Papers: 31 Dec 2022 - 6 Jan 2023

Transient receptor potential vanilloid 1 (TRPV1) ion channel is a classic analgesic target, but antagonists of TRPV1 failed in clinical trials due to their side effects like hyperthermia. Here we rationally engineer a peptide s-RhTx as a positive allosteric modulator (PAM) of TRPV1. Patch-clamp recordings demonstrate s-RhTx selectively potentiated TRPV1 activation. s-RhTx also slows down capsaicin-induced desensitization of TRPV1 in the presence of calcium to cause more calcium influx in TRPV1-expressing cells. In addition, our thermodynamic mutant cycle analysis shows that E652 in TRPV1 outer pore specifically interacts with R12 and K22 in s-RhTx. Furthermore, we demonstrate in vivo that s-RhTx exhibits long-lasting analgesic effects in noxious heat hyperalgesia and CFA-induced chronic inflammatory pain by promoting the reversible degeneration of intra-epidermal nerve fiber (IENF) expressing TRPV1 channels in mice, while their body temperature remains unaffected. Our results suggest s-RhTx is an analgesic agent as a PAM of TRPV1.

Cortical neural dynamics mediate information processing for the cerebral cortex, implicated in fundamental biological processes, such as vision and olfaction, in addition to neurological and psychiatric diseases. Spontaneous pain is a key feature of human neuropathic pain. Whether spontaneous pain pushes cortical network into an aberrant state, and if so, whether it can be brought back to a 'normal' operating range to ameliorate pain are unknown. Using a clinically relevant mouse model of neuropathic pain with spontaneous pain-like behavior, we report that orofacial spontaneous pain activated a specific area within the primary somatosensory cortex (S1), displaying synchronized neural dynamics revealed by intravital two-photon calcium imaging. This synchronization was underpinned by local GABAergic interneuron hypoactivity. Pain-induced cortical synchronization could be attenuated by manipulating local S1 networks or clinically effective pain therapies. Specifically, both chemogenetic inhibition of pain-related c-Fos-expressing neurons, and selective activation of GABAergic interneurons, significantly attenuated S1 synchronization. Clinically effective pain therapies including carbamazepine and nerve root decompression could also dampen S1 synchronization. More importantly, restoring a 'normal' range of neural dynamics, through attenuating pain-induced S1 synchronization, alleviated pain-like behavior. These results suggest spontaneous pain pushes S1 regional network into a synchronized state, whereas reversal of this synchronization alleviates pain.

Visceral pain is among the most prevalent and bothersome forms of chronic pain, but their transmission in the spinal cord is still poorly understood. Here, we conducted focal colorectal distention (fCRD) to drive both visceromotor responses (VMRs) and aversion. We first found that spinal CCK neurons were necessary for noxious fCRD to drive both VMRs and aversion under naive conditions. We next showed that spinal VGLUT3 neurons mediate visceral allodynia, whose ablation caused loss of aversion evoked by low-intensity fCRD in mice with gastrointestinal (GI) inflammation or spinal circuit disinhibition. Importantly, these neurons were dispensable for driving sensitized VMRs under both inflammatory and central disinhibition conditions. Anatomically, a subset of VGLUT3 neurons projected to parabrachial nuclei, whose photoactivation sufficiently generated aversion in mice with GI inflammation, without influencing VMRs. Our studies suggest the presence of different spinal substrates that transmit nociceptive versus affective dimensions of visceral sensory information.

Accumulating observations suggest that peripheral somatosensory ganglia may regulate nociceptive transmission, yet direct evidence is sparse. Here, in experiments on rats and mice, we show that the peripheral afferent nociceptive information in mice undergoes dynamic filtering within the dorsal root ganglion (DRG) and suggest that this filtering occurs at the axonal bifurcations (t-junctions). Using synchronous in vivo electrophysiological recordings from the peripheral and central processes of sensory neurons (in the spinal nerve and dorsal root), ganglionic transplantation of GABAergic progenitor cells, and optogenetics, we demonstrate existence of tonic and dynamic filtering of action potentials traveling through the DRG. Filtering induced by focal application of GABA or optogenetic GABA release from the DRG-transplanted GABAergic progenitor cells was specific to nociceptive fibers. Light-sheet imaging and computer modeling demonstrated that, compared to other somatosensory fiber types, nociceptors have shorter stem axons, making somatic control over t-junctional filtering more efficient. Optogenetically induced GABA release within DRG from the transplanted GABAergic cells enhanced filtering and alleviated hypersensitivity to noxious stimulation produced by chronic inflammation and neuropathic injury in vivo. These findings support "gating" of pain information by DRGs and suggest new therapeutic approaches for pain relief.

Evidence and gap maps (EGM) can be used to identify gaps within specific research areas and help guide future research agendas and directions. Currently, there are no EGMs within the broad domain of chronic musculoskeletal (MSK) pain in adults. The aim of this study was to create a contemporary EGM of interventions and outcomes used for research investigating chronic MSK pain. This EGM was based on systematic reviews of interventions published in scientific journals within the last 20 years. Embase, PubMed, the Cochrane Library, and PsycINFO were used to retrieve studies for inclusion. The quality of the included reviews was assessed using AMSTAR-II. Interventions were categorised as either physical, psychological, pharmacological, education/advice, interdisciplinary, or other. Outcomes were categorised using the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations. Of 4299 systematic reviews, 457 were included. Of these, 50% were rated critically low quality, 25% low quality, 10% moderate quality and 15% were rated high quality. Physical interventions (e.g., exercise therapy) and education were the most common interventions reported in 80% and 20% of the studies, respectively. Pain (97%) and physical functioning (87%) were the most reported outcomes in the systematic reviews. Few systematic reviews used interdisciplinary interventions (3%) and economic-related outcomes (2%). This contemporary EGM revealed a low proportion of high-quality evidence within chronic musculoskeletal (MSK) pain. This EGM clearly outlines the lack of high-quality research and the need for increased focus on interventions encompassing the entire biopsychosocial perspective.

We describe here the development and validation of the Osteoarthritis Symptom Inventory Scale (OASIS), a new self-administered questionnaire specifically designed to evaluate the various osteoarthritis (OA) pain symptoms with different dimensions related to OA pain mechanisms. The initial development phase and qualitative study generated a list of 17 descriptors reflecting OA pain and other associated symptoms, leading to the first version of the questionnaire (OASIS17). Each item was quantified on a 0-10 numerical scale. Validation was performed using 123 consecutive patients with OA pain recruited at 28 centers in France, mainly general practitioner offices. Validation involved: (i) determining the questionnaire's factorial structure through exploratory and confirmatory analyses, (ii) analyzing convergent and divergent validities (i.e., construct validity), (iii) assessing each item's test-retest reliability, and (iv) evaluating OASIS's ability to detect treatment effects (i.e., sensitivity to change). The final OASIS version includes nine items discriminating and quantifying three distinct, clinically relevant OA pain dimensions sensitive to treatment. OASIS9's psychometric properties suggest that it could improve the characterization of OA pain profiles for three clinically relevant domains: localized, neuropathic-like, and deep pain. The OASIS9 questionnaire could be used to phenotype OA pain patients and identify responders to various therapeutic interventions as a function of OA pain dimensions.

Chronic pain has been one of the leading causes of disability. Acupuncture is globally used in chronic pain management. However, the efficacy of acupuncture treatment varies across patients. Identifying individual factors and developing approaches that predict medical benefits may promise important scientific and clinical applications. Here, we investigated the psychological and neurological factors collected prior to treatment that would determine acupuncture efficacy in knee osteoarthritis. In this neuroimaging-based randomized controlled trial, 52 patients completed a baseline assessment, 4-week acupuncture or sham-acupuncture treatment, and an assessment after treatment. The patients, magnetic resonance imaging operators, and outcome evaluators were blinded to treatment group assignment. First, we found that patients receiving acupuncture treatment showed larger pain intensity improvements compared to patients in the sham-acupuncture arm. Second, positive expectation, extraversion, and emotional attention were correlated with the magnitude of clinical improvements in the acupuncture group. Third, the identified neurological metrics encompassed striatal volumes, posterior cingulate cortex (PCC) cortical thickness, PCC/precuneus fractional amplitude of low-frequency fluctuation (fALFF), striatal fALFF, and graph-based small-worldness of the DMN and striatum. Specifically, functional metrics predisposing patients to acupuncture improvement changed as a consequence of acupuncture treatment while structural metrics remained stable. Furthermore, support vector machine models applied to the questionnaire and brain features could jointly predict acupuncture improvement with an accuracy of 81.48%. Besides, the correlations and models were not significant in the sham-acupuncture group. These results demonstrate the specific psychological, brain functional, and structural predictors of acupuncture improvement and may offer opportunities to aid clinical practices.

