers and the decision to accept or re-direct patients into interdisciplinary pediatric chronic pain programs based on diagnostic completeness. We aimed to attain expert consensus on diagnostic expectations for patients who are referred to interdisciplinary pediatric chronic pain programs with six common primary chronic pain diagnoses.
Learn More >Utilizing cannabis as a therapeutic option for chronic pain (CP) has increased significantly. However, data regarding the potential immunomodulatory effects of cannabis in CP patients remain scarce. We aimed at exploring the relationship between cannabis use and inflammatory cytokines and chemokines among a cohort of CP patients. Adult patients with a CP diagnosis and medical authorization of cannabis were enrolled. Patients completed validated clinical questionnaires and self-reported the effectiveness of cannabis for symptom management. Patients' blood and cannabis samples were analyzed for the presence of four major cannabinoids, two major cannabinoid metabolites, 29 different cytokines/chemokines, and cortisol. The multivariable linear regression model was used to identify cannabis and patient factors associated with immune markers. Fifty-six patients (48±15 years; 64% females) were included, with dried cannabis (53%) being the most common type of cannabis consumed. Seventy percent of products were considered delta-9-tetrahydrocannabinol (Δ-THC)-dominant. The majority of patients (96%) self-reported effective pain management, and 76% reported a significant decrease in analgesic medication usage (≤0.001). Compared with males, female patients had higher plasma levels of cannabidiol (CBD), cannabidiolic acid, Δ-THC, and 11-hydroxy-Δ-tetrahydrocannabinol but lower concentrations of delta-9-tetrahydrocannabinolic acid and 11-nor-9-carboxy-Δ-tetrahydrocannabinol (THC-COOH). Females had significantly lower eotaxin levels (=0.04) in comparison to male patients. The regression analysis indicated that high cannabis doses were related to increased levels of interleukin (IL)-12p40 (=0.02) and IL-6 (=0.01), whereas female sex was associated with decreased eotaxin (≤0.01) concentrations. Blood CBD levels were associated with lower vascular endothelial growth factor (=0.04) concentrations, and THC-COOH was a factor related to decreased tumor necrosis factor alpha (=0.02) and IL-12p70 (=0.03). This study provides further support for the patient-perceived effectiveness of cannabis in managing CP symptoms and reducing analgesic medication consumption. The results suggest a potential sex difference in metabolizing cannabinoids, and the varying immune marker concentrations may support a possible immunomodulatory effect associated with patient sex and cannabis product type. These preliminary findings provide grounds for further validation using larger, well-designed studies with longer follow-up periods.
Learn More >Pain catastrophizing (PC) is a negative cognitive distortion to actual or anticipated pain. This study aims to investigate the relationship between pain catastrophizing, emotional intelligence, pain intensity, and quality of life (QoL) in cancer patients with chronic pain. Eighty-nine outpatients with chronic pain attending pain clinics and palliative care units were recruited. Participants were men (42.7%) and women (57.3%) with an average age of 56.44 years (SD = 14.82). Self-report psychological measures were completed, including a measure of emotional intelligence, a standard measure of PC, a scale assessing pain intensity, and a scale measuring QoL. The PC scale was found to assess three correlated yet different dimensions of pain catastrophizing (helplessness, magnification, and rumination). Moreover, as expected, patients with PC scale scores ≥ 30 had lower scores in functional QoL dimensions and higher scores in the fatigue, pain, and insomnia symptom dimensions. Regression analyses demonstrated that PC (B = - 0.391, p = 0.004), pain intensity (B = - 1.133, p < 0.001), and education (B = 2.915, p = 0.017) remained the only significant variables related to QoL, when controlling for demographic and clinical confounders. Regarding mediating effects, PC and pain intensity were jointly found to be significant mediators in the relationship between emotional intelligence and QoL. Results are discussed in the context of the clinical implications regarding interventions designed to improve cancer patients' quality of life and offer new insight, understanding, and evaluation targets in the field of pain management.
Learn More >Neuropathic pain is a debilitating disease caused by damage or diseases of the somatosensory nervous system. Previous research has indicated potential associations between neuropathic pain and aging. However, the mechanisms by which they are interconnected remain unclear. In this study, we aim to identify the common differentially expressed genes (co-DEGs) between neuropathic pain and aging through integrated bioinformatics methods and further explore the underlying molecular mechanisms.
