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Papers: 3 Sep 2022 - 9 Sep 2022

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Chronic pain causes Tau-mediated hippocampal pathology and memory deficits.

Persistent pain has been recently suggested as a risk factor for dementia. Indeed, chronic pain is frequently accompanied by maladaptive brain plasticity and cognitive deficits whose molecular underpinnings are poorly understood. Despite the emerging role of Tau as a key regulator of neuronal plasticity and pathology in diverse brain disorders, the role of Tau has never been studied in the context of chronic pain. Using a peripheral (sciatic) neuropathy to model chronic pain in mice-spared nerve injury (SNI) for 4 months-in wildtype as well as P301L-Tau transgenic mice, we hereby demonstrate that SNI triggers AD-related neuropathology characterized by Tau hyperphosphorylation, accumulation, and aggregation in hippocampus followed by neuronal atrophy and memory deficits. Molecular analysis suggests that SNI inhibits autophagy and reduces levels of the Rab35, a regulator of Tau degradation while overexpression of Rab35 or treatment with the analgesic drug gabapentin reverted the above molecular changes leading to neurostructural and memory recovery. Interestingly, genetic ablation of Tau blocks the establishment of SNI-induced hippocampal morphofunctional deficits supporting the mediating role of Tau in SNI-evoked hippocampal pathology and memory impairment. These findings reveal that exposure to chronic pain triggers Tau-related neuropathology and may be relevant for understanding how chronic pain precipitates memory loss leading to dementia.

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Got milk? Maternal immune activation during the mid-lactational period affects nutritional milk quality and adolescent offspring sensory processing in male and female rats.

Previous studies have underscored the importance of breastfeeding and parental care on offspring development and behavior. However, their contribution as dynamic variables in animal models of early life stress are often overlooked. In the present study, we investigated how lipopolysaccharide (LPS)-induced maternal immune activation (MIA) on postnatal day (P)10 affects maternal care, milk, and offspring development. MIA was associated with elevated milk corticosterone concentrations on P10, which recovered by P11. In contrast, both milk triglyceride and percent creamatocrit values demonstrated a prolonged decrease following inflammatory challenge. Adolescent MIA offspring were heavier, which is often suggestive of poor early life nutrition. While MIA did not decrease maternal care quality, there was a significant compensatory increase in maternal licking and grooming the day following inflammatory challenge. However, this did not protect against disrupted neonatal huddling or later-life alterations in sensorimotor gating, conditioned fear, mechanical allodynia, or reductions in hippocampal parvalbumin expression in MIA offspring. MIA-associated changes in brain and behavior were likely driven by differences in milk nutritional values and not by direct exposure to LPS or inflammatory molecules as neither LPS binding protein nor interleukin-6 milk levels differed between groups. These findings reflected comparable microbiome and transcriptomic patterns at the genome-wide level. Animal models of early life stress can impact both parents and their offspring. One mechanism that can mediate the effects of such stressors is changes to maternal lactation quality which our data show can confer multifaceted and compounding effects on offspring physiology and behavior.

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Gene-environment interactions explain a substantial portion of variability of common neuropsychiatric disorders.

In complex diseases, the phenotypic variability can be explained by genetic variation (G), environmental stimuli (E), and interaction of genetic and environmental factors (G-by-E effects), among which the contribution G-by-E remains largely unknown. In this study, we focus on ten major neuropsychiatric disorders using data for 138,383 United States families with 404,475 unique individuals. We show that, while gene-environment interactions account for only a small portion of the total phenotypic variance for a subset of disorders (depression, adjustment disorder, substance abuse), they explain a rather large portion of the phenotypic variation of the remaining disorders: over 20% for migraine and close to or over 30% for anxiety/phobic disorder, attention-deficit/hyperactivity disorder, recurrent headaches, sleep disorders, and post-traumatic stress disorder. In this study, we have incorporated-in the same analysis-clinical data, family pedigrees, the spatial distribution of individuals, their socioeconomic and demographic confounders, and a collection of environmental measurements.