Dysregulation of gut homeostasis is associated with irritable bowel syndrome (IBS), a chronic functional gastrointestinal disorder affecting approximately 11.2% of the global population. The poorly understood pathogenesis of IBS has impeded its treatment. Here, we report that the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) is weakly expressed in IBS but highly expressed in inflammatory bowel disease (IBD), a frequent chronic organic gastrointestinal disorder. Accordingly, knockout of Trim27 in mice causes spontaneously occurring IBS-like symptoms, including increased visceral hyperalgesia and abnormal stool features, as observed in IBS patients. Mechanistically, TRIM27 stabilizes β-catenin and thus activates Wnt/β-catenin signaling to promote intestinal stem cell (ISC) self-renewal. Consistent with these findings, Trim27 deficiency disrupts organoid formation, which is rescued by reintroducing TRIM27 or β-catenin. Furthermore, Wnt/β-catenin signaling activator treatment ameliorates IBS symptoms by promoting ISC self-renewal. Taken together, these data indicate that TRIM27 is critical for maintaining gut homeostasis, suggesting that targeting the TRIM27/Wnt/β-catenin axis could be a potential treatment strategy for IBS. Our study also indicates that TRIM27 might serve as a potential biomarker for differentiating IBS from IBD.

Many epithelial compartments undergo constitutive renewal in homeostasis but activate unique regenerative responses following injury. The clear corneal epithelium is crucial for vision and is renewed from limbal stem cells (LSCs). Using single-cell RNA sequencing, we profiled the mouse corneal epithelium in homeostasis, aging, diabetes, and dry eye disease (DED), where tear deficiency predisposes the cornea to recurrent injury. In homeostasis, we capture the transcriptional states that accomplish continuous tissue turnover. We leverage our dataset to identify candidate genes and gene networks that characterize key stages across homeostatic renewal, including markers for LSCs. In aging and diabetes, there were only mild changes with <15 dysregulated genes. The constitutive cell types that accomplish homeostatic renewal were conserved in DED but were associated with activation of cell states that comprise "adaptive regeneration." We provide global markers that distinguish cell types in homeostatic renewal vs. adaptive regeneration and markers that specifically define DED-elicited proliferating and differentiating cell types. We validate that expression of SPARC, a marker of adaptive regeneration, is also induced in corneal epithelial wound healing and accelerates wound closure in a corneal epithelial cell scratch assay. Finally, we propose a classification system for LSC markers based on their expression fidelity in homeostasis and disease. This transcriptional dissection uncovers the dramatically altered transcriptional landscape of the corneal epithelium in DED, providing a framework and atlas for future study of these ocular surface stem cells in health and disease.

Youth with complex regional pain syndrome (CRPS) commonly experience mechanical allodynia and disability. Assessment of mechanical allodynia is typically binary (present or absent), making it difficult to assess the quality and degree of mechanical allodynia before and after treatment. This study developed and validated the Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense) to provide an easy way for rehabilitation clinicians to evaluate mechanical allodynia before and after intensive interdisciplinary pain treatment. The six Pedi-Sense items demonstrated adequate internal consistency reliability (CR) at admission (CR = 0.956) and discharge (CR = 0.973), reasonably fit the hypothesized linear model of stimulus intensity (p<0.0001), and significantly loaded onto a single latent factor, mechanical allodynia (p<0.0001), at admission and discharge. Pedi-Sense scores significantly correlated with disability (r = 0.40; p = 0.004) and pain catastrophizing (r = 0.33; p = 0.017) at admission. The Pedi-Sense appeared responsive to intervention as participants' total scores improved by 1.44 points (95% CI: 0.72, 2.15) after IIPT interventions that included daily tactile desensitization. However, test-retest and interrater reliability and the specific contribution of desensitization treatment to the overall success of multi-modal pain rehabilitation still needs to be evaluated. PERSPECTIVE: This article presents the development and preliminary validation of a novel clinical assessment of static and dynamic mechanical allodynia. The Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense) allows rehabilitation clinicians to easily evaluate mechanical allodynia at the bedside with minimal training and simple equipment to guide desensitization treatment in clinical settings.

Venom-derived Na1.7 channel blockers have promising prospects in pain management. The 34-residue tarantula peptide GpTx-1 is a potent Na1.7 channel blocker. Its powerful analog [Ala, Phe, Leu, Arg]GpTx-1 (GpTx-1-71) displayed excellent Na1.7 selectivity and analgesic properties in mice. The current study aimed to elucidate the anti-hyperalgesic activities of GpTx-1-71 in inflammatory pain and reveal the underlying mechanisms. Our results demonstrated that intrathecal and intraplantar injections of GpTx-1-71 dose-dependently attenuated CFA-induced inflammatory hypersensitivity in rats. Moreover, GpTx-1-71-induced anti-hyperalgesia was significantly reduced by opioid receptor antagonists and the enkephalin antibody and diminished in proenkephalin (Penk) gene knockout animals. Consistently, GpTx-1-71 treatment increased the enkephalin level in the spinal dorsal horn and promoted the Penk transcription and enkephalin release in primary dorsal root ganglion (DRG) neurons, wherein sodium played a crucial role in these processes. Mass spectrometry analysis revealed that GpTx-1-71 mainly promoted the secretion of Met-enkephalin but not Leu-enkephalin from DRG neurons. In addition, the combination of subtherapeutic Met-enkephalin and GpTx-1-71 produced synergistic anti-hyperalgesia in CFA-induced inflammatory hypersensitivity. These findings suggest that the endogenous enkephalin pathway is essential for GpTx-1-71-induced spinal and peripheral analgesia in inflammatory pain. Perspective: This article presents a possible pharmacological mechanism underlying Na1.7 blocker-induced analgesia in inflammatory pain, which helps us to better understand and develop venom-based painkillers for incurable pain.

Resolvin D5 (RvD5) is a specialized pro-resolving lipid mediator with potent anti-inflammatory and analgesic properties. Orofacial pain conditions, especially those that are chronic, present clinical challenges in terms of pharmacological management. Thus, new therapeutic options are clearly warranted. Herein, we investigated the antinociceptive effect of RvD5 in the chronic constriction injury of the infraorbital nerve (CCI-ION) model and in the orofacial formalin test in female and male Wistar rats. Our results indicated that repeated subarachnoid medullary injections of RvD5 at 10 ng resulted in a significant reduction of heat and mechanical hyperalgesia induced by the CCI-ION in male and female rats, but males were more sensitive to RvD5 effects. In addition, after CCI-ION, interleukin-6 (IL-6) level was increased in the trigeminal nucleus caudalis of male, but not female rats, which was reduced by RvD5 repeated treatment. No changes in the levels of IL-1β were found. Minocycline blocked the effect of RvD5 in male rats but failed to affect RvD5 antinociceptive effect in females. Moreover, a single medullary injection of RvD5 caused a significant reduction of formalin-induced facial grooming, in phases I and II of the test, but only in male rats. This study demonstrated for the first time the analgesic effect of RvD5 in trigeminal pain models, and corroborated previous evidence of sex dichotomy, with a greater effect in males. This article presents a translational potential of RvD5 for targeted therapies aiming at the control of acute and chronic trigeminal pain, but further studies are needed to elucidate its sex-related mechanisms. Perspective: This study demonstrated that RvD5 may provide benefits for trigeminal neuropathic pain treatment in male and female rats, but its effect on inflammatory orofacial pain seems to be restricted only to males. Also, it provided evidence for sex dichotomy in the mechanisms related to the antinociceptive effect of RvD5.

The role of cytokines in the pathophysiology, diagnosis, and prognosis of small fiber neuropathy (SFN) is incompletely understood. We studied expression profiles of selected pro- and anti-inflammatory cytokines in RNA from white blood cells (WBC) of patients with a medical history and a clinical phenotype suggestive for SFN and compared data with healthy controls.

Changes in postsurgical opioid prescribing practices may help reduce chronic opioid use in surgical patients.

The pathophysiology of pediatric musculoskeletal (MSK) pain is unclear, contributing to persistent challenges to its management.

Neck pain is associated with decreased health-related quality of life, decreased work productivity, and increased visits to health care providers.