Learn More >Several lipoxygenase enzymes and cyclooxygenase-2 stereoselectively convert the polyunsaturated fatty acids arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and n-3 docosapentaenoic acid into numerous oxygenated products. Biosynthetic pathway studies have shown, during the resolution phase of acute inflammation, that distinct families of endogenous products are formed. These products were named specialized pro-resolving mediators, given their specialized functions in the inflammation-resolution circuit, enhancing the return of inflamed and injured tissue to homeostasis. The lipoxins, resolvins, protectins and maresins, together with the sulfido-conjugates of the resolvins, protectins and maresins, constitute the four individual families of these local mediators. When administrated in vivo in a wide range of human disease models, the specialized pro-resolving mediators display potent bioactions. The detailed and individual biosynthetic steps constituting the biochemical pathways, the metabolism, recent reports on structure-function studies and pharmacodynamic data of the protectins, are presented herein. Emphasis is on the structure-function results on the recent members of the sulfido conjugated protectins and further metabolism of protectin D1. Moreover, the members of the individual families of specialized pro-resolving mediators and their biosynthetic precursor are presented. Today 43 specialized pro-resolving mediators possessing pro-resolution and anti-inflammatory bioactions are reported and confirmed, constituting a basis for resolution pharmacology. This emerging biomedical field provides a new approach for drug discovery, that is also discussed.
Learn More >Structural and functional changes of the brain occur in many chronic pain conditions, including chronic low back pain (CLBP), and these brain abnormalities can be reversed by effective treatment. Research on the clinical applications of non-invasive brain neuromodulation (NIBS) techniques for chronic pain is increasing. Unfortunately, little is known about the effectiveness of NIBS on CLBP, which limits its application in clinical pain management. Therefore, we summarized the effectiveness and limitations of NIBS techniques on CLBP management and described the effects and mechanisms of NIBS approaches on CLBP in this review. Overall, NIBS may be effective for the treatment of CLBP. And the analgesic mechanisms of NIBS for CLBP may involve the regulation of pain signal pathway, synaptic plasticity, neuroprotective effect, neuroinflammation modulation, and variations in cerebral blood flow and metabolism. Current NIBS studies for CLBP have limitations, such as small sample size, relative low quality of evidence, and lack of mechanistic studies. Further studies on the effect of NIBS are needed, especially randomized controlled trials with high quality and large sample size.
Learn More >Pruritus of chronic spontaneous urticaria (CSU) is one of the most common and irritating sensations that severely affects the quality of life. However, the changes in the functional connectivity (FC) between thalamic subregions and other brain regions have not been fully elucidated. This study aimed to explore the potential changes in brain neural circuits by focusing on various subregions of the thalamus in patients with CSU pruritus to contribute to the understanding of chronic pruritus from the perspective of central mechanisms. A total of 56 patients with CSU and 30 healthy controls (HCs) completed the data analysis. Urticaria Activity Score 7 (UAS7), pruritus visual analog score (VAS-P), Dermatological Life Quality Index (DLQI), and immunoglobulin E (IgE) values were collected to assess clinical symptoms. Seed-based resting-state functional connectivity (rs-FC) analysis was used to assess relevant changes in the neural circuits of the brain. Compared to HCs, seeds within the caudal temporal thalamus (cTtha) on the right side of patients with CSU showed increased rs-FC with the cerebellum anterior lobe (CAL). Seeds within the lateral prefrontal thalamus (lPFtha) on the right side showed increased rs-FC with both CAL and pons, while those within the medial prefrontal thalamus (mPFtha) on the right side showed increased rs-FC with both CAL and the dorsal lateral prefrontal cortex (dlPFC) on the right side. Seeds within the posterior parietal thalamus (PPtha) on the right side showed increased rs-FC with the cerebellum posterior lobe (CPL) on the left side. The UAS7 values and IgE levels were positively correlated with the rs-FC of the right dlPFC. Our results suggest that patients with CSU may exhibit stronger rs-FC alterations between certain thalamic subregions and other brain regions. These changes affect areas of the brain involved in sensorimotor and scratching.
Learn More >Neuropathic pain is sometimes difficult to manage because of limited efficacy of analgesic monotherapy even at high doses. Combination therapy may help address this issue, but there is little evidence for its effectiveness. Therefore, we evaluated the efficacy of combination therapy with pregabalin, an anchor drug for treating neuropathic pain, using the rat L5 spinal nerve ligation model.
