Papers: 15 Oct 2022 - 21 Oct 2022

The use of spinal cord stimulation for chronic pain after lumbar spine surgery is increasing, yet rigorous evidence of its efficacy is lacking.

Functionally distinct subtypes/clusters of dorsal root ganglion (DRG) neurons may play different roles in nerve regeneration and pain. However, details about their transcriptomic changes under neuropathic pain conditions remain unclear. Chronic constriction injury (CCI) of the sciatic nerve represents a well-established model of neuropathic pain, and we conducted single-cell RNA-sequencing (scRNA-seq) to characterize subtype-specific perturbations of transcriptomes in lumbar DRG neurons on day 7 post-CCI. By using mice that selectively express an enhanced in DRG neurons, we established a highly efficient purification process to enrich neurons for scRNA-seq. We observed the emergence of four prominent CCI-induced clusters and a loss of marker genes in injured neurons. Importantly, a portion of injured neurons from several clusters were spared from injury-induced identity loss, suggesting subtype-specific transcriptomic changes in injured neurons. Moreover, uninjured neurons, which are necessary for mediating the evoked pain, also demonstrated cell-type-specific transcriptomic perturbations in these clusters, but not in others. Notably, male and female mice showed differential transcriptomic changes in multiple neuronal clusters after CCI, suggesting transcriptomic sexual dimorphism in DRG neurons after nerve injury. Using as a proof-of-principle, RNAscope study provided further evidence of increased in injured neurons after CCI, supporting scRNA-seq analysis, and calcium imaging study unraveled a functional role of in neuronal excitability. These findings may contribute to the identification of new target genes and the development of DRG neuron cell-type-specific therapies for optimizing neuropathic pain treatment and nerve regeneration.

Pain is a common symptom in patients referred to polyneuropathy assessment. Diagnostic evaluation and choice of treatment may depend on whether the pain is likely to be neuropathic or not. The present study aimed to investigate the diagnostic accuracy of three tools commonly used to differentiate between neuropathic and non-neuropathic pain. To accomplish this, we included patients with bilateral distal lower extremity pain, referred to neurological outpatient clinics at five Norwegian University hospitals for polyneuropathy assessment. The patients filled in Norwegian versions of painDETECT, the Self-completed Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), and the clinician-rated Douleur Neuropathique 4 (DN4). All patients underwent a clinical examination and nerve conduction measurements, and were classified according to the NeuPSIG neuropathic pain criteria (reference standard). In total, 729 patients were included, of which 63% had neuropathic pain by the reference standard. Only DN4 demonstrated high sensitivity (0.87), while all three tools had low specificity (≤0.65). Importantly, the tools' predictive ability was unsatisfactory; The probability of getting a correct test result was three quarters at best, and at worst, no better than two fifths. Consequently, we show that neither DN4, painDETECT nor S-LANSS can be confidently used to assess neuropathic pain in a neurological outpatient population with symptoms of polyneuropathy.

Leukotriene B4 (LTB4) is a potent lipid mediator involved in the recruitment and activation of neutrophils, which is an important feature of tissue injury and inflammation. The biological effects of LTB4 are primarily mediated through the high-affinity LTB4 receptor, BLT1. Postoperative incisional pain is characterized by persistent acute pain at the site of tissue injury and is associated with local inflammation. Here, we compared the role of LTB4-BLT1 signaling in postoperative incisional pain between BLT1-knockout (BLT1KO) and wild-type (BLT1WT) mice. A planter incision model was developed, and mechanical pain hypersensitivity was determined using the von Frey test before and after incision. Local infiltration of neutrophils and inflammatory monocytes was quantified by flow cytometry. Inflammatory cytokine levels in the incised tissue were also determined. Mechanical pain hypersensitivity was significantly reduced in BLT1KO mice compared to BLT1WT mice at 2, 3, and 4 days after incision. LTB4 levels in the tissue at the incision site peaked 3 hours after the incision. Infiltrated neutrophils peaked 1 day after the incision in both BLT1KO and BLT1WT mice. The accumulation of inflammatory monocytes increased 1-3 days after the incision and was significantly more reduced in BLT1KO mice than in BLT1WT mice. In BLT1KO mice, Interleukin-1β and Tumor Necrosis Factor-α levels 1 day after the incision were significantly lower than those of BLT1WT mice. Our data suggest that LTB4 is produced and activates its receptor BLT1 in the very early phase of tissue injury, and that LTB4-BLT1 signaling exacerbates pain responses by promoting local infiltration of inflammatory monocytes and cytokine production. Thus, LTB4-BLT1 signaling is a potential target for therapeutic intervention of acute and persistent pain induced by tissue injury.

Prostaglandin E is classically considered a major mediator of inflammatory pain, by acting on neuronal G protein-coupled EP2 and EP4 receptors. However, the neuronal EP3 receptor, colocalized with EP2 and EP4 receptor, is G protein-coupled and antagonises the pronociceptive prostaglandin E effect. Here we investigated the cellular signalling mechanisms by which the EP3 receptor reduces EP2 and EP4 receptor-evoked pronociceptive effects in sensory neurons.

There is a need to identify objective cortical electrophysiological correlates for pain relief that could potentially contribute to a better pain management. However, the field of developing brain biomarkers for pain relief is still largely underexplored.

Chronic pain is a debilitating condition that influences the social, economic, and psychological aspects of patients' lives. Hence, the need for better treatment is drawing extensive interest from the research community. Developmental molecules such as Wnt, ephrins, and semaphorins are acknowledged as central players in the proper growth of a biological system. Their receptors and ligands are expressed in a wide variety in both neurons and glial cells, which are implicated in pain development, maintenance, and resolution. Thereby, it is not surprising that the impairment of those pathways affects the activities and functions of the entire cell. Evidence indicates aberrant activation of their pathways in the nervous system in rodent models of chronic pain. In those conditions, Wnt, ephrin, and semaphorin signaling participate in enhancing neuronal excitability, peripheral sensitization, synaptic plasticity, and the production and release of inflammatory cytokines. This review summarizes the current knowledge on three main developmental pathways and their mechanisms linked with the pathogenesis and progression of pain, considering their impacts on neuronal and glial cells in experimental animal models. Elucidations of the downstream pathways may provide a new mechanism for the involvement of Wnt, ephrin, and semaphorin pathways in pain chronicity.