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A novel methodology to integrate outcomes regarding perioperative pain experience into a composite score: prediction model development and validation.

An integrated score that globally assesses perioperative pain experience and rationally weights each component has not yet been developed.

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Endogenous oxytocin exerts anti-nociceptive and anti-inflammatory effects in rats.

Oxytocin is involved in pain transmission, although the detailed mechanism is not fully understood. Here, we generate a transgenic rat line that expresses human muscarinic acetylcholine receptors (hM3Dq) and mCherry in oxytocin neurons. We report that clozapine-N-oxide (CNO) treatment of our oxytocin-hM3Dq-mCherry rats exclusively activates oxytocin neurons within the supraoptic and paraventricular nuclei, leading to activation of neurons in the locus coeruleus (LC) and dorsal raphe nucleus (DR), and differential gene expression in GABA-ergic neurons in the L5 spinal dorsal horn. Hyperalgesia, which is robustly exacerbated in experimental pain models, is significantly attenuated after CNO injection. The analgesic effects of CNO are ablated by co-treatment with oxytocin receptor antagonist. Endogenous oxytocin also exerts anti-inflammatory effects via activation of the hypothalamus-pituitary-adrenal axis. Moreover, inhibition of mast cell degranulation is found to be involved in the response. Taken together, our results suggest that oxytocin may exert anti-nociceptive and anti-inflammatory effects via both neuronal and humoral pathways.

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The relationship between pain-related psychological factors and maximal physical performance in low back pain: a systematic review and meta-analysis.

Theoretical frameworks explain how pain-related psychological factors may influence physical performance. In this systematic review and meta-analysis, we evaluated the evidence regarding the relationship between pain-related psychological factors and maximal physical performance in patients with low back pain (LBP). Pubmed, Embase, CINAHL and Web of Science databases were searched from inception to May 2022. Cross-sectional or longitudinal studies reporting cross-sectional measures of association between at least one pain-related psychological factor and a quantitatively measured outcome of maximal physical performance in patients with LBP were eligible for inclusion. Thirty-eight studies (n=2490; 27 cross-sectional studies, n=1647 (66%); 11 longitudinal studies, n=843 (34%)) were included, with 92% of participants (n=2284) having chronic LBP. Results showed that pain-related fear, pain catastrophising and anticipated pain were consistently and negatively associated with maximal physical performance in chronic LBP, whereas pain-self efficacy showed positive correlations. Overall, magnitudes of absolute pooled r-values were small (r≤0.25), except for anticipated pain, which was moderately associated with maximal physical performance (r=-0.34 to -0.37). Subanalyses and sensitivity analyses yielded similar pooled correlation coefficients. Certainty of evidence using the GRADE recommendations was very low to moderate for pain-related fear, and very low to low for the other pain-related psychological factors. Prospero registration: CRD42021227486. Perspective: Overall, small pooled correlation coefficients were shown between pain-related psychological factors and maximal physical performance in chronic LBP. Certainty of evidence was very low to low for all pain-related psychological factors other than pain-related fear. Future studies taking into account limitations of the current literature may therefore change these conclusions.

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Consensus statement on smoking cessation in patients with pain.

Smoking is closely associated with the development of various cancers and tobacco-related illnesses such as cardiovascular and respiratory disorders. However, data are scarce on the relationship between smoking and both acute and chronic pain. In addition to nicotine, tobacco smoke contains more than 4000 different compounds. Although nicotine is not the sole cause of smoking-induced diseases, it plays a critical role in pain-related pathophysiology. Despite the acute analgesic effects of nicotine, long-term exposure leads to tolerance and increased pain sensitivity due to nicotinic acetylcholine receptor desensitization and neuronal plastic changes. The purpose of smoking cessation interventions in smoking patients with pain is primarily not only to reduce their pain and associated limitations in activities of daily living, but also to improve the outcomes of underlying pain-causing conditions and reduce the risks of tobacco-related disorders. This statement aims to summarize the available evidence on the impact of smoking on pain and to inform medical professionals of the significance of smoking cessation in patients with pain.