Learn More >Pruritus is a common complication in patients with primary biliary cholangitis (PBC). The pathogenesis is not clear, and also the precise therapeutic measures remain alluring. In order to systematically evaluate the efficacy and safety of drug interventions in the treatment of pruritus associated with PBC, this systemic review and meta-analysis was conducted. The randomized controlled trials (RCTs) on drug interventions in the treatment of pruritus associated with primary cholangitis were searched in the electronic databases of PubMed, EMBASE, Cochrane Library, Web of Science, and ClinicalTrials.gov. Two researchers independently screened the literature, extracted and integrated the data, and assessed the bias risk of the selected literature, according to the . Finally, the STATA 15.0 software was used for the meta-analysis. A total of 23 RCTs involving 2,194 patients were studied, that included 12 pharmacological interventions. In terms of itching relief, compared with placebo, UDCA, methotrexate and GSK2330672 had a definite effect in improving pruritus (pruritus remission rate before and after treatment, 0.05). In terms of serum indexes, compared with placebo group, UDCA, OCA, rifampicin, cyclosporine, NGM282, seladelpar and colchicine may improve blood alkaline phosphatase (ALP) ( 0.05), but only rifampicin showed low heterogeneity. UDCA, bezafibrate, OCA, rifampicin, NGM282 and others may improve blood γ-glutamyl transpeptidase (γ-GGT) ( 0.05), but due to the high heterogeneity and the limitation of research samples, a clear conclusion cannot be drawn. In terms of adverse events, except high (>15 mg/kg/day) and low doses (<13 mg/kg/day) of UDCA increased the incidence of adverse events, there were no risk of increasing the incidence of adverse events compared with placebo ( 0.05), and a moderate dose of UDCA (13-15 mg/kg/day) and malotilate (1,500 mg/day) may also help in reducing the incidence of adverse events ( 0.05). UDCA, methotrexate and GSK2330672 may relieve itching in patients with PBC, but there is a lack of robust evidence to support their effect on ALP or γ-GGT. Due to the heterogeneity in the published studies, based on the present review, we cannot explicitly recommend any specific drug for the treatment of PBC-related pruritus. link-https://osf.io/2g8ya, identifier 10.17605/OSF.IO/2G8YA.
Learn More >The World Health Organization (WHO), in its last review of its International Classification of Diseases, established a new classification for chronic pain. Among the principal categories, of particular interest is chronic primary pain as a new type of diagnosis in those cases in which the etiology of the disease is not clear, being termed as chronic primary visceral pain when it is situated in the thorax, abdomen, or pelvis. Due to the novelty of the term, the objective of the systematic review was to examine the psychopathological and neuropsychological disorders associated with chronic primary visceral pain. We carried out a search of the scientific literature following the PRISMA directives using the Pubmed, Medline, PsycInfo and Scopus databases. A total of 33 articles were selected after applying the inclusion and exclusion criteria. The analysis of the studies showed that most persons with chronic primary visceral pain suffer from at least one psychological disorder; the most prevalent being anxiety, depressive or somatoform disorders. The most frequent psychopathological symptoms are anxiety, depression and somatization. Similarly, the findings are insufficient to determine the existence of deficits in the domains of executive functioning, memory and intelligence. However, the existence of attention biases does seem to be clear. This review supposes a starting point for conceptualizing chronic primary visceral pain. It is necessary to continue further research so as to obtain a better understanding of this pathology and the disorders associated.
Learn More >To systematically evaluate the clinical efficacy of pregabalin and gabapentin in the treatment of postherpetic neuralgia (PHN), including the difference in pain control and occurrence of adverse reactions.
Learn More >To examine associations between factors of social inclusion and participation and productivity loss in employed persons with chronic pain, assessed for an interprofessional pain rehabilitation programme. We hypothesized that factors of social inclusion and participation and work related social factors are significantly associated with productivity when experiencing chronic pain and we expected a moderate effect.
Learn More >Satellite glial cells (SGCs) of the dorsal root ganglia (DRG) ensure homeostasis and proportional excitability of sensory neurons and gained interest in the field of development and maintenance of neuropathic pain. Pigs represent a suitable species for translational medicine with a more similar anatomy and physiology to humans compared to rodents, and are used in research regarding treatment of neuropathic pain. Knowledge of anatomical and physiological features of porcine SGCs is prerequisite for interpreting potential alterations. However, state of knowledge is still limited. In the present study, light microscopy, ultrastructural analysis and immunofluorescence staining was performed. SGCs tightly surround DRG neurons with little vascularized connective tissue between SGC-neuron units, containing, among others, axons and Schwann cells. DRG were mainly composed of large sized neurons (∼59%), accompanied by fewer medium sized (∼36%) and small sized sensory neurons (∼6%). An increase of neuronal body size was concomitant with an increased number of surrounding SGCs. The majority of porcine SGCs expressed glutamine synthetase and inwardly rectifying potassium channel Kir 4.1, known as SGC-specific markers in other species. Similar to canine SGCs, marked numbers of porcine SGCs were immunopositive for glial fibrillary acidic protein, 2',3'-cyclic-nucleotide 3'-phosphodiesterase and the transcription factor Sox2. Low to moderate numbers of SGCs showed aquaporin 4-immunoreactivity (AQP4) as described for murine SGCs. AQP4-immunoreactivity was primarily found in SGCs ensheathing small and medium sized neuronal somata. Low numbers of SGCs were immunopositive for ionized calcium-binding adapter molecule 1, indicating a potential immune cell character. No immunoreactivity for common leukocyte antigen CD45 nor neural/glial antigen 2 was detected. The present study provides essential insights into the characteristic features of non-activated porcine SGCs, contributing to a better understanding of this cell population and its functional aspects. This will help to interpret possible changes that might occur under activating conditions such as pain.