Fibromyalgia (FM) is a disease characterized by the presence of chronic and widespread musculoskeletal pain, which causes a high negative impact on the quality of life (QoL). Although there are many studies about the QoL of patients with FM, it is unknown which variables have a main influence on it. Therefore, in the present study, we aimed to determine which FM symptoms predict a worse QoL and also to establish whether lifestyle and multi-medication are associated to QoL. We assessed a sample of 134 women with FM using a semi-structured clinical interview to explore lifestyle (diet, exercise, smoking) and medication use, and questionnaires to cover the main symptoms of this disease and QoL (SF-36). We found that the patients with FM had a poor QoL, being "physical pain" and "vitality" the most affected domains. A linear regression analysis showed that depression and anxiety assessed by HADS were the FM symptoms which most significantly predicted QoL, explaining 49% of the variance. Concerning lifestyle/medication influences, we found that multiple drug treatment and smoking also predicted a worse QoL (14%). Moreover, patients who practiced exercise regularly showed better QoL than patients who did not (regardless of the severity of FM). Thus, our results suggest that treatment strategies to improve QoL in FM should be focused on improving psychological distress, promoting regular exercise and reducing smoking and multi-medication. The data highlights the role of positive self-management practices to improve QoL in FM.

Atopic dermatitis (AD) is a relatively common inflammatory skin disease marked by eczematous lesions and pruritus often leading to significant morbidity and quality of life impairment for those affected. Recent studies have shown that patients with skin of color (SOC) carry a larger disease burden than patients of European descent. In the USA, these disparities are partly due to structural, environmental, and interpersonal racism. From a global perspective, there is a paucity of research on the burden of atopic dermatitis and other inflammatory skin diseases experienced by the record numbers of refugees, migrants, and asylum seekers around the world. Although it is still unclear whether the true prevalence of AD in displaced communities is higher compared with the general population, those who are displaced suffer from unique risk factors that render them especially vulnerable. In this review, we outline a number of factors contributing to AD susceptibility and/or aggravation in displaced communities. These include poor living conditions, climate change events, psychological stress, and lack of access to medical care and health-related behaviors.

To systematically review the effectiveness and safety of telemedicine combined with usual care (in-person visits) compared to usual care for the therapeutic management and follow-up assessment of neurologic diseases.

Approximately one in four total knee replacement patients develop persistent pain. Identification of those at higher risk could help inform optimal management.

To compare the clinical effectiveness of sodium polynucleotide, classic hyaluronic acid, and crosslinked hyaluronic acid for the management of painful knee osteoarthritis.

Clinical data on cancer-induced pain (CIP) demonstrate widespread changes in sensory function. It is characterized in humans not only by stimulus-invoked pain, but also by spontaneous pain. In our previous studies in an animal model of CIP, we observed changes in intrinsic membrane properties and excitability of dorsal root ganglion (DRG) sensory neurons corresponding to mechanical allodynia and hyperalgesia, of which abnormal activities of Aβ-fiber sensory neurons are consistent in a rat model of peripheral neuropathic pain (NEP).

Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by severe joint pain. There are conflicting results for the association of Interleukin 4 (IL4) variable number tandem repeats (VNTR; rs8179190) polymorphism with RA. Therefore, we performed a meta-analysis of the available studies to investigate the association of IL4 VNTR polymorphism with RA risk and severity in the overall populations and Asian, Egyptian, European, and Turkish ethnicities by sub-group analyses. Eight studies involving 1993 RA patients and 1732 controls were included in this meta-analysis. We found increased RA risk for the susceptible "R2R2" genotype and "R2" allele under heterozygous, recessive, and allelic models in the Asian populations (p < 0.00001, p < 0.0001, p = 0.001). We observed a significant association between "R2R2" genotype and "R2" allele for RA protection in the Turkish population under heterozygous, recessive, and allelic models (p = 0.01, p = 0.004, p = 0.002). Disease severity-based analysis revealed significant association for "R2R2" genotype and "R2" allele with RA severity under homozygous, heterozygous, recessive, dominant, and allelic models(p = 0.0004, p = 0.03, p = 0.02, p = 0.003, p = 0.01), specifically in Asian populations (p = 0.009, p = 0.02, p = 0.003, p = 0.03, p = 0.01) and under heterozygous, dominant, and allelic genetic models in Egyptian (p = 0.0001, p < 0.0001, p < 0.0001) and European (p = 0.002, p = 0.0007, p = 0.0006) populations. In silico analysis suggested that the susceptible "R2" allele changes the RNA secondary structure to a stable form by changing minimum free energy(ΔG) from – 115.20 to – 136.40 kcal/mol, which might lead to increased stability of IL-4 in RA patients. Overall, the meta-analysis suggests for the involvement of susceptible "R2" allele with RA risk in the Asian populations, RA severity in the overall populations (specifically in Asian, Egyptian, & European populations), and RA protection in the Turkish population.

Global interest in the non-intoxicating cannabis constituent, cannabidiol (CBD), is increasing with claims of therapeutic effects across a diversity of health conditions. At present, there is sufficient clinical trial evidence to support the use of high oral doses of CBD (e.g., 10-50 mg/kg) in treating intractable childhood epilepsies. However, a question remains as to whether "low-dose" CBD products confer any therapeutic benefits. This is an important question to answer, as low-dose CBD products are widely available in many countries, often as nutraceutical formulations. The present review therefore evaluated the efficacy and safety of low oral doses of CBD. The review includes interventional studies that measured the clinical efficacy in any health condition and/or safety and tolerability of oral CBD dosed at less than or equal to 400 mg per day in adult populations (i.e., ≥18 years of age). Studies were excluded if the product administered had a Δ -tetrahydrocannabinol content greater than 2.0%. Therapeutic benefits of CBD became more clearly evident at doses greater than or equal to 300 mg. Increased dosing from 60 to 400 mg/day did not appear to be associated with an increased frequency of adverse effects. At doses of 300-400 mg, there is evidence of efficacy with respect to reduced anxiety, as well as anti-addiction effects in drug-dependent individuals. More marginal and less consistent therapeutic effects on insomnia, neurological disorders, and chronic pain were also apparent. Larger more robust clinical trials are needed to confirm the therapeutic potential of lower (i.e., <300 mg/day) oral doses of CBD.