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Non-aura visual disturbance with high visual aura rating scale scores has stronger association with migraine chronification than typical aura.

To investigate the clinical correlates of visual symptoms in patients with migraine.

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Continuum of sensory profiles in diabetes mellitus patients with and without neuropathy and pain.

Quantitative sensory testing (QST) assesses the functional integrity of small and large nerve fibre afferents and central somatosensory pathways; QST was assumed to provide insight into the mechanisms of neuropathy. We analysed QST profiles and phenotypes in diabetes mellitus patients to study whether these could differentiate patients with and without pain and neuropathy.

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Rapid Pruritus Reduction With Ruxolitinib Cream Treatment in Patients With Atopic Dermatitis.

Ruxolitinib cream is a topical formulation of ruxolitinib, a Janus kinase (JAK) 1/JAK2 inhibitor.

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Papain as a Potential New Experimental Model of Non-histaminergic Itch.

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Identification of potential key circular RNAs related to cognitive impairment after chronic constriction injury of the sciatic nerve.

Chronic neuropathic pain is commonly accompanied by cognitive impairment. However, the underlying mechanism in the occurrence of cognitive deficits under constant nociceptive irritation remains elusive. Herein, we established a chronic neuropathic pain model by chronic constriction injury (CCI) of the unilateral sciatic nerve in rats. Behavioral tests indicated that CCI rats with long-term nociceptive threshold decline developed significant dysfunction of working memory and recognitive memory starting at 14 days and lasting for at least 21 days. Afterward, circRNA expression profiles in the hippocampus of CCI and sham rats were analyzed high-throughput sequencing to explore the potential key factors associated with cognitive impairment induced by ongoing nociception, which showed 76 differentially expressed circRNAs, 39 upregulated and 37 downregulated, in the CCI group. These differentially expressed circRNA host genes were validated to be primarily associated with inflammation and apoptotic signaling pathways according to GO/KEGG analysis and the circRNA-miRNA-mRNA network, which was also confirmed through the analysis of neuroinflammation and neuronal apoptosis. Consequently, we assumed that enhanced neuroinflammation and neuronal apoptosis might act as potential regulators of cognitive impairment induced by chronic neuropathic pain. The identification of the regulatory mechanism would provide promising clinical biomarkers or therapeutic targets in the diagnostic prediction and intervention treatment of memory deficits under neuropathic pain conditions.

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Social network change after new-onset pain among middle-aged and older European adults.

This study examines how onset of chronic pain affects characteristics of personal social networks among adults aged 51+ across Europe.

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Salivary CGRP and Erenumab Treatment Response: Towards Precision Medicine in Migraine.

We aimed (1) to analyze salivary calcitonin gene-related peptide (CGRP) levels in patients with migraine, (2) to predict erenumab response from baseline CGRP levels, and (3) to evaluate CGRP change post-treatment.

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The relationship of headache as a symptom to COVID-19 survival: A systematic review and meta-analysis of survival of 43,169 inpatients with COVID-19.

To study the relationship between coronavirus disease 2019 (COVID-19) mortality and headache among patients evaluated for COVID-19 in Emergency Departments and hospitals.

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Dimethyl Fumarate Attenuates Pain Behaviors in Osteoarthritis Rats via Induction of Nrf2-Mediated Mitochondrial Biogenesis.

Osteoarthritis (OA), a chronic degenerative disease, leads to pain and loss of function. Existing treatments for OA pain have limited efficacy and show significant side effects. Dimethyl fumarate, a robust nuclear factor erythroid 2-related factor 2 (Nrf2) activator, could alleviate pain behaviors in chronic pain. This study aims to investigate the role of dimethyl fumarate in a rat model of OA and its underlying mechanisms.

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Modulation of melatonin to the thalamic lesion-induced pain and comorbid sleep disturbance in the animal model of the central post-stroke hemorrhage.