Learn More >Psychological factors of emotional distress and cognition have an important role in the understanding and management of endometriosis; however, their temporal relationship with key pain variables is not fully understood. This exploratory study sought to establish the temporal relationship between psychological and pain-related factors in a 12-month prospective study of 208 Australian women with endometriosis. Participants, aged 18-50 years and living in Australia, were recruited via social media and completed baseline (May 2019) and 12-month follow-up (June 2020) surveys. Participants who reported a diagnosis of endometriosis and menses in the past 12 months were included in the study. Structural equation modelling was used to determine the temporal effects of psychological and pain-related factors in endometriosis. In a covariate-adjusted model, baseline emotional distress was the only variable to predict pain catastrophizing (β = .24, p < .01), functional pain disability (β = .16, p < .05) and concomitant emotional distress (β = .55, p < .001) 12 months later, adjusting for age and chronic illness. Women who exhibit symptoms of distress may be at risk of poorer psychological and physical function at 12 months. Further research is required to understand the impact of psychological management early in the disease course.
Learn More >Appropriate perioperative pain control is essential to aid in patients' recovery after surgery; however, acute postsurgical pain remains poorly treated and there continues to be an overreliance on opiates. Perioperative pain control starts in the operating room, and opiate-free anesthesia (OFA), where no opiates are used intraoperatively, has been proposed as a feasible strategy to further minimize opiates in the perioperative period. In this article, we address the potential benefits and shortcomings of OFA, while exploring tools available to accomplish multimodal anesthesia and ideally OFA, and the evidence behind the techniques proposed.
Learn More >The periaqueductal gray (PAG) is an important relay center for the descending pathways that regulate nociceptive information transduction. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play critical roles in the nerve injury-induced pain hypersensitivity. Previous studies have identified that HCN1 and HCN2 channel protein located in the ventral-lateral periaqueductal gray (vlPAG), a region important for pain regulation. However, it is not clear whether the HCN channel in vlPAG is involved in bone cancer pain (BCP). In this study, we assessed the role of HCN channels in BCP by measuring changes of HCN channel expression and activity in vlPAG neurons in bone cancer rats. In the present study, the BCP model was established by injecting SHZ-88 breast cancer cells into the right tibia bone marrow in rats. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured to evaluate pain behavior in rats. HCN1 and HCN2 channels expression in vlPAG were detected by using Western Blot and immunohistochemistry. In addition, the cAMP level in vlPAG neurons was detected by ELISA, and HCN channel current (I) of vlPAG neurons was recorded by whole cell patch-clamp to evaluate HCN channel activity. As a result, decreased MWT and TWL were observed in rats on 7d after SHZ-88 cell inoculation, and the allodynia was sustained until 21d after inoculation. At the same time, HCN1 and HCN2 channels expression and neuronal I in vlPAG were significantly increased in BCP rats. In addition, the level of cAMP in vlPAG also increased after SHZ-88 cell inoculation. Furthermore, intravlPAG injection of ZD7288 (HCN channels antagonist) could significantly reduce hyperalgesia and the elevation of cAMP in vlPAG in BCP rats. Our observations suggest that the elevation of cAMP may promote the activation of HCN channels in vlPAG in bone cancer rats, thereby promoting the development of bone cancer pain.
Learn More >Dopamine ameliorates hyperglycemic memory-induced microvascular dysfunction in diabetic retinopathy.
Dopamine is a neurotransmitter that mediates visual function in the retina and diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of blindness; however, the role of dopamine in retinal vascular dysfunction in DR remains unclear. Here, we report a mechanism of hyperglycemic memory (HGM)-induced retinal microvascular dysfunction and the protective effect of dopamine against the HGM-induced retinal microvascular leakage and abnormalities. We found that HGM induced persistent oxidative stress, mitochondrial membrane potential collapse and fission, and adherens junction disassembly and subsequent vascular leakage after blood glucose normalization in the mouse retinas. These persistent hyperglycemic stresses were inhibited by dopamine treatment in human retinal endothelial cells and by intravitreal injection of levodopa in the retinas of HGM mice. Moreover, levodopa supplementation ameliorated HGM-induced pericyte degeneration, acellular capillary and pericyte ghost generation, and endothelial apoptosis in the mouse retinas. Our findings suggest that dopamine alleviates HGM-induced retinal microvascular leakage and abnormalities by inhibiting persistent oxidative stress and mitochondrial dysfunction.