Virtual reality (VR) has the potential to lessen pain and anxiety experienced by pediatric patients undergoing burn wound care procedures. Population-specific variables require novel technological application and thus, a systematic review among studies on its impact is warranted.

The anesthetic management of fetal operative procedures (FOP) is a highly debated topic. Literature on fetal pain perception and response to external stimuli is rapidly expanding. Nonetheless, there is no consensus on the fetal consciousness nor on the instruments to measure pain levels. As a result, no guidelines or clinical recommendations on anesthesia modality during FOP are available. This systematic literature review aimed to collect the available knowledge on the most common fetal interventions, and summarize the reported outcomes for each anesthetic approach. Additional aim was to provide an overall evaluation of the most commonly used anesthetic agents.

Despite rapid advances in the field of chronic pain, it remains extremely challenging in the clinic. Pain treatment strategies have not improved for decades as opioids remain the main prescribed drugs for chronic pain management. However, long-term use of opioids often leads to detrimental side effects. Therefore, uncovering the mechanisms underlying the development and maintenance of chronic pain may aid the discovery of novel therapeutics to benefit patients with chronic pain. Substantial evidence indicates downregulation of α7 nicotinic acetylcholine receptors (α7 nAChR) in the sciatic nerve, dorsal root ganglia, and spinal cord dorsal horn in rodent models of chronic pain. Moreover, our recent study and results from other laboratories demonstrate that potentiation of α7 nAChR attenuates pain behaviors in various murine models of chronic pain. This review summarized and discussed the preclinical evidence demonstrating the therapeutic potential of α7 nAChR agonists and allosteric modulators in chronic pain. This evidence indicates that potentiation of α7 nAChR is beneficial in chronic pain, mostly by alleviating neuroinflammation. Overall, α7 nAChR-based therapy for chronic pain is an area with great promise, but more research regarding its detailed mechanisms is warranted.

Chronic pain remains to be a clinical challenge and is recognized as a major health problem with varying impacts on quality of life. Currently, the first-line therapy for chronic pain is opioids, which are often accompanied by unwanted psychoactive side effects. Thus, new and effective treatments for chronic pain are urgently needed and eagerly pursued. Inflammatory cytokines, especially interleukin-17 (IL-17), are reportedly potential therapeutic targets owing to their pivotal role in chronic pain from the neuroinflammation perspective. Recently, substantial evidence confirmed that IL-17 and IL-17 receptors (IL-17Rs) were increased in neuropathic, inflammatory, and cancer pain models. Notably, IL-17/IL-17R antibodies also reportedly relieve or cure inflammatory- and pain-related diseases. However, existing studies have reported controversial results regarding IL-17/IL-17Rs as potential therapeutic targets in diverse animal models of chronic pain. In this review, we present a summary of published studies and discuss the evidence, from basic to clinical to research, regarding the role and mechanism of action between IL-17 and diverse kinds of chronic pain in animal models and clinical patients. Furthermore, we evaluated IL-17-based therapy as a potential therapeutic strategy for inflammatory- and pain-related disease. Importantly, we also discussed clinical trials of IL-17/IL-17R targeting monoclonal antibodies. Overall, we found that IL-17 is a potential therapeutic target for chronic pain from the perspective of neuroinflammation.

As an immune dysregulation-related disease, although ulcerative colitis (UC) primarily affects the intestinal tract, extraintestinal manifestations of the disease are evident, particularly in the oral cavity. Herein, we have reviewed the various oral presentations, potential pathogenesis, and treatment of oral lesions related to UC. The oral manifestations of UC include specific and nonspecific manifestations, with the former including pyostomatitis vegetans and the latter encompassing recurrent aphthous ulcers, atrophic glossitis, burning mouth syndrome, angular cheilitis, dry mouth, taste change, halitosis, and periodontitis. Although the aetiology of UC has not been fully determined, the factors leading to its development include immune system dysregulation, dysbiosis, and malnutrition. The principle of treating oral lesions in UC is to relieve pain, accelerate the healing of lesions, and prevent secondary infection, and the primary procedure is to control intestinal diseases. Systemic corticosteroids are the preferred treatment options, besides, topical and systemic administration combined with dietary guidance can also be applied. Oral manifestations of UC might accompany or precede the diagnosis of UC, albeit with the absence of intestinal symptoms; therefore, oral lesions, especially pyostomatitis vegetans, recurrent aphthous ulcer and periodontitis, could be used as good mucocutaneous signs to judge the occurrence and severity of UC, thus facilitating the early diagnosis and treatment of UC and avoiding severe consequences, such as colon cancer.

Specialized pain rehabilitation is recognized as the treatment of choice for youth with pain-related disability. Appropriate outcomes for program evaluation are critical. This study aimed to summarize the effect domains and methods used to assess them, map them to the PedIMMPACT statement, and highlight future directions.