Central post-stroke pain (CPSP) is a highly refractory form of central neuropathic pain that has been poorly studied mechanistically. Recent observations have emphasized the critical role of the spinal dorsal horn in CPSP. However, the underlying mechanisms remain unclear. In this study, rats were subjected to thalamic hemorrhage to investigate the role of spinal monocyte chemoattractant protein-1 (MCP-1) and C-C motif chemokine receptor 2 (CCR2) in the development of CPSP. Immunohistochemical staining and ELISA were used to assess the expression changes of c-Fos, Iba-1, GFAP, MCP-1, and CCR2 in the dorsal horn of the lumbar spinal cord following thalamic hemorrhage, and the involvement of spinal MCP-1 in CPSP was examined by performing intrathecal anti-MCP-1 mAb injection to neutralize the spinal extracellular MCP-1. We demonstrated that intra-thalamic collagenase microinjection induced persistent bilateral mechanical pain hypersensitivity and facilitated the spontaneous pain behaviors evoked by intraplantar bee venom injection. Accompanying CPSP, the expression of c-Fos, Iba-1, and GFAP in the lumbar spinal dorsal horn was significantly increased up to 28 days post-intra-thalamic collagenase microinjection. Intrathecal injection of minocycline and fluorocitrate dramatically reverses the bilateral mechanical pain hypersensitivity. Moreover, intra-thalamic collagenase microinjection dramatically induced the up-regulation of MCP-1 but had no effect on the expression of CCR2 in the bilateral lumbar spinal dorsal horn, and MCP-1 was primarily localized in the neuron. Intrathecal injection of anti-MCP-1 mAb was also able to reverse CPSP and reduce the expression of c-Fos, Iba-1, and GFAP in the lumbar spinal dorsal horn. These findings indicated that spinal MCP-1 contributes to CPSP by mediating the activation of spinal neurons and glial cells following thalamic hemorrhage stroke, which may provide insights into pharmacologic treatment for CPSP.

Chronic pain is a major socio-economic burden globally. The most frequent origin for chronic pain is musculoskeletal. In inflammatory musculoskeletal diseases, such as rheumatoid arthritis (RA), chronic pain is a primary determinant of deleterious quality of life. The pivotal role of peripheral inflammation in the initiation and perpetuation of nociceptive pain is well-established among these patients. However, the persistence of pain, even after the apparent resolution of peripheral inflammation, alludes to the co-existence of different pain states. Recent advances in neurobiological knowledge have highlighted the importance of nociplastic pain mechanisms. In this review we aim to explore the biology of pain with a particular focus on nociplastic pain and RA. This article is protected by copyright. All rights reserved.

Advanced practice clinicians (APCs), defined as nurse practitioners and physician assistants, are increasingly being incorporated into surgical teams. Despite this inclusion, there are no recent national data on the role of these clinicians in surgical opioid prescribing or the dosing of such prescriptions.

Among cancer survivors who have completed curative-intent treatment, the high prevalence and adverse consequences of chronic pain are well documented. Yet, research on clinicians' experiences with and perspectives on managing chronic pain among cancer survivors is critically lacking.

Alkaloids from the botanical (commonly referred to as "kratom") interact with opioid, adrenergic, serotonergic, and other receptors to provide myriad reported effects, including analgesia, energy, improved mood, and relaxation, among others. These alkaloids are complex and unique and may serve as a blueprint for the development of novel molecules to treat various substance use disorders.

Knee osteoarthritis (OA) is characterized by knee cartilage degeneration and secondary bone hyperplasia, resulting in pain, stiffness, and gait disturbance. The relationship between knee OA and neurodegenerative diseases is still unclear. This study used an Alzheimer's disease (AD) mouse model to observe whether osteoarthritis accelerates dementia progression by analyzing brain histology and neuroinflammation. Knee OA was induced by destabilizing the medial meniscus (DMM) in control (WT) and AD (5xFAD) mice before pathological symptoms. Mouse knee joints were scanned with a micro-CT scanner. A sham operation was used as control. Motor and cognitive abilities were tested after OA induction. Neurodegeneration, β-amyloid plaque formation, and neuroinflammation were analyzed by immunostaining, Western blotting, and RT-PCR in brain tissues. Compared with sham controls, OA in AD mice increased inflammatory cytokine levels in brain tissues. Furthermore, OA significantly increased β-amyloid deposition and neuronal loss in AD mice compared to sham controls. In conclusion, knee OA accelerated amyloid plaque deposition and neurodegeneration in AD-OA mice, suggesting that OA is a risk factor for AD.

Due to the prevalence of chronic pain worldwide, there is an urgent need to improve pain management strategies. While opioid drugs have long been used to treat chronic pain, their use is severely limited by adverse effects and abuse liability. Neurostimulation techniques have emerged as a promising option for chronic pain that is refractory to other treatments. While different neurostimulation strategies have been applied to many neural structures implicated in pain processing, there is variability in efficacy between patients, underscoring the need to optimize neurostimulation techniques for use in pain management. This optimization requires a deeper understanding of the mechanisms underlying neurostimulation-induced pain relief. Here, we discuss the most commonly used neurostimulation techniques for treating chronic pain. We present evidence that neurostimulation-induced analgesia is in part driven by the release of endogenous opioids and that this endogenous opioid release is a common endpoint between different methods of neurostimulation. Finally, we introduce technological and clinical innovations that are being explored to optimize neurostimulation techniques for the treatment of pain, including multidisciplinary efforts between neuroscience research and clinical treatment that may refine the efficacy of neurostimulation based on its underlying mechanisms.

Besides the established role of dopamine neurons and projections in nociceptive stimuli, the involvement of ventral tegmental area (VTA) glutamatergic projections to nucleus accumbens (NAc) in pain remains unknown. In the present study, we aimed to examine the role of VTA glutamatergic projections to NAc in painful stimuli and its related behavioral changes.

To compare clinical features in youth with continuous headache from migraine, persistent post-traumatic headache, and new daily persistent headache to determine if they are similar, contrary to their distinction in the International Classification of Headache Disorders.

Persistent non-specific back pain is now established as a biopsychosocial phenomenon that can be meaningfully affected by individuals' cognitions, emotions, lifestyle factors, and family and social relationships. Recent guidelines for the treatment of adolescents with persistent non-specific back pain, as well as those for youth with mixed chronic pain, strongly recommend interdisciplinary care in which adolescents receive treatment for both mind and body. The objective of this scoping review was to examine the interventions evaluated in randomized trials for adolescents with persistent back pain to determine if they correspond to these guidelines and to reveal future research priorities.

Cerebral projections of nociceptive stimuli are of great interest as targets for neuromodulation in chronic pain. To study cerebral networks involved in processing noxious stimuli, researchers often rely on thermo-nociception to induce pain. However, various limitations exist in many pain-inducing techniques, such as not accounting for individual variations in pain and trial structure predictability.

Poor family functioning has been reported to be associated with the severity of chronic pain in outpatients, but the association has not been fully addressed in general populations. The present study aimed to examine the association between family dysfunction levels and the presence of chronic pain in a community-dwelling Japanese population.

Opioids are the gold standard drug for pain management, however, their effect on gastric dysfunction is relatively understudied. Opioid users have a higher incidence of gastric pathology leading to increased hospitalization. Herein, we investigated the consequence of morphine use on gastric pathology and the underlying mechanisms. We further investigated the therapeutic benefit of proton pump inhibition as a pharmacological target to overcome morphine-mediated gastric inflammation.

Pathological pain subtypes can be classified as either neuropathic pain, caused by a somatosensory nervous system lesion or disease, or nociplastic pain, which develops without evidence of somatosensory system damage. Since there is no gold standard for the diagnosis of pathological pain subtypes, the proper classification of individual patients is currently an unmet challenge for clinicians. While the determination of specific biomarkers for each condition by current biochemical techniques is a complex task, the use of multimolecular techniques, such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), combined with artificial intelligence allows specific fingerprints for pathological pain-subtypes to be obtained, which may be useful for diagnosis. We analyzed whether the information provided by the mass spectra of serum samples of four experimental models of neuropathic and nociplastic pain combined with their functional pain outcomes could enable pathological pain subtype classification by artificial neural networks. As a result, a simple and innovative clinical decision support method has been developed that combines MALDI-TOF MS serum spectra and pain evaluation with its subsequent data analysis by artificial neural networks and allows the identification and classification of pathological pain subtypes in experimental models with a high level of specificity.