Learn More >Painmanagement after oral surgeries is essential to enhance recovery, reduce negative outcomes and improve the experience of the patient. Naltrexone (NTX) is a non-selective opioid receptor antagonist that has been shown to modulate neuro-inflammation when employed in low to ultra-low doses. In addition, ultra-low dose naltrexone (ULDN) has been shown to potentiate opioids' analgesia and to have opioid-sparing effects. Herein it was investigated the effect of ULDN in a model of postoperative orofacial pain in rats, and it was tested the hypothesis that blockade of TLR4-signalling pathway contributes to its antinociceptive effect. Systemic NTX reduced heat hyperalgesia in female rats and heat and mechanical hyperalgesia in male rats after incision surgery. Combined treatment with NTX and morphine, both at ineffective doses, resulted in a significant reduction of heat hyperalgesia in male rats. NTX injection at the incision site failed to change heat hyperalgesia, but injection at the trigeminal ganglion (TG) or subnucleus caudalis (Sp5C) caused a significant reduction in heat hyperalgesia. At these sites, blockade of TLR4 impeded NTX effect. Lipopolysaccharide (LPS) injection in the intraoral mucosa resulted in facial heat hyperalgesia and increase in IL-1β levels in the TG, which were reduced by systemic NTX. Stimulation of macrophages with LPS resulted in increase of nitric oxide, IL-1β and CXCL-2 levels which were reduced by NTX. Altogether, these results provide evidence for an antinociceptive effect of ULDN in postoperative orofacial pain and suggest that blockade of TLR4 and downstream signaling pathway contribute to its effect.
Learn More >Many experimental sleep deprivation (SD) studies were conducted to clarify the causal relationship between sleep and pain. This systematic review and meta-analysis aimed to update the evidence regarding the effects of different experimental SD paradigms on various pain outcomes. Five databases were searched from their inception to June 2022. Separate random-effects models were used to estimate the pooled effect sizes (ES) of different experimental SD paradigms on various pain outcomes. Thirty-one studies involving 699 healthy individuals and 47 individuals with chronic pain were included. For healthy individuals, limited evidence substantiated that total SD significantly reduced pain threshold and tolerance (ES 0.74-0.95), while moderate evidence supported that partial SD significantly increased spontaneous pain intensity (ES 0.30). Very limited to moderate evidence showed that sleep fragmentation significantly increased peripheral and central sensitization in healthy individuals (ES 0.42-0.79). Further, there was very limited evidence that total or partial SD significantly aggravated spontaneous pain intensity in people with chronic pain. Our results accentuated that different SD paradigms differentially increased subjective pain intensity and worsened peripheral/central pain sensitization in healthy individuals, whereas the corresponding findings in people with chronic pain remain uncertain. Further rigorous studies are warranted to quantify their relationships in clinical populations.
Learn More >Pain is a variably experienced symptom during pregnancy, and women scheduled for cesarean delivery, an increasingly common procedure, are a relatively understudied group who may be at higher pain risk. While biopsychosocial factors are known to modulate many types of chronic pain, their contribution to late pregnancy pain has not been comprehensively studied. We aimed to identify biopsychosocial factors associated with greater pain severity and interference during the last week of pregnancy.
Learn More >Fabry disease (FD) is a rare lysosomal storage disorder, characterized by a reduction in α-galactosidase A enzyme activity and the progressive accumulation of globotriaosylceramide (GL3) and its metabolites in the cells of various organs. Agalsidase beta, an enzyme replacement therapy (ERT), is approved for use in patients with FD in Europe, Canada, Australia, South America, and Asia, and is the only ERT approved for use in the United States. In this review, we discuss the clinical relevance of GL3 accumulation, the effect of agalsidase beta on GL3 in target tissues, and the association between treatment-related tissue GL3 clearance and long-term structure, function, or clinical outcomes. Accumulation of GL3 in the kidney, heart, vasculature, neurons, skin, gastrointestinal tract and auditory system correlates to cellular damage and irreversible organ damage, as a result of sclerosis, fibrosis, apoptosis, inflammation, and endothelial dysfunction. Damage leads to renal dysfunction and end-stage renal disease; myocardial hypertrophy with heart failure and arrhythmias; ischemic stroke; neuropathic pain; skin lesions; intestinal ischemia and dysmotility; and hearing loss. Treatment with agalsidase beta is effective in substantially clearing GL3 in a range of cells from the tissues affected by FD. Agalsidase beta has also been shown to slow renal decline and lower the overall risk of clinical progression, demonstrating an indirect link between treatment-related GL3 clearance and stabilization of FD.
Learn More >Considerable functional and structural alterations, or plasticity, in the central nervous system (CNS) are accompanied by numerous chronic pain syndromes. Sensitization of the peripheral (primary hyperalgesia) or central (secondary hyperalgesia) nervous system as unhelpful neuroplasticity may result in stimulus-induced pain (hyperalgesia and allodynia). Furthermore, nociception induces extensive plasticity in the peripheral and central neural systems in pathological disease states. Disease-induced plasticity at both structural and functional levels is evident as alterations in different molecules, synapses, cellular function and network activity. In the present article, we review plasticity-induced pain and pain-induced plasticity. Moreover, we will review the pain matrix. Furthermore, we will focus on recent developments of the CNS alterations in long-lasting pain in some clinical entities encountered in rehabilitation. These clinical entities comprise nonspecific low back pain, complex regional pain syndrome, postamputation phantom pain, fibromyalgia, and chronic pain after spinal cord injury. Moreover, we will review the clinical treatment for the inhibition of pathological pain.