Platinum-based chemotherapeutic treatment of cancer patients is associated with debilitating adverse effects. Several adverse effects have been well investigated, and can be managed satisfactorily, but chemotherapy-induced peripheral neuropathy (CIPN) remains poorly treated. Our primary aim in this study was to investigate the neuroprotective effect of the immunomodulatory drug rapamycin in the mitigation of cisplatin-induced neurotoxicity. Pain assays were performed to determine whether rapamycin would prevent or significantly decrease cisplatin-induced neurotoxicity in adult male Balb/c mice. Neuropathic pain induced by both chronic and acute exposure to cisplatin was measured by hot plate assay, cold plate assay, tail-flick test, and plantar test. Rapamycin co-treatment resulted in significant reduction in cisplatin-induced nociceptive-like symptoms. To understand the underlying mechanisms behind rapamycin-mediated neuroprotection, we investigated its effect on certain inflammatory mediators implicated in the propagation of chemotherapy-induced neurotoxicity. Interestingly, cisplatin was found to significantly increase peripheral IL-17A expression and CD8- T cells, which were remarkably reversed by the pre-treatment of mice with rapamycin. In addition, rapamycin reduced the cisplatin-induced neuronal apoptosis marked by decreased neuronal caspase-3 activity. The rapamycin neuroprotective effect was also associated with reversal of the changes in protein expression of p21, p53, and PUMA. Collectively, rapamycin alleviated some features of cisplatin-induced neurotoxicity in mice and can be further investigated for the treatment of cisplatin-induced peripheral neuropathy.

The Brazilian Headache Society (Sociedade Brasileira de Cefaleia, SBCe, in Portuguese) nominated a Committee of Authors with the aim of establishing a consensus with recommendations regarding prophylactic treatment for episodic migraine based on articles published in the worldwide literature, as well as personal experience. Migraine affects 1 billion people around the world and more than 30 million Brazilians. In addition, it is an underdiagnosed and undertreated disorder. It is well known within the medical community of neurologists, and especially among headache specialists, that there is a need to disseminate knowledge about prophylactic treatment for migraine. For this purpose, together with the need for drug updates and to expand knowledge of the disease itself (frequency, intensity, duration, impact and perhaps the progression of migraine), this Consensus was developed, following a full online methodology, by 12 groups who reviewed and wrote about the pharmacological categories of the drugs used and, at the end of the process, met to read and establish conclusions for this document. The drug classes studied were: anticonvulsants, tricyclic antidepressants, monoclonal anti-calcitonin gene-related peptide (anti-CGRP) antibodies, beta-blockers, antihypertensives, calcium channel inhibitors, other antidepressants (selective serotonin reuptake inhibitors, SSRIs, and dual-action antidepressants), other drugs, and polytherapy. Hormonal treatment and anti-inflammatories and triptans in minimum prophylaxis schemes (miniprophylaxis) will be covered in a specific chapter. The drug classes studied for part I of the Consensus were: anticonvulsants, tricyclic antidepressants, monoclonal anti-CGRP antibodies, and beta-blockers.

Neck with shoulder muscle stiffness/pain is a common disorder. Commonly used physical therapy, pharmacotherapy, acupuncture, and moxibustion only temporarily alleviate the disorder in most cases, thus the disorder often recurs. Low power laser therapy is often used for neck and shoulder stiffness/pain and has been effective in clinical trials. In this study, we evaluated the safety and effectiveness of a newly developed self-care device for disorders including neck with shoulder muscle stiffness/pain. The device incorporates light-emitting diodes (LEDs), which are safer than lasers, as its light source. Ten adults with neck with shoulder muscle stiffness/pain were subject to LED irradiation (wavelength 780 nm ± 15 nm, output 750 mW, power density 3.8 W/cm2, energy density 5.7×102 J/cm2) for 3 minutes on the affected shoulder at a standard acupuncture point (GB21, Jianjing). Immediately after irradiation, the subjective symptoms of the neck with shoulder muscle stiffness and pain evaluated by a visual analog scale were improved from 58.3 mm ± 18.7 mm to 45.5 mm ± 21.5 mm and from 45.8 mm ± 23.3 mm to 39.4 mm ± 21.8 mm, respectively. The symptoms further improved after 15 minutes of irradiation. The skin temperature at the irradiated point increased from 34.3°C ± 1.1°C to 41.0°C ± 0.7°C. The increase in skin temperature was observed within approximately 5 cm of the irradiated area. There was no effect on the heart rate variability, a measure of the autonomic nervous system; however, the baroreflex sensitivity was slightly increased. No irradiation-related adverse skin events were observed. Our LED irradiation device was found to be safe, and it improved the subjective symptoms of muscle stiff neck with shoulders.

Low back pain (LBP) is a chronic condition that causes great individual suffering and economic burden. The major contributor of LBP is intervertebral disc degeneration (IDD), which is caused by a spectrum of homeostasis alteration, including the apoptosis of nucleus pulposus (NP) and annulus fibrosus (AF) cells, degradation of extracellular matrix (ECM), calcification of cartilaginous endplates (CEP) and so on. Currently, the therapeutic strategy for IDD includes conservative and surgery treatment. Nevertheless, none of them could reverse the progressive destruction of the intervertebral disc. Hence, it is pivotal to pursue a new therapeutic approach. Exosomes, nano-sized substances with diameters of 30-150 nm, can be synthesized and secreted by various types of cells. They play an important role in intercellular communication. Increasing evidence implicates that exosomes could impact the intracellular transcription activities, thereby inhibiting or accelerating the proliferation and apoptosis of cells. Thus, it is a new therapeutic source for IDD. This review chiefly focuses on generalizing and clarifying the roles of exosomes in the onset and deterioration of IDD, and their therapeutic potential.

In everyday clinical practice, healthcare professionals often meet chronic pain patients with a poor nutritional status. A poor nutritional status such as malnutrition, unhealthy dietary behaviors, and a suboptimal dietary intake can play a significant role in the occurrence, development, and prognosis of chronic pain. The relationship between nutrition and chronic pain is complex and may involve many underlying mechanisms such as oxidative stress, inflammation, and glucose metabolism. As such, pain management requires a comprehensive and interdisciplinary approach that includes nutrition. Nutrition is the top modifiable lifestyle factor for chronic non-communicable diseases including chronic pain. Optimizing one's dietary intake and behavior needs to be considered in pain management. Thus, this narrative review reports and summarizes the existing evidence regarding (1) the nutrition-related health of people experiencing pain (2) the underlying potential mechanisms that explain the interaction between nutrition and chronic pain, and (3) the role of nutrition screening, assessment and evaluation for people experiencing pain and the scope of nutrition practice in pain management. Future directions in the nutrition and chronic pain field are also discussed.