In the phase 3b, randomized, double-blind, placebo-controlled DELIVER clinical trial, eptinezumab reduced migraine frequency and headache in adults with two to four prior preventive treatment failures. Here the effect of eptinezumab on coinciding patient-reported outcomes is reported.

Previous research supports the usefulness of hypnosis (HYP), mindfulness meditation (MM), and prayer as pain self-management strategies in adults with chronic pain. However, their effects on acute pain have been less researched, and no previous head-to-head study compared the immediate effects of these three approaches on pain-related outcomes. This study compared the immediate effects of HYP, MM, and Christian prayer (CP) on pain intensity, pain tolerance, and stress as assessed by heart rate variability (HRV).

During the last decade, osteoarthritis (OA) has become one of the most prevalent musculoskeletal diseases worldwide. OA is characterized by progressive loss of articular cartilage, abnormal remodeling of subchondral bone, hyperplasia of synovial cells, and growth of osteophytes, which lead to chronic pain and disability. The pathological mechanisms underlying OA initiation and progression are still poorly understood. Non-coding RNAs (ncRNAs) constitute a large portion of the transcriptome that do not encode proteins but function in numerous biological processes. Cumulating evidence has revealed a strong association between the changes in expression levels of ncRNA and the disease progression of OA. Moreover, loss- and gain-of-function studies utilizing transgenic animal models have demonstrated that ncRNAs exert vital functions in regulating cartilage homeostasis, degeneration, and regeneration, and changes in ncRNA expression can promote or decelerate the progression of OA through distinct molecular mechanisms. Recent studies highlighted the potential of ncRNAs to serve as diagnostic biomarkers, prognostic indicators, and therapeutic targets for OA. MiRNAs and lncRNAs are two major classes of ncRNAs that have been the most widely studied in cartilage tissues. In this review, we focused on miRNAs and lncRNAs and provided a comprehensive understanding of their functional roles as well as molecular mechanisms in cartilage homeostasis and OA pathogenesis.

To evaluate potential drug-drug interactions of ubrogepant and atogepant.

We aimed to identify migraine treatment features preferred by patients and treatment outcomes most valued by patients.

We wanted to determine whether socioeconomic inequalities in primary care consultation rates for two major, disabling musculoskeletal conditions in England narrowed or widened between 2004 and 2019.

Neuropathic pain (NP) caused by the injury or dysfunction of the nervous system is a chronic pain state accompanied by hyperalgesia, and the available clinical treatment is relatively scarce. Hyperalgesia mediated by pro-inflammatory factors and chemokines plays an important role in the occurrence and maintenance of NP.

Keloids and hypertrophic scars (excessive scarring) are relatively understudied disfiguring chronic skin conditions with high treatment resistance.

Accumulating evidence suggests that trigeminal neuralgia (TN) causes structural and functional alterations in the brain. However, only a few studies have focused on cerebral blood flow (CBF) changes in patients with TN. This study aimed to explore whether altered cerebral perfusion patterns exist in patients with TN and investigate the relationship between abnormal regional CBF (rCBF) and clinical characteristics of TN.

Back pain is more prevalent among women than men. The association with sex could be related to pregnancy and childbirth, unique female conditions. This association has not been thoroughly evaluated.

To determine whether multivariate pattern regression analysis based on gray matter (GM) images constrained to the sensorimotor network could accurately predict trigeminal heat pain sensitivity in healthy individuals.

Intervertebral disc (IVD) degeneration (IDD) is the main contributor to chronic low back pain. To date, the present therapies mainly focus on treating the symptoms caused by IDD rather than addressing the problem itself. For this reason, researchers have searched for a suitable biomaterial to repair and/or regenerate the IVD. A promising candidate to fill this gap is silk, which has already been used as a biomaterial for many years. Therefore, this review aims first to elaborate on the different origins from which silk is harvested, the individual composition, and the characteristics of each silk type. Another goal is to enlighten why silk is so suitable as a biomaterial, discuss its functionalization, and how it could be used for tissue engineering purposes. The second part of this review aims to provide an overview of preclinical studies using silk-based biomaterials to repair the inner region of the IVD, the nucleus pulposus (NP), and the IVD's outer area, the annulus fibrosus (AF). Since the NP and the AF differ fundamentally in their structure, different therapeutic approaches are required. Consequently, silk-containing hydrogels have been used mainly to repair the NP, and silk-based scaffolds have been used for the AF. Although most preclinical studies have shown promising results in IVD-related repair and regeneration, their clinical transition is yet to come.

Intervertebral disc degeneration (IVDD) is the pathological basis of disc herniation, spinal stenosis, and other related diseases, and the lower back pain it produces lays a heavy financial burden on individuals and society. Thus, it is essential to comprehend IVDD's pathophysiology. Numerous factors, such as inflammatory factors, oxidative stress, apoptosis, matrix metalloproteinases, are linked to IVDD pathogenesis. Despite the fact that many researches has provided explanations for the pathophysiology of IVDD, these studies are typically singular, restricted, and isolated, expound only on one or two components, and do not systematically analyze and summarize the numerous influencing elements. In addition, we discovered that the incidence of many chronic diseases in the field of orthopedics may be thoroughly and systematically defined in terms of immunological systems. In order to provide a theoretical foundation for an in-depth understanding of the pathological process of IVDD and the formulation of more effective prevention and treatment measures, this review provides a comprehensive and systematic account of the pathogenesis of IVDD from the physical to the molecular barriers of the intervertebral disc, from the nucleus pulposus tissue to the cellular to the immune-molecular level.

To estimate the relative frequencies of hemicrania continua and its clinical features in adult patients who were evaluated for headache in a clinic-based setting.

Many studies have attempted to link multifidus (MF) fat infiltration with muscle quality and chronic low back pain (cLBP), but there is no consensus on these relationships.

Understanding the relationship between chronic pain conditions and suicidal behavior-suicide attempt, other intentional self-harm, and death by suicide-is imperative for suicide prevention efforts. Although chronic pain conditions are associated with suicidal behaviors, these associations might be attributed to unmeasured confounding or mediated via pain comorbidity.

Galcanezumab (GMB) improved quality of life and reduced disability of patients with episodic (EM) and chronic migraine (CM) in Phase 3 trials. To estimate indirect cost savings associated with GMB treatment in patients with migraine in the United States (US). We analyzed data of patients from the US from three randomized, Phase 3, double-blind, placebo (PBO)-controlled GMB studies: EVOLVE-1 and EVOLVE-2 (EM patients), REGAIN (CM patients). Annual indirect costs were calculated using items of Migraine Disability Assessment (MIDAS) questionnaire: lost time/productivity at work/school, household work, and leisure time. All costs were annualized and expressed in 2019 US dollars. While the main analysis considered lost time/productivity at work/school and household work as a full day, a sensitivity analysis was performed by discounting them by half. For EM, annual indirect costs savings were estimated using mixed model repeated measures analysis. For CM, ANCOVA models were used to estimate annual indirect costs savings as change from baseline. The analysis included 805 patients with EM (mean age = 41.4y; PBO = 534; GMB = 271) and 423 patients with CM (mean age = 38.9y; PBO = 279; GMB = 144). Compared to PBO, GMB significantly reduced annual indirect costs among patients with EM at 3 months (least square mean [95% confidence interval] work/school=$1883.6 [603.64, 3163.65], p = 0.0040, household work=$628.9 [352.95, 904.88], p < 0.0001, and leisure activity=$499.17 [42.36, 955.98], p = 0.0323) and 6 months (work/school=$2382.29 [1065.48, 3699.10], p = 0.0004, household work=$559.45 [268.99, 849.90], p = 0.0002, and leisure activity=$753.81 [334.35, 1173.27], p = 0.0004), whereas significant difference was not observed among patients with CM. Sensitivity analysis results were similar to primary analysis results. GMB treatment versus PBO resulted in significantly greater indirect cost savings in patients with EM through improved productivity at work/school, household work, and leisure days. Patients with CM receiving GMB versus PBO attained greater cost savings, although not statistically significant, through reduced lost productivity at work/school.