Learn More >Adolescent obesity augments and impedes the treatment of chronic pain. This is associated with increased systemic inflammation and is more prominent in females. In addition, pain and obesity each independently affect the hypothalamic-pituitary-adrenal (HPA) axis. However, the interaction of pain and obesity on the HPA axis and the potential for sexual dimorphism in this phenomenon is not established. We hypothesized that dysregulation of the HPA axis occurs in female human adolescents with chronic pain, obesity, or the combination of the two and is associated with gonadal steroids. We measured serum cortisol, estradiol, and testosterone in 13-17-year-old adolescent females ( = 79) from venous blood drawn during the daytime (0830-1730 h) and analyzed the data and partitioned by morning vs. afternoon sampling time. Subjects were categorized as healthy weight/no pain (controls; BMI = 56 percentile [37-71]), healthy weight with chronic pain, obese without pain (BMI = 97 percentile [95-99]), or the combination of obesity and chronic pain. Serum cortisol was lower with chronic pain and/or obesity compared to healthy controls and was lower with chronic pain and obesity compared to chronic pain alone (healthy weight). The lower serum cortisol in the pain alone group was more prominent in the morning compared to the afternoon. There was no relationship between serum estradiol and testosterone and study group. The decrease in the anti-inflammatory and other pain-ameliorating effects of cortisol may contribute to chronic pain and its resistance to treatment with concurrent obesity in female adolescents.
Learn More >Neuropathic pain is a widespread problem with a big impact on quality of life. The currently used drug regimens are often insufficiently effective or cause – sometimes unacceptable – side effects. Intravenous lidocaine could be an alternative treatment, by blocking spontaneous depolarization and hyperexcitability in upregulated sodium channels in nociceptors. Research so far has shown varying results but the treatment protocols differed a lot and follow-up was usually short. In our hospital, lidocaine infusions have been applied for many years in a unique treatment protocol consisting of a relatively high dose of lidocaine (1000 mg) administered over 25 hours. Our aim is to share information on both the efficacy and safety of this treatment schedule.
Learn More >P2X receptors are ATP-gated ion channels which play a role in many pathophysiological conditions. They are considered as novel drug targets, particularly in the fields of pain, (neuro) inflammation, and cancer. Due to difficulties in developing drug-like orthosteric ligands that bind to the highly polar ATP binding site, the design of positive and negative allosteric modulators (PAMs and NAMs) is a promising strategy. The P2X4 receptor was proposed as a novel target for neuropathic and inflammatory pain (antagonists), and for the treatment of alcoholism (PAMs). So far, little is known about the allosteric binding site(s) of P2X4 receptors. The aim of this study is to identify the binding site (s) of the macrocyclic natural product ivermectin, the urea derivative BX430, and the antidepressant drug paroxetine that act as allosteric modulators of P2X4 receptors.
Learn More >Reactive astrocytes play a complex role in multiple sclerosis, and the astrocytes reactivity is an important factor in the pathogenesis of pain. It is of great significance to explore the genesis and development mechanism of pain in the early stage of multiple sclerosis (MS) for early intervention of the disease. This study aims to explore astrocyte reactivity at different stages of the experimental autoimmune encephalomyelitis (EAE) model, a mouse model of MS, and the role of astrocytes in the pain in the early stage of the EAE. In this study, we demonstrated that spinal dorsal horn astrocytes were activated in the pre-clinical stage of EAE mice, and the inhibition of spinal cord astrocyte reactivity effectively alleviates pain symptoms in EAE mice. On the other hand, spinal cord microglia were not directly participated in the early EAE pain. Moreover, the ion channel LRRC8A mediated the reactivity of spinal dorsal horn astrocytes by regulating the STAT3 pathway, therefore playing a role in the early pain of EAE.
Learn More >Chronic pain is prevalent amongst society, making it necessary to find strategies to manage chronic pain. Regular exercise is efficacious; however, pain is a barrier to initiating exercise. A single exercise session is also believed to acutely reduce pain, however, the evidence for this is less robust.
Learn More >Self-management support is considered an important component in the physiotherapeutic treatment of people with chronic low back pain. The stratified blended physiotherapy intervention e-Exercise Low Back Pain is an example of a self-management intervention. More insight may contribute to improving blended interventions to stimulate self-management after treatment and thus hopefully prevent chronicity and/or relapses in patients with chronic low back pain.