The devastating chronic central post stroke pain is associated with variety of comorbidities. Disrupted sleep is a severe comorbidity, causing an increase in the suicide rate, due to CPSP's pain symptom. Melatonin is a well-known jet-lag compound, which helps in entrainment of sleep cycle. Accordingly, whether melatonin as a therapeutic measurement for the regulation of sleep disturbance related to central post stroke pain remains unclear. Exogenous melatonin administration entrained the disrupted 24hr circadian cycle, more effectively after 2w and 3w of administration. The effect of melatonin was persisted on 4th week too, when melatonin administration was discontinued. Also, melatonin ameliorated the pain due to distorted sleep-activity behavior after melatonin administration for 3 weeks. The low levels of melatonin in blood plasma due to CPSP were restored after 3 weeks of melatonin administration. After 30 mg/kg melatonin administrations for 3weeks, all the disrupted resting and activity behaviors were reduced during light and dark periods. The results suggested that melatonin significantly ameliorated CPSP's pain symptoms and comorbid sleep disturbance showing in activity behavior.

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Reported Outcomes in Interdisciplinary Pain Treatment: An Overview of Systematic Reviews and Meta-Analyses of Randomised Controlled Trials.

There is considerable diversity of outcome selections and methodologies for handling the multiple outcomes across all systematic reviews (SRs) of Interdisciplinary Pain Treatment (IPT) due to the complexity. This diversity presents difficulties for healthcare decision makers. Better recommendations about how to select outcomes in SRs (with or without meta-analysis) are needed to explicitly demonstrate the effectiveness of IPT.

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Efficacy of Peripheral Nerve Field Stimulation for the Management of Chronic Low Back Pain and Persistent Spinal Pain Syndrome: A Narrative Review.

Various approaches have been developed with a view to treating the back pain component in patients with chronic low back pain (CLBP) and persistent spinal pain syndrome (PSPS). Emerging evidence shows that peripheral nerve field stimulation (PNFS) may be an efficacious therapeutic modality against axial low back pain. Hence, the aim of the review was to evaluate the analgesic efficacy and safety of PNFS, when used alone or as an adjunct to spinal cord stimulation (SCS), for managing CLBP and PSPS.

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Sex-related differences in oxaliplatin-induced changes in the expression of transient receptor potential channels and their contribution to cold hypersensitivity.

Transient receptor potential (TRP) channels are involved in the development of oxaliplatin-induced neuropathic pain, a frequent and debilitating side effect of cancer therapy. Here we explored whether oxaliplatin-induced changes in the expression of TRP channels, as well as the development of pain-related behaviours, differed between male and female animals. Adult rats were injected with oxaliplatin or saline and mechanical and cold allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels of TRPV1, TRPM8 and TRPA1 were assessed in lumbar ganglia and spinal cord by using real time RT-PCR. Oxaliplatin administration induced mechanical and cold hypersensitivity and allodynia in both sexes, with more severe responses to cold stimulation detected in females. Oxaliplatin also induced a significant increase in the expression of TRPV1, TRPM8 and TRPA1 in lumbar dorsal root ganglia. Interestingly, while TRPV1 and TRPA1 upregulation showed no sex difference, the increase in TRPM8 mRNA levels was more pronounced in female ganglia, correlating with the increased sensitivity to innocuous cold stimuli observed in females. TRPV1 and TRPM8 were also found to be upregulated in the spinal cord of animals of both sexes. Our results reveal previously undescribed changes in the expression of TRP channels occurring in peripheral ganglia and spinal cord of both male and female oxaliplatin-treated animals, with some of these changes exhibiting sex-related differences that could underlie the development of sex-specific patterns of pain-related behaviours.

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Real-world effectiveness and safety of tildrakizumab in long term-treatment of plaque psoriasis: Results from the non-interventional, prospective, multicenter study TILOT.

Plaque psoriasis is a chronic inflammatory disorder affecting the skin and impacting quality of life. Tildrakizumab (TIL) is an IL-23 inhibitor licensed for moderate-to-severe plaque psoriasis. Regulatory approval of medicinal products is based on safety and efficacy data from randomized controlled trials (RCTs) which impose stringent selection criteria. Long-term non-interventional studies (NIS) are needed to establish effectiveness and safety in daily practice bridging the gap between RCTs and the real-world setting.