In the past few years, there has been extraordinary interest in how the gut communicates with the brain. This is because substantial and gathering data has emerged to suggest that sensory nerve pathways between the gut and brain may contribute much more widely in heath and disease, than was originally presumed. In the skin, the different types of sensory nerve endings have been thoroughly characterized, including the morphology of different nerve endings and the sensory modalities they encode. This knowledge is lacking for most types of visceral afferents, particularly spinal afferents that innervate abdominal organs, like the gut. In fact, only recently have the nerve endings of spinal afferents in any visceral organ been identified. What is clear is that spinal afferents play the major role in pain perception from the gut to the brain. Perhaps surprisingly, the majority of spinal afferent nerve endings in the gut express the ion channel TRPV1, which is often considered to be a marker of "nociceptive" neurons. And, a majority of gut-projecting spinal afferent neurons expressing TRPV1 are activated at low thresholds, in the "normal" physiological range, well below the normal threshold for detection of painful sensations. This introduces a major conundrum regarding visceral nociception. How should we define a "nociceptor" in the gut? We discuss the notion that nociception from the gut wall maybe a process encrypted into multiple different morphological types of spinal afferent nerve ending, rather than a single class of sensory ending, like free-endings, suggested to underlie nociception in skin.

Understand the continuity and changes in headache not-otherwise-specified (NOS), migraine, and post-traumatic headache (PTH) diagnoses after the transition from ICD-9-CM to ICD-10-CM in the Veterans Health Administration (VHA).

Pruritus has an extensive impact on functional, social and psychosocial behaviour. The association between pruritus and psychological well-being has mostly been studied among selected patient groups, whereas population-based studies are lacking. The aim of this study was to determine the association between pruritus and insomnia, quality of life, depression and anxiety at the population level in the general population. A cross-sectional population-based study was conducted in 2012 to 2013. Study subjects (n = 6,809) belonging to the Northern Finland Birth Cohort 1966 Study participated in a large follow-up study at the age of 45-47 years. They completed an extensive health questionnaire including questions on pruritus and several previously validated questionnaires regarding symptoms of psychosocial well-being. Pruritus affected 19.9% of the study subjects weekly, being more common in women than in men (p < 0.001). A significant association was found between both localized and generalized pruritus and symptoms of insomnia, depression, anxiety and decreased quality of life. The association was seen even in those with mild psychological symptoms/insomnia, and it affected both sexes. The severity of psychological symptoms increased with increasing frequency of pruritus. In conclusion, pruritus has a multiple effect on psychosocial well-being. Physicians should consider possible psychosocial symptoms in patients with pruritus.

Given the rapid advances in communication technology and the need that emerged from the COVID-19 pandemic, telehealth initiatives have been widely used worldwide. This masterclass aims to provide an overview of telerehabilitation for musculoskeletal conditions, synthesizing the different terminologies used to describe telehealth and telerehabilitation, its effectiveness and how to use it in clinical practice, barriers and facilitators for the implementation in health services, and discuss the need of a curriculum education for the near future.

Chronic pain is a common and complex problem, with an unknown etiology. Psychedelics like lysergic acid diethylamide (LSD) and psilocybin, may play a role in the management of chronic pain. Through activation of the serotonin-2A (5-HT ) receptor, several neurophysiological responses result in the disruption of functional connections in brain regions associated with chronic pain. Healthy reconnections can be made through neuroplastic effects, resulting in sustained pain relief. However, this process is not fully understood and evidence of efficacy is limited and of low quality. In cancer and palliative related pain, the analgesic potential of psychedelics was established decades ago, and the current literature shows promising results on efficacy and safety in patients with cancer-related psychological distress. In other areas, patients suffering from severe headache disorders like migraine and cluster headache who have self-medicated with psychedelics report both acute and prophylactic efficacy of LSD and psilocybin. Randomized control trials are now being conducted to study the effects in cluster headache Furthermore, psychedelics have a generally favorable safety profile especially when compared to other analgesics like opioids. In addition, psychedelics do not have the addictive potential of opioids. Given the current epidemic use of opioids, and that patients are in desperate need of an alternative treatment, it is important that further research is conducted on the efficacy of psychedelics in chronic pain conditions.

Migraine is a major health burden worldwide with complex pathophysiology and multifarious underlying mechanisms. One poorly understood issue concerns the early steps in the generation of migraine pain. To elucidate the basic process of migraine pain further, it seems useful to consider key molecular players that may operate synergistically to evoke headache. While the neuropeptide CGRP is an important contributor, we propose that extracellular ATP (that generally plays a powerful nociceptive role) is also a major component of migraine headache, acting in concert with CGRP to stimulate trigeminal nociceptive neurons. The aim of the present focused review is to highlight the role of ATP activating its P2X3 membrane receptors selectively expressed by sensory neurons including their nerve fiber terminals in the meninges. Specifically, we present data on the homeostasis of ATP and related purines in the trigeminovascular system and in the CNS; the basic properties of ATP signalling at peripheral and central nerve terminals; the characteristics of P2X3 and related receptors in trigeminal neurons; the critical speed and persistence of P2X3 receptor activity; their cohabitation at the so-called meningeal neuro-immune synapse; the identity of certain endogenous agents cooperating with ATP to induce neuronal sensitization in the trigeminal sensory system; the role of P2X3 receptors in familial type migraine; the current state of P2X3 receptor antagonists and their pharmacological perspectives in migraine. It is proposed that the unique kinetic properties of P2X3 receptors activated by ATP offer an interesting translational value to stimulate future studies for innovative treatments of migraine pain.

Neuropathic pain is a risk factor for cognitive defects. The ubiquitous expression of AQP4 in astrocytes throughout the central nervous system is altered in the neurodegenerative disease. However, the exact role of AQP4 in cognitive impairment induced by chronic neuropathic pain remains unclear. In this study, we discovered that AQP4 protein and mRNA expression decreased time-dependently in the model of chronic neuropathic pain-induced cognitive disorder. AQP4 overexpression recovered mice from cognitive impairment. Furthermore, the concentration of Aβ1-42 in the serum and hippocampus reduced in mice with AQP4 overexpression adeno-associated virus injection. In conclusion, AQP4 in astrocytes is important in mitigating cognitive impairment caused by chronic neuropathic pain.

Complex regional pain syndrome (CRPS) is a chronic condition following inciting events such as fractures or surgeries with sensorimotor and autonomic manifestations and poor prognosis. This review aimed to provide conclusive evidence about the sensory phenotype of CRPS based on quantitative sensory testing (QST) to understand the underlying pain mechanisms and guide treatment strategies.

The present chapter explores how immersive virtual reality (VR) systems can be used for pain research and treatment. Pain is a universal, yet entirely subjective and multifaceted unpleasant experience. One of the earliest VR studies on pain highlighted the role of attention in pain modulation. However, the role of body representation in pain modulation has also been described as a crucial factor. Through virtual reality systems, it is possible to modulate both attention to pain and body representation. In this chapter, first we define how immersive VR can be used to create the illusion of being present in immersive VR environments and argue why VR can be an effective tool for distracting patients from acute pain. However, distraction seems to be less useful in chronic pain treatment. Chronic pain can be highly disabling and can significantly impact not only the sufferer's quality of life, but also their perceptions of the bodily self. Close neural connections between the body matrix and pain open a chance for influencing pain through bodily illusions. This chapter explores approaches to inducing body ownership illusions in VR and discusses how they have been applied in pain research. The present chapter also covers a set of practical indications and methodological caveats of immersive VR and solutions for overcoming them. Finally, we outline several promising future research directions and highlight several yet unexplored areas.

Cluster headache exists diagnostically in a chronic and episodic variant between which patients can convert. We aimed to describe how many patients change phenotype, elucidate possible factors associated with this transition and identify differences in clinical features between primary and secondary phenotypes. 540 well-defined cluster headache patients according to current ICHD-criteria completed a cross-sectional semi-structured interview. Total transition-incidence for the cohort was 20.7%. Conversion from chronic to episodic was reported by 6.3% and transition from episodic to chronic by 14.4% with attack side shift as a possible predictor (p = 0.007). Compared to primary chronic patients, secondary chronic patients had more frequent (60 vs 34 per month, p = 0.0487), but shorter (60 vs 90 minutes, p = 0.041) attacks. Secondary episodic patients experienced shorter remission periods than primary episodic patients (6 vs 11 months, p = 0.010). Treatment response was poor in all groups and only one third had effective prevention. Cluster headache is a fluctuating disorder with a fifth of our cohort having experienced at least one phenotype change during course of disease. Apart from attack side shifts, no predictors for transition were identified. Severity differed between primary and secondary subtypes. Overall, there is an urgent need for better understanding of cluster headache.