Learn More >Proprioception is a deep sensation that perceives the position of each part of the body, state of movement and muscle contraction, and resistance and mass applied to the body. Proprioceptive feedback influences movement and positional accuracy, resulting in key somatosensory functions for human postural control. Proprioception encompasses signals received from proprioceptors located in the skin, subcutaneous tissue, muscles, tendons, and joint capsules, commonly known as mechanoreceptors. The muscle spindle, a crucial proprioceptor, is stretched during eccentric contraction of muscle, thus generating an action potential on afferent fibers to convey a proprioceptive information to the sensorimotor cortex in the brain. For exercise therapy in patients with locomotor disease, proprioception serves an essential function for motor control; thus, this should be considered to obtain effective muscle output. As postural control is achieved by proprioceptive function according to the balance between the lower limb and trunk, relative proprioceptive weighting ratio can help clarify proprioceptive control using muscle response to mechanical vibration. The absence of proprioceptive information congruent with motor intention activates cortical center monitoring incongruence of sensation, leading to pathological pain. Therapeutic procedures may aim to restore the integrity of cortical information processing in musculoskeletal chronic pain. Poor proprioception is one of the main causes of decreased postural balance control in elderly patients with low back pain (LBP). It has been hypothesized that proprioception of the lower limbs deteriorates with age-related muscle mass loss (sarcopenia), which increases the proprioceptive burden on the lumbar spine. Accurate diagnosis of the proprioceptive function is important for establishing a treatment procedure for proprioceptive recovery, and further prospective research is required to clarify the relationship between proprioception and LBP improvement.
Learn More >Accurately identifying high-need, high-cost (HNHC) patients to reduce their preventable or modifiable health care use for their chronic conditions is a priority and a challenge for U.S. policymakers, health care delivery systems, and payers.
Learn More >Pain is an uncomfortable sensation in the body. Kaempferol is a flavonoid with antinociceptive effects. Transient receptor potential (TRP) channels have been characterized in the sensory system.
Learn More >Persistent headache attributed to past stroke (PHAPS) is a controversial entity, recently included in the third edition of the International Classification of Headache Disorders (ICHD-3) despite being described only in retrospective studies.
Learn More >To investigate experiences and reflections on challenges in everyday life of people living with limb-girdle muscular dystrophy (LGMD) and chronic pain in order to improve rehabilitation services.
Learn More >To evaluate efficacy and satisfaction of dextromethorphan as a non-narcotic adjuvant to current analgesic regimens for medication abortion.
Learn More >Physiotherapy, with a specific focus on pelvic health, is one service used in the multidisciplinary management of adolescent persistent pelvic pain (PPP). However, there has been little investigations into the accessibility of physiotherapy for adolescents with PPP.
Learn More >To investigate whether activity pacing interventions (alone or in conjunction with other evidence-based interventions) improve fatigue, physical function, psychological distress, depression, and anxiety in people with chronic fatigue syndrome (CFS).
Learn More >The risk of opioid addiction among people with chronic pain is elevated in those using opioids to self-medicate physical or emotional pain or distress. The purpose of this study is to test the main effect of distress tolerance (DT) on opioid use disorder (OUD) status in people with chronic pain, and the potential moderating effect of DT in the relationship between known addiction risk factors and the development of OUD.
Learn More >Acupuncture is commonly used as a treatment for migraines. Animal studies have suggested that acupuncture can decrease neuropeptides, immune cells, and proinflammatory and excitatory neurotransmitters, which are associated with the pathogenesis of neuroinflammation. In addition, acupuncture participates in the development of peripheral and central sensitization through modulation of the release of neuronal-sensitization-related mediators (brain-derived neurotrophic factor, glutamate), endocannabinoid system, and serotonin system activation. Clinical studies have demonstrated that acupuncture may be a beneficial migraine treatment, particularly in decreasing pain intensity, duration, emotional comorbidity, and days of acute medication intake. However, specific clinical effectiveness has not been substantiated, and the mechanisms underlying its efficacy remain obscure. With the development of biomedical and neuroimaging techniques, the neural mechanism of acupuncture in migraine has gained increasing attention. Neuroimaging studies have indicated that acupuncture may alter the abnormal functional activity and connectivity of the descending pain modulatory system, default mode network, thalamus, frontal-parietal network, occipital-temporal network, and cerebellum. Acupuncture may reduce neuroinflammation, regulate peripheral and central sensitization, and normalize abnormal brain activity, thereby preventing pain signal transmission. To summarize the effects and neural mechanisms of acupuncture in migraine, we performed a systematic review of literature about migraine and acupuncture. We summarized the characteristics of current clinical studies, including the types of participants, study designs, and clinical outcomes. The published findings from basic neuroimaging studies support the hypothesis that acupuncture alters abnormal neuroplasticity and brain activity. The benefits of acupuncture require further investigation through basic and clinical studies.
Learn More >The aims of this study are to 1) determine the scope of musculoskeletal (MSK)-related clinical research in Sweden; 2) collate the amount of first-tier funding received; 3) discuss strategies and infrastructure supporting future MSK clinical trials in Sweden.