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Cluster headache – The worst possible pain on YouTube.

In clinical practice, patients with cluster headache often ask questions or mention information that they have seen or heard on the Internet. Because YouTube (www.youtube.com) is the second most visited Web site worldwide and offers a plethora of video content, we found it timely to ascertain the quality of information on cluster headache that is freely available on YouTube. We conducted an inquiry on YouTube on January 24, 2022, with the search term "cluster headache." Eligible YouTube videos included those with ≥10,000 views and content related to cluster headache. We assessed the quality and reliability of the videos with the Global Quality Scale and DISCERN, respectively. The search strategy identified 644 videos of which 134 were eligible for inclusion. The sources of the included videos were categorized as "healthcare professional/institution" (n = 45), "personal experience" (n = 52), and "other" (n = 37). According to the Global Quality Scale, 70 (52%) were low quality, 34 (25%) were of moderate quality, and 30 (22%) were of high quality. According to DISCERN, 104 (78%) were of low reliability, 28 (21%) were of moderate reliability, and 2 (1%) were of high reliability. The quality and reliability of cluster headache-related information on YouTube has room for improvement, even the content provided by healthcare providers. These findings should incentivize stakeholders, for example, government services, professional societies, healthcare providers, to provide accessible and better information on cluster headache.

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Computational psychiatry: from synapses to sentience.

This review considers computational psychiatry from a particular viewpoint: namely, a commitment to explaining psychopathology in terms of pathophysiology. It rests on the notion of a generative model as underwriting (i) sentient processing in the brain, and (ii) the scientific process in psychiatry. The story starts with a view of the brain-from cognitive and computational neuroscience-as an organ of inference and prediction. This offers a formal description of neuronal message passing, distributed processing and belief propagation in neuronal networks; and how certain kinds of dysconnection lead to aberrant belief updating and false inference. The dysconnections in question can be read as a pernicious synaptopathy that fits comfortably with formal notions of how we-or our brains-encode uncertainty or its complement, precision. It then considers how the ensuing process theories are tested empirically, with an emphasis on the computational modelling of neuronal circuits and synaptic gain control that mediates attentional set, active inference, learning and planning. The opportunities afforded by this sort of modelling are considered in light of in silico experiments; namely, computational neuropsychology, computational phenotyping and the promises of a computational nosology for psychiatry. The resulting survey of computational approaches is not scholarly or exhaustive. Rather, its aim is to review a theoretical narrative that is emerging across subdisciplines within psychiatry and empirical scales of investigation. These range from epilepsy research to neurodegenerative disorders; from post-traumatic stress disorder to the management of chronic pain, from schizophrenia to functional medical symptoms.

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Allodynia, Hyperalgesia, (Quantitative) Sensory Testing and Conditioned Pain Modulation in Patients With Complex Regional Pain Syndrome Before and After Spinal Cord Stimulation Therapy.

Complex regional pain syndrome (CRPS) is a chronic debilitating disease characterized by sensory abnormalities. Spinal cord stimulation (SCS) is an effective therapy for CRPS, but few studies have investigated the effects of SCS therapy on sensory characteristics. Therefore, this study investigated the effect of SCS on allodynia, hyperalgesia, electrical quantitative sensory testing (QST) parameters, and conditioned pain modulation (CPM) effect.

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RNA sequencing profiling of mRNAs, long noncoding RNAs, and circular RNAs in Trigeminal Ganglion following Temporomandibular Joint inflammation.