Over the past 15 years, the research field on Mas-related G protein-coupled receptors (Mrgprs), a relatively new family of rhodopsin A-like G protein-coupled receptors, has expanded enormously, and a plethora of recent studies have provided evidence that several of these Mrgpr family members play an important role in the underlying mechanisms of itch and pain, as well as in the initiation and modulation of inflammatory/allergic responses. Initial studies mainly focused on the skin, but more recently also visceral organs such as the respiratory and gastrointestinal (GI) tracts emerged as sites for Mrgpr involvement. It has become clear that the gastrointestinal tract and its innervation in close association with the immune system represent a novel expression site for Mrgprs where they contribute to the interoceptive mechanisms maintaining homeostasis and might constitute promising targets in chronic abdominal pain disorders. In this short review, we provide an update of our current knowledge on the expression, distribution, and function of members of this Mrgpr family in intrinsic and extrinsic neuro-immune pathways related to the gastrointestinal tract, their mediatory role(s) in gut neuro-immune signaling, and their involvement in visceral afferent (nociceptive) pathways.

Trigeminal neuralgia (TN) is an orofacial pain disorder that is more prevalent in females than males. Although an increasing number of studies point to sex differences in chronic pain, how sex impacts TN patients' journeys to care has not been previously addressed. This study sought to investigate sex differences in patients' journeys to diagnosis, referral, and treatment of TN within a large national context.

Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (CNS). The most common clinical manifestations of MS are spasticity, pain, vesico-urethral disorders, cognitive impairments, chronic fatigue and sexual dysfunction. This review aims to explore the possible therapeutic options for managing sexual dysfunction in people with MS (PwMS).

Giant cell arteritis is the most common vasculitis in adults above 50 years old. The disease is characterized by granulomatous inflammation of medium and large arteries, particularly the temporal artery, and is associated acutely with headache, claudication, and visual disturbances. Diagnosis of the disease is often complicated by its protean presentation and lack of consistently reliable testing. The utility of color doppler ultrasound at the point-of-care and FDG-PET in longitudinal evaluation remain under continued investigation. Novel techniques for risk assessment with Halo scoring and stratification through axillary vessel ultrasound are becoming commonplace. Moreover, the recent introduction of the biologic tocilizumab marks a paradigm shift toward using glucocorticoid-sparing strategies as the primary treatment modality. Notwithstanding these developments, patients continue to have substantial rates of relapse and biologic agents have their own side effect profile. Trials are underway to answer questions about optimal diagnostic modality, regiment choice, and duration.

The geriatric and health characteristics of older adults make them more susceptible to the effects of opioids than younger groups. The number of older adults in the United States visiting the emergency department (ED) and overusing opioids has increased in recent years. Research examining their relationship is, however, limited.

To assess the utility, safety, and accuracy of in-office needle arthroscopic (IONA) synovial biopsy as a diagnostic tool during treatment of drug-resistant monoarticular inflammatory arthritis of the knee.

Neuropathic pain is a frequent complication of chemotherapy-induced peripheral neurotoxicity (CIPN). Chemotherapy-induced peripheral neuropathies may serve as a model to study mechanisms of neuropathic pain, since several other common causes of peripheral neuropathy like painful diabetic neuropathy may be due to both neuropathic and non-neuropathic pain mechanisms like ischemia and inflammation. Experimental studies are ideally suited to study changes in morphology, phenotype and electrophysiologic characteristics of primary afferent neurons that are affected by chemotherapy and to correlate these changes to behaviors reflective of evoked pain, mainly hyperalgesia and allodynia. However, hyperalgesia and allodynia may only represent one aspect of human pain, i.e., the sensory-discriminative component, while patients with CIPN often describe their pain using words like annoying, tiring and dreadful, which are affective-emotional descriptors that cannot be tested in experimental animals. To understand why some patients with CIPN develop neuropathic pain and others not, and which are the components of neuropathic pain that they are experiencing, experimental and clinical pain research should be combined. Emerging evidence suggests that changes in subsets of primary afferent nerve fibers may contribute to specific aspects of neuropathic pain in both preclinical models and in patients with CIPN. In addition, the role of cutaneous neuroimmune interactions is considered. Since obtaining dorsal root ganglia and peripheral nerves in patients is problematic, analyses performed on skin biopsies from preclinical models as well as patients provide an opportunity to study changes in primary afferent nerve fibers and to associate these changes to human pain. In addition, other biomarkers of small fiber damage in CIPN, like corneal confocal microscope and quantitative sensory testing, may be considered.

Treatment response to spinal cord stimulation (SCS) is focused on the magnitude of effects on pain intensity. However, chronic pain is a multidimensional condition that may affect individuals in different ways and as such it seems reductionist to evaluate treatment response based solely on a unidimensional measure such as pain intensity.

There is an increasing recognition of the importance of patient engagement and involvement in health research, specifically within the field of rheumatology. In general, researchers in this specialty appreciate the value of patients as partners in research. In practice, however, the majority of researchers does not involve patients on their research teams. Many researchers find it difficult to match their needs for patient engagement and the potential contributions from individuals living with rheumatic disease. In this Viewpoint, we provide researchers and patients practical tips for matching 'supply and demand,' based on our own experiences as patient engagement consultants and trainers in rheumatology research. All authors started as a 'naïve' patient or caregiver, an identity that evolved through a process of 'adversarial growth': positive changes that are experienced as a result of the struggle with highly challenging life circumstances. Here, we introduce four stages of adversarial growth in the context of research. We submit that all types of patients have their own experiences, qualities and skills, and can add specific input to research. The recommendations for engagement are not strict directives. They are meant as starting points for discussion or interview. Regardless of individual qualities and knowledge, we believe that all patients engaged in research have a single goal in common: to contribute to research that ultimately will change the lives of many other patients.

This article aims to review the challenges in axial spondyloarthritis diagnosis and identify the possible contributing factors.

Fibromyalgia (FM) is a chronic condition characterized by widespread pain, sleep disorder, fatigue, other somatic symptoms. Clinical pilates method is therapeutic modality that can be used in improving the symptoms. The aim of this study was to investigate the effectiveness of reformer pilates exercises in individuals with FM and to compare with home mat pilates.

This descriptive study aimed to assess the characteristics of pelvic pain and explore predictive factors for pelvic pain in transgender (trans) individuals using testosterone therapy. An online cross-sectional survey was open between August 28, 2020, and December 31, 2020, to trans people presumed female at birth, using testosterone for gender affirmation, living in Australia, and >16 years of age. The survey explored characteristics of pelvic pain following initiation of testosterone therapy, type and length of testosterone therapy, menstruation history, and relevant sexual, gynecological, and mental health experiences. Logistic regression was applied to estimate the effect size of possible factors contributing to pain after starting testosterone. Among 486 participants (median age = 27 years), 351 (72.42%) reported experiencing pelvic pain following initiation of testosterone therapy, described most commonly as in the suprapubic region and as "cramping." Median duration of testosterone therapy was 32 months. Persistent menstruation, current or previous history of post-traumatic stress disorder, and experiences of pain with orgasm were associated with higher odds of pelvic pain after testosterone therapy. No association was observed with genital dryness, intrauterine device use, previous pregnancy, penetrative sexual activities, touching external genitalia, or known diagnoses of endometriosis, vulvodynia, vaginismus, depression, anxiety, or obesity. Pelvic pain is frequently reported in trans people following initiation of testosterone therapy. Given the association with persistent menstruation and orgasm, as well as the known androgen sensitivity of the pelvic floor musculature, further research into pelvic floor muscle dysfunction as a contributor is warranted.

Sciatica causes intense pain. No satisfactory therapeutic drugs exist to treat sciatica. This study aimed to probe the potential mechanism of ferulic acid in sciatica treatment.

Drug overdose deaths greatly increased during the COVID-19 pandemic, with 100,306 cases occurring in the United States over 12 months from 2020 to 2021, an increase of 28.5% from the year before. Three quarters of these deaths involved opioids, and this epidemic has seriously complicated chronic pain management. The role of nurse practitioners (NPs) in opioid prescription has expanded since Affordable Care Act passage in 2010, but their prescription of opioids for chronic pain management is not well understood.

To explore parental experiences in personal functioning and parenting associated with having a child experiencing chronic non-cancer pain.