Learn More >Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that predominantly affects the axial skeleton and is characterized by inflammatory back pain. While much has been published regarding non-steroidal anti-inflammatory drugs and tumor necrosis factor inhibitors, other classes of medications which leverage alternate molecular mechanisms receive less attention. In this review, we summarize a few of the novel targets in axSpA, review the putative mechanism of action of therapies that focus on these targets, and reference the germane recently completed, ongoing, or proposed randomized controlled clinical trials. The agents addressed include inhibitors of interleukin-23, interleukin-17, janus kinases, granulocyte-macrophage colony-stimulating factor, macrophage migration inhibitory factor, antibodies recognizing T cell receptor beta variable 9 gene positive clones, as well as inhibitors of mitogen-activated protein kinase-activated protein kinase-2.
Learn More >Chronic pain is a common disease; about 20% of people worldwide suffer from it. While compared with the research on the prevalence and management of chronic pain in developed countries, there is a relative lack of research in this field in China. This research aims to construct the China Pain Health Index (CPHI) to evaluate the current status of the prevalence and management of chronic pain in the Chinese population.
Learn More >Three patient-reported outcome (PRO) questionnaires-Worst Pruritus Numerical Rating Scale (WP-NRS), Atopic Dermatitis Symptom Scale (ADerm-SS), and Atopic Dermatitis Impact Scale (ADerm-IS)-were developed to assess the symptoms and impacts of atopic dermatitis (AD). Severity strata for these PROs are needed to aid in their interpretation.
Learn More >Osteoarthritis is a progressive degenerative disease affecting joints. It is associated with structural and functional changes that cause lameness and pain in dogs. Mesenchymal stem cells (MSCs) are considered an ideal therapeutic candidate for treating inflammatory musculoskeletal conditions due to their paracrine and immunomodulatory characteristics. They are delivered intravenously or as intra-articular injections for treating canine osteoarthritis. However, studies have confirmed that the osteoarthritic synovial fluid is cytotoxic to cultured MSCs. Therefore, intra-articular transplantation of viable MSCs should be considered counterproductive since it minimizes cellular viability. Similarly, the intravenous administration of MSCs limits the therapeutic effects on the organ of interest since most of the administered cells get trapped in the lungs. Therefore, cell-free therapeutic strategies such as conditioned media and extracellular vesicles (EVs) can potentially become the future of MSC-based therapy in managing canine osteoarthritis. It overcomes the limitations of MSC-based therapy, such as tumor differentiation, immunogenicity, and pulmonary embolization, and has advantages like low immunogenicity and off-shelf availability. In addition, they eliminate problems such as low cell survival, transmission of infections, and unpredictable behavior of the transplanted MSCs, thereby acting as a safe alternative to cell-based therapeutics. However, very limited data is available on the efficacy and safety of cell-free therapy using MSCs for managing canine osteoarthritis. Therefore, large-scale, multicentric, randomized clinical controlled trials are required to establish the therapeutic efficacy and safety of MSC-based cell-free therapy in clinical cases of canine osteoarthritis.
Learn More >Low back pain (LBP) clinical practice guidelines recommend referral for patients with persistent LBP however discordance persists between recommended care and implementation in practice. Understanding patient experiences of referral practices and physiotherapy care could be important for optimizing LBP management in primary care settings.
Learn More >Rosacea is a common chronic inflammatory facial skin disorder. Standardized evaluation of the severity and extent of rosacea is important for baseline assessment and treatment effect. The currently used Investigator's Global Assessment (IGA) is unspecific and fails to consider subtypes/phenotypes of rosacea and area involvement. The Rosacea Area and Severity Index (RASI) was developed to give a more nuanced evaluation of rosacea features in four facial skin areas adjusted to the relative importance of each area of the face to obtain an overall severity score.
Learn More >Skin is the largest, environmentally exposed (barrier) organ, capable of integrating various signals into effective defensive responses. The functional significance of interactions among the epidermis and the immune and nervous systems in regulating and maintaining skin barrier function is only now becoming recognized in relation to skin pathophysiology. This review focuses on newly described pathways that involve soluble mediator-mediated crosstalk between these compartments. Dysregulation of these connections can lead to chronic inflammatory diseases and/or pathologic conditions associated with chronic pain or itch.
Learn More >Cardiovascular disease affects close to half of the United States population and many of these patients will develop chronic pain syndromes as a result of their disease process. This article provides an overview of several pain syndromes that result, directly or indirectly, from cardiovascular disease including peripheral arterial disease, angina, thoracic outlet syndrome, postamputation pain, complex regional pain syndrome, and poststroke pain. Psychological and medical comorbidities that affect the medical decision-making process in the treatment of chronic pain associated with cardiovascular disease are also discussed.
Learn More >Ehlers-Danlos syndromes (EDS) are connective tissue disorders with multi-systemic symptoms. Management of chronic pain and other symptoms of EDS is a challenge for patients and clinicians. Mindfulness-based approaches for chronic pain produce improvement in pain symptoms. Mindfulness meditation could be an acceptable and readily accessible therapy for pain in EDS. This study evaluated the effect of daily practice of mindfulness meditation on pain experience and quality-of-life in EDS.
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