Peripheral and central sensitizations of the trigeminal nervous system are the main mechanisms to promote the development and maintenance of chronic orofacial pain characterized by allodynia, hyperalgesia, and ectopic pain after trigeminal nerve injury or inflammation. Although the pathomechanisms of chronic orofacial pain are complex and not well known, sufficient clinical and preclinical evidence supports the contribution of the N-methyl-D-aspartate receptors (NMDARs, a subclass of ionotropic glutamate receptors) to the trigeminal nociceptive signal processing pathway under various pathological conditions. NMDARs not only have been implicated as a potential mediator of pain-related neuroplasticity in the peripheral nervous system (PNS) but also mediate excitatory synaptic transmission and synaptic plasticity in the central nervous system (CNS). In this review, we focus on the pivotal roles and mechanisms of NMDARs in the trigeminal nervous system under orofacial neuropathic and inflammatory pain. In particular, we summarize the types, components, and distribution of NMDARs in the trigeminal nervous system. Besides, we discuss the regulatory roles of neuron-nonneuronal cell/neuron-neuron communication mediated by NMDARs in the peripheral mechanisms of chronic orofacial pain following neuropathic injury and inflammation. Furthermore, we review the functional roles and mechanisms of NMDARs in the ascending and descending circuits under orofacial neuropathic and inflammatory pain conditions, which contribute to the central sensitization. These findings are not only relevant to understanding the underlying mechanisms, but also shed new light on the targeted therapy of chronic orofacial pain.

Structural approaches to promoting health focus on policies and practices affecting health at the community level and concentrate on systems and forces of society, including distribution of power, that foster disadvantage and diminish health and well-being. In this paper we advocate consideration of structural approaches to explore macro level influences on the burden of persistent pain on society. We argue that health promotion is an appropriate discipline to ameliorate painogenic environments and that a "settings approach" offers a crucial vehicle to do this. We encourage consideration of socio-ecological frameworks to explore factors affecting human development at individual, interpersonal, organizational, societal, and environmental levels because persistent pain is multifaceted and complex and unlikely to be understood from a single level of analysis. We acknowledge criticisms that the structural approach may appear unachievable due to its heavy reliance on inter-sectoral collaboration. We argue that a settings approach may offer solutions because it straddles "practical" and cross-sectorial forces impacting on the health of people. A healthy settings approach invests in social systems where health is not the primary remit and utilises synergistic action between settings to promote greater health gains. We offer the example of obesogenic environments being a useful concept to develop strategies to tackle childhood obesity in school-settings, community-settings, shops, and sports clubs; and that this settings approach has been more effective than one organisation tackling the issue in isolation. We argue that a settings approach should prove useful for understanding painogenic environments and tackling the burden of persistent pain.

Multiple clinical trials with different exercise protocols have demonstrated efficacy in the management of migraine. However, there is no head-to-head comparison of efficacy between the different exercise interventions.

This article describes commonly used experimental and clinical biomarkers of neuronal injury and neurodegeneration for the evaluation of neuropathology and monitoring of therapeutic interventions. Biomarkers are vital for diagnostics of brain disease and therapeutic monitoring. A biomarker can be objectively measured and evaluated as a proxy indicator for the pathophysiological process or response to therapeutic interventions. There are complex hurdles in understanding the molecular pathophysiology of neurological disorders and the ability to diagnose them at initial stages. Novel biomarkers for neurological diseases may surpass these issues, especially for early identification of disease risk. Validated biomarkers can measure the severity and progression of both acute neuronal injury and chronic neurological diseases such as epilepsy, migraine, Alzheimer's disease, Parkinson's disease, Huntington's disease, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and other brain diseases. Biomarkers are deployed to study progression and response to treatment, including noninvasive imaging tools for both acute and chronic brain conditions. Neuronal biomarkers are classified into four core subtypes: blood-based, immunohistochemical-based, neuroimaging-based, and electrophysiological biomarkers. Neuronal conditions have progressive stages, such as acute injury, inflammation, neurodegeneration, and neurogenesis, which can serve as indices of pathological status. Biomarkers are critical for the targeted identification of specific molecules, cells, tissues, or proteins that dramatically alter throughout the progression of brain conditions. There has been tremendous progress with biomarkers in acute conditions and chronic diseases affecting the central nervous system.

Treatment of chronic pain is challenged by concurrent anxiety symptoms. Dexmedetomidine is known to produce sedation, analgesia, and anxiolysis. However, the neural mechanism of dexmedetomidine-elicited anxiolysis remains elusive. Here, we aimed to test the hypothesis that the anterior cingulate cortex might be involved in dexmedetomidine-induced anxiolysis in pain.

Physical activity-based rehabilitative interventions represent the main treatment concept for people suffering from spinal cord injury (SCI). The role such interventions play in the relief of neuropathic pain (NP) states is emerging, along with underlying mechanisms resulting in SCI-induced NP (SCI-NP). Animal models have been used to investigate the benefits of activity-based interventions (ABI), such as treadmill training, wheel running, walking, swimming, and bipedal standing. These activity-based paradigms have been shown to modulate inflammatory-related alterations as well as induce functional and structural changes in the spinal cord gray matter circuitry correlated with pain behaviors. Thus far, the research available provides an incomplete picture of the cellular and molecular pathways involved in this beneficial effect. Continued research is essential for understanding how such interventions benefit SCI patients suffering from NP and allow the development of individualized rehabilitative therapies. This article reviews preclinical studies on this specific topic, goes over mechanisms involved in SCI-NP in relation to ABI, and then discusses the effectiveness of different activity-based paradigms as they relate to different forms, intensity, initiation times, and duration of ABI. This article also summarizes the mechanisms of respective interventions to ameliorate NP after SCI and provides suggestions for future research directions.