Patients with temporomandibular joint disorders (TMD) have high levels of inflammatory pain-related disability, which seriously affects their physical and mental health. However, an effective treatment is yet to be developed. Both circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) contribute to regulating pain conduction. In our current study, we report the expression profiles of circRNAs, lncRNAs, and mRNAs in the trigeminal ganglion (TG) associated with complete Freund's adjuvant (CFA)-induced TMD inflammation pain. The collected TGs from the experimental (CFA) and control (saline) groups were processed for deep RNA sequencing. Overall, 1078,909,068 clean reads were obtained. A total of 15,657 novel lncRNAs were identified, where 281 lncRNAs were differentially expressed on CFA3D and 350 lncRNAs were differentially expressed on CFA6D. In addition, a total of 55,441 mRNAs and 27,805 circRNAs were identified, where 3,914 mRNAs and 91 circRNAs were found differentially expressed, between the CFA3D and saline groups, while 4,232 mRNAs and 98 DE circRNAs were differentially expressed between the CFA6D and saline groups. Based on functional analyses, we found that the most significant enriched biological processes of the upregulated mRNAs were involved in the immunity, neuron projection, inflammatory response, MAPK signaling pathway, Ras signaling pathway, chemokine signaling pathway, and inflammatory response in TG. Further analyses of Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway suggest the involvement of dysregulated genes in the pain occurrence mechanism. Our findings provide a resource for expression patterns of gene transcripts in regions related to pain. These results suggest that apoptosis and neuroinflammation are important pathogenic mechanisms underlying TMD pain. Some of the reported differentially expressed genes might be considered promising therapeutic targets. The current research study revealed the expression profiles of circRNAs, lncRNAs, and mRNAs during TMD inflammation pain and sheds light on the roles of circRNAs and lncRNAs underlying the pain pathway in the trigeminal system of TMD inflammation pain.

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Modelling migraine-related features in the nitroglycerin animal model: trigeminal hyperalgesia is associated with affective status and motor behavior.

Migraine is a complex neurovascular disorder characterized by recurrent attacks of pain and other associated symptoms. Emotional-affective aspects are important components of pain, but so far they have been little explored in animal models of migraine. In this study, we aimed to explore the correlation between trigeminal hyperalgesia and affective status or behavioral components in a migraine-specific animal model. Male Sprague-Dawley rats were treated with nitroglycerin (10 mg/kg, i.p.) or its vehicle. Four hours later, anxiety, motor/exploratory behavior and grooming (a nociception index) were evaluated with the open field test. Rats were then exposed to formalin in the orofacial region to evaluate trigeminal hyperalgesia. The data analysis shows an inverse correlation between trigeminal hyperalgesia and motor or exploratory behavior, and a positive association with anxiety-like behavior or self-grooming. These findings further expand on the translational value of the migraine-specific model based on nitroglycerin administration and prompt additional parameters that can be investigated to explore migraine disease in its complexity.

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High-fat diet causes mechanical allodynia in the absence of injury or diabetic pathology.

Understanding the interactions between diet, obesity, and diabetes is important to tease out mechanisms in painful pathology. Western diet is rich in fats, producing high amounts of circulating bioactive metabolites. However, no research has assessed how a high-fat diet (HFD) alone may sensitize an individual to non-painful stimuli in the absence of obesity or diabetic pathology. To investigate this, we tested the ability of a HFD to stimulate diet-induced hyperalgesic priming, or diet sensitization in male and female mice. Our results revealed that 8 weeks of HFD did not alter baseline pain sensitivity, but both male and female HFD-fed animals exhibited robust mechanical allodynia when exposed to a subthreshold dose of intraplantar Prostaglandin E (PGE) compared to mice on chow diet. Furthermore, calcium imaging in isolated primary sensory neurons of both sexes revealed HFD induced an increased percentage of capsaicin-responsive neurons compared to their chow counterparts. Immunohistochemistry (IHC) showed a HFD-induced upregulation of ATF3, a neuronal marker of injury, in lumbar dorsal root ganglia (DRG). This suggests that a HFD induces allodynia in the absence of a pre-existing condition or injury via dietary components. With this new understanding of how a HFD can contribute to the onset of pain, we can understand the dissociation behind the comorbidities associated with obesity and diabetes to develop pharmacological interventions to treat them more efficiently.

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Level of therapeutic innovation from the registration studies of the new drugs for the prophylaxis of migraine.