Anterior cruciate ligament reconstruction (ACLR) using hamstring tendon (HT) graft aims to stabilise the knee, but it may bring some complications like anterior knee (AKP) pain that can have consequences on the functional aspect of this surgery. The aim of this study was to compare isokinetic knee strength and functional outcomes between patients with and without AKP following an ACLR using HT graft during the first-year post-surgery. Three hundred and thirty subjects operated by ACLR using hamstring tendon graft were included in our retrospective cohort and divided into two groups: a group with AKP (AKP+ group) and one without AKP (AKP-group). In our population, 14.8% of the patients had AKP. At 4 post-operative months, subjects with pain had lower isokinetic strength limb symmetry index (LSI) for knee flexors and extensors, and a lower Lysholm score than subjects without pain (p < 0.0001). These differences did not persist at 7 post-operative months, and there was no difference in the one-leg hop test. After multivariate analysis, we highlighted the impact of time on the evolution of these parameters. Yet, the exact definition of AKP after ACLR remains to be clearly defined since an imprecise diagnosis may lead to inappropriate management. Pre-operative information about this type of complication, which evolves favourably with time, could be useful for patients. Indeed, AKP can occur after ACLR, even if a HT graft has been used, compared to other surgical procedures using the knee extensor apparatus as patellar tendon graft (AKP is associated with the donor site morbidity). In case of AKP after ACLR, monitoring the muscle inhibition by isokinetic tests may enable clinicians to adapt the retraining and the return to sport.

This systematic review aimed to assess the efficacy and safety of Drospirenone and Ethinylestradiol Tablets (II) in the treatment of dysmenorrhea.

Calcium (Ca ) is an important second messenger in charge of many critical processes in the central nervous system (CNS), including membrane excitability, neurotransmission, learning, memory, cell proliferation, and apoptosis. In this way, the voltage-gated calcium channels (VGCCs) act as a key supply for Ca entry into the cytoplasm and organelles. Importantly, the dysregulation of these channels has been reported in many neurological diseases of young-onset, with associated genetic factors, such as migraine, multiple sclerosis, and Huntington's disease. Notably, the literature has pointed to the role of N-type Ca channels (NTCCs) in controlling a variety of processes, including pain, inflammation, and excitotoxicity. Moreover, several Ca channel blockers that are used for therapeutic purposes have been shown to act on the N-type channels. Therefore, this review provides an overview of the NTCCs in neurological disorders focusing mainly on Huntington's disease, multiple sclerosis, and migraine. It will discuss possible strategies to generate novel therapeutic strategies.

The study examined the relationship between dietary zinc intake and migraine.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used pharmaceuticals and tons of kilos are produced annually. Ibuprofen is one of the core medicines of non-steroidal anti-inflammatory drug and is primarily used for reduced pain, fever and tissue inflammation. It is also available for the treatment of osteoarthritis, rheumatoid arthritis, tendonitis, etc. It is still one of the most prescribed non-steroidal anti-inflammatory drugs in contemporary times. Although ibuprofen is a drug that has been used for years, it is also known to have various serious toxic effects.

To evaluate the efficacy and safety of galcanezumab in patients with migraine in a real-world setting in Japan.

The etiology of neck/shoulder pain is complex. Our purpose was to investigate if respiratory disorders are risk factors for troublesome neck/shoulder pain in people with no or occasional neck/shoulder pain.

Psoriasis is an inflammatory condition brought on by the immune system. This study aimed to perform a systematic review related to psoriatic arthritis (PsA) of the temporomandibular joint (TMJ).

The medical care of patients with myositis is a great challenge in clinical practice. This is due to the rarity of these disease, the complexity of diagnosis and management as well as the lack of systematic analyses.

Chronic neuropathic pain is often debilitating and can have a significant impact on sleep health and quality of life. There is limited information on the impact of cannabinoids on sleep health when treating neuropathic pain.

Sphenopalatine ganglion (SPG) is a peripheral structure that plays an important role in cluster headache (CH). Hence, a reliable method to measure the volume of SPG is crucial for studying the peripheral mechanism of CH. Additionally, the association between the clinical profiles and the morphology of the SPG in CH remains undetermined. This study aims to use the manual measurement of SPG volume to investigate its associations with CH, including headache laterality, cranial autonomic symptoms (CASs), presence of restlessness or agitation, and other clinical profiles.

Globally, chronic pain affects more than 30% of people worldwide and is the leading cause of disability and health care utilisation. Access to timely, person-centred, cost-effective programs is unattainable for most. People living in regional, rural and remote areas are disproportionately affected due to scarcity of services and qualified, multidisciplinary health and medical professionals. Caring and supporting people with chronic pain involves a range of interventions that incorporate a multifaceted bio-psychosocial approach. Tertiary and primary chronic pain services are optimally placed to deliver integrated models of care. This pilot study explored the effectiveness of an integrated Guided Self-Help (GSH) program within a multidisciplinary tertiary pain unit in a public hospital in Australia.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment, resulting in pain, numbness, instability, and thus affecting quality of life (QoL), occasionally leading to discontinuation of chemotherapy. Pharmacological treatments are not sufficient. Non-pharmacological interventions (NPIs) have also been tried. This study aimed to systematically review the efficacy of NPIs on pain and QoL in patients suffering from CIPN.

To perform a systematic review assessing the relationship between functional somatic syndromes (FSSs) and patient-reported outcome measures (PROMs), post-operative opioid consumption, and hospitalization costs after shoulder and elbow surgery.

Although the association of chronic pain with work-life balance has been studied, the interaction effect of multiple pain sites on work-life balance is yet to be studiedOBJECTIVE:To evaluate the most prevalent CP site among healthcare workers, the demographic characteristics of the individuals with the predominant pain type and to assess and compare the impact of each pain site on their work-life balance.

Pain, distress, and activities of daily living impact the lives of those with chronic pain. This study investigated distress (depressive symptoms, anxiety) on the relationship between pain (intensity and pain interference) and activities of daily living in individuals with fibromyalgia while controlling for age.

One social mechanism by which marginalization is enacted is via ostracism. Recent research has demonstrated ostracism's impact on physical health, but little is known about the relationship between accumulated lifetime experiences of ostracism and pain. Despite recent calls for added attention to social modulation of pain and social indicators of pain disparities, the impact of specific social factors on pain-including those of ostracism-are not well understood. Results of laboratory studies on the effects of acute ostracism experiences on pain sensitivity have been mixed. However, these studies have not considered lived and repeated experiences of ostracism, and primarily included single static measures of pain sensitivity. Additionally, inclusion and representation of the relationship between ostracism experiences and pain among people with minoritized identities are lacking in the current literature. In this study, we explored accumulated lifetime experiences of ostracism as a potential contributing factor to enhanced pain and one social mechanism by which societal inequity may create and maintain inequity in pain. We extracted measures of lifetime experiences of ostracism from six studies focused on social factors and (non-chronic) pain conducted between 2016 and 2020 ( = 505 adults). To retain and examine diversity within the sample, we used moderation and within-group analyses. Results indicate that greater experiences of lifetime ostracism are associated with lower cold pain tolerance, but not other pain measures, in the whole sample. Moderation and within-group analyses reveal opposing patterns of results between populations included in the extant literature (White participants, convenience samples) and those under-represented in the scientific literature (racialized groups, community samples). This study provides an example of a diversity science approach to examining social indicators of pain, illustrates the limited generalizability of previous studies on ostracism and pain, and highlights the need for increased representation and inclusion to understand mechanisms of pain and inequity.

Chronic pain (CP) patients tend to represent aberrant functional brain activity. Acupuncture is an effective clinical treatment for CP, and some fMRI studies were conducted to discover the alternation of brain regions after acupuncture therapy for CP. However, the heterogeneity of neuroimaging studies has prevented researchers from systematically generalizing the central mechanisms of acupuncture in the treatment of CP.

The balance of ion concentrations inside and outside the cell is an essential homeostatic mechanism in neurons and serves as the basis for a variety of physiological activities. In the central nervous system, NKCC1 and KCC2, members of the SLC12 cation-chloride co-transporter (CCC) family, participate in physiological and pathophysiological processes by regulating intracellular and extracellular chloride ion concentrations, which can further regulate the GABAergic system. Over recent years, studies have shown that NKCC1 and KCC2 are essential for the maintenance of Cl homeostasis in neural cells. NKCC1 transports Cl into cells while KCC2 transports Cl out of cells, thereby regulating chloride balance and neuronal excitability. An imbalance of NKCC1 and KCC2 after spinal cord injury will disrupt CI homeostasis, resulting in the transformation of GABA neurons from an inhibitory state into an excitatory state, which subsequently alters the spinal cord neural network and leads to conditions such as spasticity and neuropathic pain, among others. Meanwhile, studies have shown that KCC2 is also an essential target for motor function reconstruction after spinal cord injury. This review mainly introduces the physiological structure and function of NKCC1 and KCC2 and discusses their pathophysiological roles after spinal cord injury.