Cognitive impairment after surgery is a common problem, affects mainly the elderly, and can be divided into postoperative delirium and postoperative cognitive dysfunction. Both phenomena are accompanied by neuroinflammation; however, the precise molecular mechanisms underlying cognitive impairment after anesthesia are not yet fully understood. Anesthesiological drugs can have a longer-term influence on protein transcription, thus, epigenetics is a possible mechanism that impacts on cognitive function. Epigenetic mechanisms may be responsible for long-lasting effects and may implicate novel therapeutic approaches. Hence, we here summarize the existing literature connecting postoperative cognitive impairment to anesthesia. It becomes clear that anesthetics alter the expression of DNA and histone modifying enzymes, which, in turn, affect epigenetic markers, such as methylation, histone acetylation and histone methylation on inflammatory genes (e.g., TNF-alpha, IL-6 or IL1 beta) and genes which are responsible for neuronal development (such as brain-derived neurotrophic factor). Neuroinflammation is generally increased after anesthesia and neuronal growth decreased. All these changes can induce cognitive impairment. The inhibition of histone deacetylase especially alleviates cognitive impairment after surgery and might be a novel therapeutic option for treatment. However, further research with human subjects is necessary because most findings are from animal models.

The objective of this meta-analysis was to identify whether headache increase the risk of dry eye disease (DED).

The primary objective of this quality improvement (QI) study was to increase peripheral nerve block (PNB) administration for ankle fracture surgeries (AFSs) at our institution to above 50% by January 1st, 2021.

The comparative benefits and harms of opioids for musculoskeletal pain in the emergency department (ED) are uncertain.

Metastatic spread of prostate cancer to the skeleton may result in debilitating bone pain. In this review, we address mechanisms underpinning the pathobiology of metastatic prostate cancer induced bone pain (PCIBP) that include sensitization and sprouting of primary afferent sensory nerve fibres in bone. We also review current treatments and pain responses evoked by various treatment modalities in clinical trials in this patient population.

Polymyalgia rheumatica and giant cell arteritis are inflammatory conditions that occur predominantly in people 50 years and older, with peak incidence at 70 to 75 years of age. Polymyalgia rheumatica is more common and typically presents with constitutional symptoms, proximal muscle pain, and elevated inflammatory markers. Diagnosis of polymyalgia rheumatica is clinical, consisting of at least two weeks of proximal muscle pain, constitutional symptoms, and elevated erythrocyte sedimentation rate or C-reactive protein. Treatment of polymyalgia rheumatica includes moderate-dose glucocorticoids with a prolonged taper. Giant cell arteritis, also known as temporal arteritis, usually presents with new-onset headache, visual disturbances or changes, constitutional symptoms, scalp tenderness, and temporal artery symptoms. Inflammatory markers are markedly elevated. Temporal arterial biopsy should be used for diagnosis. However, color duplex ultrasonography, magnetic resonance imaging, and fluorodeoxyglucose positron emission tomography may be helpful when biopsy is negative or unavailable. All patients with suspected giant cell arteritis should receive empiric high-dose glucocorticoids because the condition may lead to blindness if untreated. Tocilizumab is approved by the U.S. Food and Drug Administration for giant cell arteritis and should be considered in addition to glucocorticoids for initial therapy. Polymyalgia rheumatica and giant cell arteritis respond quickly to appropriate dosing of glucocorticoids but typically require prolonged treatment and have high rates of relapse; therefore, monitoring for glucocorticoid-related adverse effects and symptoms of relapse is necessary. Methotrexate may be considered as an adjunct to glucocorticoids in patients with polymyalgia rheumatica or giant cell arteritis who are at high risk of relapse.

Endometriosis is an inflammatory condition caused by the presence of endometrial tissue in extra-uterine locations and can involve bowel, bladder, and all peritoneal structures. It is one of the most common gynecologic disorders, affecting up to 10% of people of reproductive age. Presentation of endometriosis can vary widely, from infertility in asymptomatic people to debilitating pelvic pain, dysmenorrhea, and period-related gastrointestinal or urinary symptoms. Diagnosis of endometriosis in the primary care setting is clinical and often challenging, frequently resulting in delayed diagnosis and treatment. Although transvaginal ultrasonography is used to evaluate endometriosis of deep pelvic sites to rule out other causes of pelvic pain, magnetic resonance imaging is preferred if deep infiltrating endometriosis is suspected. Laparoscopy with biopsy remains the definitive method for diagnosis, although several gynecologic organizations recommend empiric therapy without immediate surgical diagnosis. Combined hormonal contraceptives with or without nonsteroidal anti-inflammatory drugs are first-line options in managing symptoms and have a tolerable adverse effect profile. Second-line treatments include gonadotropin-releasing hormone (GnRH) receptor agonists with add-back therapy, GnRH receptor antagonists, and danazol. Aromatase inhibitors are reserved for severe disease. All of these treatments are effective but may cause additional adverse effects. Referral to gynecology for surgical management is indicated if empiric therapy is ineffective, immediate diagnosis and treatment are necessary, or patients desire pregnancy. Alternative treatments have limited benefit in alleviating pain symptoms but may warrant further investigation.

Foot function is usually assessed using self-reported outcome measures which remain subjective in patients with rheumatoid arthritis (RA). Physical performance tests were recommended for functional assessment in lower limb osteoarthritis. However, foot function assessment's guidelines in RA are lacking. We aimed to investigate the correlation between a self-reported outcome measure and two performance-based physical tests for assessing foot function in RA patients.

The aim of this study was to describe cases of patients with presumable dysimmune small-fiber neuropathy (SFN)-related neuropathic corneal pain (NCP), presenting with autoantibodies against trisulfated heparin disaccharide (TS-HDS) or fibroblast growth factor receptor-3 (FGFR-3).

During lumbar decompressive spine surgery, the epidural space is easily accessible. This intraoperative situation allows surgeons to apply an epidural bolus of analgesia at the end of the surgical procedure. In literature, several papers about the methods and effectiveness of delivering local analgesia during lumbar decompressive spine surgery have been published.