Migraine is one of the most prevalent and disabling medical illnesses. Preventive drugs are used to reduce the frequency, severity, and duration of attacks. Most patients were no longer on their medication due to contraindications or poor clinical response. Therefore, there is need for novel prophylactic agents for migraine. New preventive treatments are those of the class of calcitonin gene related peptide (CGRP)-targeting therapies. We aimed to assess the real level of therapeutic innovation of these new drugs.

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The acceptability of photovoice as a method for incorporating resilience-enhancing factors into pediatric pain research.

Recurrent or chronic pain affects 11-38% of children and adolescents. Pediatric pain research typically focuses on risk factors, such as anxiety and parent functional disability, but resilience-building, protective factors also play an important role in the pain experience. New methods to incorporate resilience-enhancing factors into pain research are needed. Photovoice is a highly participatory research method, where participants take photos to address a common question, caption their photos, and discuss the meaning of the photos in a group. The main objective of this study was to determine whether photovoice is an acceptable method to young people living with chronic pain for identifying and sharing sources of joy. Another objective was to explore sources of joy. Sixteen adolescents and young adults participated, which involved meeting in a group to discuss the goal of the study, taking photographs of self-identified sources of joy over a two-week period, and meeting as a group again to discuss the photographs and participate in a focus group about the experience. Results suggest that photovoice is an acceptable method, as all participants took photographs and attended both meetings, and three themes from the focus group data suggested the participants considered photovoice to be appropriate: 1.) Relief associated with meeting peers, 2.) Potential to benefit young people living with pain, and 3.) Potential to raise awareness. Three themes emerged from the discussion of the photographs to describe sources of joy: 1.) Gratitude for everyday pleasures and accomplishments, 2.) Support from pets, and 3.) Journey of acceptance. Results add to the strengths-based literature on pediatric pain by identifying an acceptable method that could be further explored for use as an intervention to enhance protective factors such as positive affect, gratitude, and social support and to compare the experiences of different populations of youth living with pain.

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Efficacy and Safety of NSAIDs in Infants: A Comprehensive Review of the Literature of the Past 20 Years.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in infants, children, and adolescents worldwide; however, despite sufficient evidence of the beneficial effects of NSAIDs in children and adolescents, there is a lack of comprehensive data in infants. The present review summarizes the current knowledge on the safety and efficacy of various NSAIDs used in infants for which data are available, and includes ibuprofen, dexibuprofen, ketoprofen, flurbiprofen, naproxen, diclofenac, ketorolac, indomethacin, niflumic acid, meloxicam, celecoxib, parecoxib, rofecoxib, acetylsalicylic acid, and nimesulide. The efficacy of NSAIDs has been documented for a variety of conditions, such as fever and pain. NSAIDs are also the main pillars of anti-inflammatory treatment, such as in pediatric inflammatory rheumatic diseases. Limited data are available on the safety of most NSAIDs in infants. Adverse drug reactions may be renal, gastrointestinal, hematological, or immunologic. Since NSAIDs are among the most frequently used drugs in the pediatric population, safety and efficacy studies can be performed as part of normal clinical routine, even in young infants. Available data sources, such as (electronic) medical records, should be used for safety and efficacy analyses. On a larger scale, existing data sources, e.g. adverse drug reaction programs/networks, spontaneous national reporting systems, and electronic medical records should be assessed with child-specific methods in order to detect safety signals pertinent to certain pediatric age groups or disease entities. To improve the safety of NSAIDs in infants, treatment needs to be initiated with the lowest age-appropriate or weight-based dose. Duration of treatment and amount of drug used should be regularly evaluated and maximum dose limits and other recommendations by the manufacturer or expert committees should be followed. Treatment for non-chronic conditions such as fever and acute (postoperative) pain should be kept as short as possible. Patients with chronic conditions should be regularly monitored for possible adverse effects of NSAIDs.

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Sex-specific role of the circadian transcription factor NPAS2 in opioid tolerance, withdrawal and analgesia.