Pyroptosis is defined as inflammation-induced programmed cell death. However, gene expression levels related to pyroptosis and their role in neuropathic pain (NP) remain unclear. The present study aimed to develop and validate an NP-predictive signature based on the genes associated with pyroptosis. Gene expression level profiles were downloaded from the Gene Expression Omnibus database. Weighted gene co-expression network analysis was used to identify the pyroptotic genes most highly associated with NP. NP-related pyroptosis gene signature was constructed using multivariate logistic regression. A rat model of neuropathic pain was established through chronic constriction injury to analyse the inflammatory infiltration and myelin damage around the sciatic nerve, and examine the expression levels of macrophage markers S100 calcium-binding protein β (S100β) and ionized calcium-binding adapter molecule 1 (Iba-1). Finally, flow cytometry analysis was used to examine the lipopolysaccharide (LPS)-induced cell death ratio of RSC96 cells (Schwann cells), while the expression levels of LPS-induced pyroptosis-related genes in RSC96 cells were measured via reverse transcription-quantitative PCR. The results demonstrated that pyroptosis-related genes (gasdermin D, NLR family pyrin domain containing 3, neuronal apoptosis inhibitory protein and NLR family CARD domain containing 4) were identified to increase the risk of NP. NP-related pyroptosis signatures were constructed based on these four genes. Moreover, the high-risk group had a higher level of macrophage infiltration compared with the low-risk group, as determined by the CIBERSORT algorithm. H&E staining results showed that the myelin structure of the sciatic nerve tissue of chronic constriction injury (CCI) rats was destroyed and inflammatory cells infiltrated around neurons. The results of immunohistochemistry showed that compared with in the sham group, the expression levels of Iba-1 and sS100β in the sciatic nerve of the CCI group were increased. Furthermore, the expression levels of cell death and pyroptosis-related genes in Schwann cells induced by LPS were increased compared with in the control group. In conclusion, an NP-related pyroptosis gene signature was constructed based on four pyroptosis-related genes and it was found that the expression of pyroptosis-related genes was upregulated in the early steps of the neuroinflammatory process in RSC96 cells.

The reduced antidepressant and antihyperalgesic effects of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine during maintenance treatment has been reported, but little is known about the molecular mechanism of this phenomenon. In three comorbid pain and depression animal models (genetic predisposition, chronic social stress, arthritis), we showed that the fluoxetine's antidepressant and antihyperalgesic effects were reduced during the maintenance treatment. Fluoxetine exposure induced upregulation of the 5-hydroxytryptamine 1A (5-HT1A) auto-receptor and indoleamine 2,3 dioxygenase 1 (IDO1, a rate-limiting enzyme of tryptophan metabolism) in the brainstem dorsal raphe nucleus (DRN), which shifted the tryptophan metabolism away from the 5-HT biosynthesis. Mechanistically, IDO1 upregulation was downstream to fluoxetine-induced 5-HT1A receptor expression because 1) antagonism of the 5-HT1A receptor with WAY100635 or 5-HT1A receptor knockout blocked the IDO1 upregulation, and 2) inhibition of IDO1 activity did not block the 5-HT1A receptor upregulation following fluoxetine exposure. Importantly, inhibition of either the 5-HT1A receptor or IDO1 activity sustained the fluoxetine's antidepressant and antihyperalgesic effects, indicating that 5-HT1A-mediated IDO1 upregulation in the brainstem DRN contributed to the reduced antidepressant and antihyperalgesic effects of fluoxetine. These results suggest a new strategy to improving the therapeutic efficacy of SSRI during maintenance treatment.

Central sensitization is an umbrella term for facilitated synaptic plasticity. This editorial (1) explains the differences between homosynaptic and heterosynaptic plasticity, (2) explains the role of glia cells in dorsal horn neuroplasticity, and (3) briefly discusses the clinical relevance of central sensitization and nociplastic pain. Part 5 covers wind-up, classical central sensitization, and long-term potentiation. .

Chronic non-cancer pain (CNCP) is complex and often requires multimodal management comprising of both pharmacological and non-pharmacological treatments. To inform delivery of CNCP management, it is important to understand how current health services providing non-pharmacological treatments are accessed by exploring the experiences of people attempting to access services. In doing so, this study sought to explore the underlying drivers of service access barriers.

Diabetic neuropathic pain (DNP) is the most common disabling complication of diabetes. Emerging evidence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area; however, the underlying molecular events remain poorly understood. Here we found that an axon guidance molecule, Netrin-3 (Ntn-3), was expressed in the sensory neurons of mouse dorsal root ganglia (DRGs), and downregulation of Ntn-3 expression was highly correlated with the severity of DNP in a diabetic mouse model. Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice. In contrast, the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice. In conclusion, our studies identified Ntn-3 as an important regulator of DNP pathogenesis by gating the aberrant sprouting of sensory axons, indicating that Ntn-3 is a potential druggable target for DNP treatment.

Although the short- to medium-term efficacy of Gamma Knife therapy for drug-resistant essential trigeminal neuralgia has been reported, long-term evaluations are limited. We evaluated patient data obtained at least 10 years post-treatment and examined the significance of this treatment using new endpoints.

Pain is prevalent among breast cancer survivors and can persist for years, impeding quality of life. Both prevention and pain treatment are important. However, this requires an interdisciplinary approach and complex models of care. We report on the design and implementation of an intervention that follows a step-wise care model, aimed at timely and adequate pain follow-up among breast cancer survivors.

Guselkumab, an anti-interleukin-23 biologic therapy, has been shown to significantly reduce disease activity and improve patient-reported outcome measures (PROMs) among patients with moderate-to-severe plaque psoriasis in clinical trials. However, characterization of the real-world effectiveness of guselkumab among patients living in the USA and Canada is warranted.

 Peripheral nerve surgeons often require additional imaging for examination, diagnostic testing, and preoperative planning. Point-of-care ultrasound (US) is a cost-effective, accessible, and well-established technique that can assist the surgeon in diagnosing and treating select peripheral nerve pathologies. With this knowledge, the properly trained surgeon may perform US-guided nerve blocks to help accurately diagnose and treat causes of neuropathic pain. We offer this paper, not as an exhaustive review, but as a selection of various peripheral nerve pathologies, which the senior author treats, and their associated US examination findings. Our goal is to encourage other peripheral nerve surgeons to incorporate US into their practices.

The overall aim was to explore the prevalence and persistent regular prescription of opioids and paracetamol among nursing home (NH) residents with dementia at admission and over time. A total of 996 residents with dementia, mean (SD) age 84.5 (7.6) years and (36.1% men), were included at admission (A1). Yearly assessments were performed for two years (A2 and A3) or until death. Pain was assessed using the Mobilization-Observation-Behavior-Intensity-Dementia-2 (MOBID-2) Pain Scale. Information regarding prescription of analgesics, general physical health, personal activities of daily living, severity of dementia, neuropsychiatric symptoms, and prescription of psychotropic drugs was collected. A generalized linear mixed model was used to explore whether pain severity was associated with persistent and persistent prescription of opioids and/or paracetamol across timepoints. At A1, 495 of 996 (49.7%) NH residents were prescribed analgesics and prevalence increased at the follow-ups (A2: n = 630, 65.1%; A3: n = 382, 71.2%). Paracetamol was the most frequently prescribed analgesic at all assessments (A1: 45.5%; A2: 59.5%; A3: 67.1%). Opioid prescriptions were quite prevalent (A1: 18.1%; A2: 25.1%; A3: 28.3%), with odds approximately 13 times (OR = 13.3, 95% CI 6.8-26.0) and 9 times (OR = 8.6, 95% CI 3.7-20.3) higher for prescription at follow-up A2 and A3, respectively, relative to prescription at A1. In adjusted analyses, higher pain intensity and poor physical health were associated with prescription and persistent prescription of opioids and paracetamol. In conclusion, prevalence and persistent prescription of analgesics were high in NH residents with dementia. The odds for the prescription of opioids at follow-up were high if prescribed at baseline. Interdisciplinary collaboration, routine assessment of pain at admission and regularly thereafter, and systematic drug reviews are essential to adequately assess and treat pain in NH residents with dementia.

Fremanezumab is a humanized monoclonal antibody against calcitonin gene-related peptide for subcutaneous use to suppress migraine attacks. A phase 3 study was conducted to investigate the safety of autoinjector (AI)-assisted self-injection of fremanezumab 225 mg.