Chronic pain inflicts damage in multiple spheres of patient's life and remains a challenge for health care providers. Real-world evidence derived from outcome registries represents a key aspect of the ongoing systematic assessment and future development of neurostimulation devices.

The Basal ganglia (BG) played a crucial role in the brain-level mechanisms of chronic pain disorders. However, the functional changes of BG in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) are still poorly understood. This study investigated the BG subregions' resting-state functional connectivity (rs-FC) in CP/CPPS patients compared with healthy controls.

To evaluate the additional effect of high frequency (HF) or low frequency (LF) transcutaneous electrical nerve stimulation (TENS) in a specific therapeutic exercise program for the treatment of patients with chronic neck pain.

Fibromyalgia is a chronic pain syndrome characterized by dysfunctional processing of nociceptive stimulation. Neuroimaging studies have pointed out that pain-related network functioning seems to be altered in these patients. It is thought that this clinical symptomatology may be maintained or even strengthened because of an enhanced expectancy for painful stimuli or its forthcoming appearance. However, neural electrophysiological correlates associated with such attentional mechanisms have been scarcely explored. In the current study, expectancy processes of upcoming laser stimulation (painful and non-painful) and its further processing were explored by event-related potentials (ERPs). Nineteen fibromyalgia patients and twenty healthy control volunteers took part in the experiment. Behavioral measures (reaction times and subjective pain perception) were also collected. We manipulated the pain/no pain expectancy through an S1-S2 paradigm (cue-target). S1 (image: triangle or square) predicted the S2 appearance (laser stimulation: warmth or pinprick sensation). Laser stimuli were delivered using a CO laser device. Temporal and spatial principal component analyses were employed to define and quantify the ERP component reliability. Statistical analyses revealed the existence of an abnormal pattern of pain expectancy in patients with fibromyalgia. Specifically, our results showed attenuated amplitudes at posterior lCNV component in anticipation of painful stimulation that was not found in healthy participants. In contrast, although larger P2 amplitudes to painful compared to innocuous events were shown, patients did not show any amplitude change in this laser-evoked response as a function of pain predictive cues (as occurred in the healthy control group). Additionally, analyses of the subjective perception of pain and reaction time indicated that laser stimuli preceded by pain cues were rated as more painful than those signaling non-pain expectancy and were associated with faster responses. Differences between groups were not found. The present findings suggest the presence of dysfunction in pain expectation mechanisms in fibromyalgia that eventually may make it difficult for patients to correctly interpret signs that prevent pain symptoms. Furthermore, the abnormal pattern in pain expectancy displayed by fibromyalgia patients could result in ineffective pain coping strategies. Understanding the neural correlates of pain processing and its modulatory factors is crucial to identify treatments for chronic pain syndromes.

Migraine is a neurovascular disease with a high disability rate. Acupuncture treatment has emerged as a safe and viable alternative prophylactic therapy that can effectively alleviate the duration and frequency of migraine attacks. However, the therapeutic mechanisms underlying the effects of acupuncture are yet to be systematically elucidated. In this study, we enrolled female patients with migraine without aura ( = 20) and healthy controls ( = 10). Patients received acupuncture treatment on DU20, DU24, bilateral GB13, GB8, and GB20, applied three times per week over the course of 4 weeks for 12 sessions in total. Blood samples were collected from the median cubital vein before and after acupuncture treatment. Proteomic and metabolomic profiling was performed using liquid chromatography-mass spectrometry to determine the characteristics of differentially expressed molecules and expression of their corresponding biological pathways as well as to elucidate the pathogenesis of migraine and the biological effects underlying the treatment of migraine with acupuncture. Proteomic and metabolomic profiling of plasma samples from patients with migraine without aura before and after acupuncture treatment revealed enrichment of immune-related pathway functions and the arginine synthesis pathway. Joint pathway analyses revealed significant enrichment of the pentose phosphate and glycolysis/gluconeogenesis pathways in patients with migraine. The glycolysis/gluconeogenesis and riboflavin metabolism pathways were significantly enriched after acupuncture treatment. The expression levels of various key proteins and metabolites, including α-D-glucose, flavin adenine dinucleotide, biliverdin reductase B, and L-glutamate, were significantly differentially expressed before and after acupuncture treatment in patients with migraine without aura. Treatment of migraine with acupuncture was associated with significant changes in key molecules and pathways, indicative of physiological changes in the trigeminovascular system, glutamate neurotoxicity, and other migraine-related physiological changes. Overall, our comprehensive analysis using proteomic and metabolomic profiling demonstrates that energy metabolism may serve as a key correlative link in the occurrence of migraine and the therapeutic effects of acupuncture treatment. Our findings may facilitate the identification of diagnostic and therapeutic modalities in the ongoing search for effective treatments for migraine attacks.

Migraine is known to be associated with vascular dysfunction. However, sufficient evidence has not been reported in this regard. This study aims to assess subclinical atherosclerosis and endothelial function via Doppler Sonography in migraine patients.

The leading school of thought views fibromyalgia as a central sensitization syndrome. Nociplastic pain is the recently proposed term to mechanistically explain central sensitization. Accumulating research suggests an alternate explanation; fibromyalgia can be conceptualized as a neuropathic pain syndrome and dorsal root ganglia (not the brain) as the primary fibromyalgia pain source. There is no need to propose nociplastic pain as new chronic pain mechanism.

Osteoarthritis (OA) is a degenerative joint disease and is the main cause of chronic pain and functional disability in adults. Articular cartilage is a hydrated soft tissue that is composed of normally quiescent chondrocytes at a low density, a dense network of collagen fibrils with a pore size of 60-200 nm, and aggrecan proteoglycans with high-density negative charge. Although certain drugs, nucleic acids, and proteins have the potential to slow the progression of OA and restore the joints, these treatments have not been clinically applied owing to the lack of an effective delivery system capable of breaking through the cartilage barrier. Recently, the development of nanotechnology for delivery systems renders new ideas and treatment methods viable in overcoming the limited penetration. In this review, we focus on current research on such applications of nanotechnology, including exosomes, protein-based cationic nanocarriers, cationic liposomes/solid lipid nanoparticles, amino acid-based nanocarriers, polyamide derivatives-based nanocarriers, manganese dioxide, and carbon nanotubes. Exosomes are the smallest known nanoscale extracellular vesicles, and they can quickly deliver nucleic acids or proteins to the required depth. Through electrostatic interactions, nanocarriers with appropriate balance in cationic property and particle size have a strong ability to penetrate cartilage. Although substantial preclinical evidence has been obtained, further optimization is necessary for clinical transformation. STATEMENT OF SIGNIFICANCE: : The dense cartilage matrix with high-negative charge was associated with reduced therapeutic effect in osteoarthritis patients with deep pathological changes. However, a systematic review in nanodevices for deep cartilage penetration is still lacking. Current approaches to assure penetration of nanosystems into the depth of cartilage were reviewed, including nanoscale extracellular vesicles from different cell lines and nanocarriers with appropriate balance in cationic property and size particle. Moreover, nanodevices entering clinical trials and further optimization were also discussed, providing important guiding significance to future research.

High-impact temporomandibular disorder (TMD) pain may involve brain mechanisms related to maladaptive central pain modulation. We investigated brain responses to stimulation of trigeminal sites not typically associated with TMD pain by applying noxious dentoalveolar pressure to high- and low-impact TMD pain cases and pain-free controls during functional magnetic resonance imaging (fMRI). Fifty female participants were recruited and assigned to one of three groups based on the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and Graded Chronic Pain Scale: controls (n = 17), low-impact (n = 17) and high-impact TMD (n = 16). Multimodal whole-brain MRI was acquired following the Human Connectome Project Lifespan protocol, including stimulus-evoked fMRI scans during which painful dentoalveolar pressure was applied to the buccal gingiva of participants. Group analyses were performed using non-parametric permutation tests for parcellated cortical and subcortical neuroimaging data. There were no significant between-group differences for brain activations/deactivations evoked by the noxious dentoalveolar pressure. For individual group mean activations/deactivations, a gradient in the number of parcels surviving thresholding was found according to the TMD pain grade, with the highest number seen in the high-impact group. Among the brain regions activated in chronic TMD pain groups were those previously implicated in sensory-discriminative and motivational-affective pain processing. These results suggest that dentoalveolar pressure pain evokes abnormal brain responses to sensory processing of noxious stimuli in high-impact TMD pain participants, which supports the presence of maladaptive brain plasticity in chronic TMD pain.

Quality of life (QoL) and sleep, which are essential for well-being in the mental, physical, and socioeconomic domains, are impaired in psoriatic patients. However, the exact role of the clinical subtype of psoriasis in this aspect remains poorly studied.

Fibromyalgia (FM) is a disease characterized by widespread musculoskeletal chronic pain that impairs the patient's quality of life and is considered a somatization disorder. The symptoms of the disease also affect the patient mentally, mainly since invisible pain is the only thing that indicates its existence. A typical symptom that characterizes FM patients is the lack of acceptance of the disease since its pathophysiology is not elucidated, hence the deficiencies in its management, or rather, cognitively, the belief that there is no disease to manage. The current paper aims to shed light on the new treatment methods at a holistic level, that is, cognitive, physical, and pharmacological therapies.

Our aim was to assess the association between four inflammatory polymorphisms with the development of post-COVID pain and to associate these polymorphisms with the clinical pain phenotype in individuals who had been hospitalized by COVID-19. Three potential genotypes of IL-6 (rs1800796), IL-10 (rs1800896), TNF-α (rs1800629), and IFITM3 (rs12252) single nucleotide polymorphisms (SNPs) were obtained from no-stimulated saliva samples from 293 (49.5% female, mean age: 55.6 ± 12.9 years) previously hospitalized COVID-19 survivors by polymerase chain reactions. Pain phenotyping consisted of the evaluation of pain features, sensitization-associated symptoms, anxiety levels, depressive levels, sleep quality, catastrophizing, and kinesiophobia levels in patients with post-COVID pain. Analyses were conducted to associate clinical features with genotypes. One hundred and seventeen (39.9%) patients experienced post-COVID pain 17.8 ± 5.2 months after hospital discharge. No significant differences in the distribution of the genotype variants of any SNPs were identified between COVID-19 survivors with and without post-COVID pain (all, &gt; 0.47). Similarly, the clinical pain phenotype was not significantly different between patients with and without post-COVID pain since no differences in any variable were observed for any SNPs. In conclusion, four SNPs associated with inflammatory and immune responses did not appear to be associated with post-COVID pain in previously hospitalized COVID-19 survivors. Further, neither of the SNPs were involved in the phenotyping features of post-COVID pain.

Chronic pain results from a complex series of biomechanical, inflammatory, neurological, psychological, social, and environmental mechanisms. Pain and pain-related diseases are the leading causes of disability and disease burden globally. Employing nature-based interventions for the treatment of pain is an emerging field. Current theory driving the suggested mechanism(s) linking the pain reducing effects of nature-based interventions is lacking. A two-step approach was taken to complete a theoretical review and analysis. First, a literature review was completed to gather a substantive amount of research related to theoretical frameworks on the topic of nature-based interventions and pain. Secondly, a theoretical analysis as proposed by Walker and Avant was completed to explore current theoretical frameworks accepted in the literature on nature-based interventions and pain. Stress reduction theory and attention restoration theory were the most common theoretical frameworks identified. Neither theoretical framework explicitly identifies, describes, or intends to adequately measure the concept of pain, revealing a limitation for their application in research with nature-based interventions and pain. Theoretical development is needed, as it pertains to nature-based interventions and pain. Without this development, research on nature-based interventions and pain will continue to use proxy concepts for measurement and may result in misrepresented findings.