Opioids like fentanyl remain the mainstay treatment for chronic pain. Unfortunately, opioid's high dependence liability has led to the current opioid crisis, in part, because of side-effects that develop during long-term use, including analgesic tolerance and physical dependence. Both tolerance and dependence to opioids may lead to escalation of required doses to achieve previous therapeutic efficacy. Additionally, altered sleep and circadian rhythms are common in people on opioid therapy. Opioids impact sleep and circadian rhythms, while disruptions to sleep and circadian rhythms likely mediate the effects of opioids. However, the mechanisms underlying these bidirectional relationships between circadian rhythms and opioids remain largely unknown. The circadian protein, neuronal PAS domain protein 2 (NPAS2), regulates circadian-dependent gene transcription in structure of the central nervous system that modulate opioids and pain. Here, male and female wild-type and NPAS2-deficient (NPAS2-/-) mice were used to investigate the role of NPAS2 in fentanyl analgesia, tolerance, hyperalgesia and physical dependence. Overall, thermal pain thresholds, acute analgesia and tolerance to a fixed dose of fentanyl were largely similar between wild-type and NPAS2-/- mice. However, female NPAS2-/- exhibited augmented analgesic tolerance and significantly more behavioral symptoms of physical dependence to fentanyl. Only male NPAS2-/- mice had increased fentanyl-induced hypersensitivity, when compared with wild-type males. Together, our findings suggest sex-specific effects of NPAS2 signaling in the regulation of fentanyl-induced tolerance, hyperalgesia and dependence.

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Intervening GSK3 Signaling Attenuates Cutaneous Inflammation and Itch in Mice: Implication for Future Therapeutic Development.

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Neuropathic ocular surface pain: Emerging drug targets and therapeutic implications.

– Dysfunction at various levels of the somatosensory system can lead to ocular surface pain with a neuropathic component. Compared to nociceptive pain (pain due to a noxious stimulus at the ocular surface), neuropathic pain tends to be more chronic and refractory to therapies, making it an important source of morbidity in the population. An understanding of the options available for neuropathic ocular surface pain, including new and emerging therapies, is thus an important topic.

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Redesigning care for back pain in an Australian hospital setting: A service evaluation to identify need for change.

This needs assessment study examined current processes of physiotherapy care for adults with back pain in a large teaching hospital serving a multicultural community in Sydney, Australia. Evaluation of current practices is a necessary first step in the design of a patient-centred, multidisciplinary service that promotes best practice in back pain management.

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Quantity changes in acute headache medication use among patients with chronic migraine treated with eptinezumab: subanalysis of the PROMISE-2 study.

Patients with chronic migraine (CM) treated with eptinezumab in the PROMISE-2 trial achieved greater reductions in migraine and headache frequency, impact, and acute headache medication (AHM) use than did patients who received placebo. This post hoc analysis examines relationships between headache frequency reductions and changes in AHM use in patients in PROMISE-2.

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Real-World Patient Experience of CGRP-Targeting Therapy for Migraine: a Narrative Review.

To summarize available calcitonin gene-related peptide (CGRP)-targeting therapies for migraine and discuss their use in real-world populations.

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Safety of OnabotulinumtoxinA in the [management of] chronic migraine in pregnancy.

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Editorial: Temperature-dependent mechanisms of neuron functioning: Emerging concepts.

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Headache: what to ask, how to examine, and what scales to use. Recommendations of the Spanish society of neurology’s headache study group.

INTRODUCCIóN: La cefalea es el motivo de consulta neurológico más prevalente en los distintos niveles asistenciales, donde la anamnesis y exploración son primordiales para realizar un diagnóstico y tratamiento adecuados. Con la intención de unificar la atención de esta patología, el Grupo de Estudio de Cefalea de la Sociedad Española de Neurología (GECSEN) ha decidido elaborar unas recomendaciones consensuadas para mejorar y garantizar una adecuada asistencia en Atención Primaria, Urgencias y Neurología. METODOLOGíA: El documento es práctico, sigue el orden de la dinámica de actuación durante una consulta: anamnesis, escalas que cuantifican el impacto y la discapacidad y exploración. Además, finaliza con pautas para realizar un seguimiento adecuado y un manejo de las expectativas del paciente con el tratamiento pautado. CONCLUSIONES: Esperamos ofrecer una herramienta que mejore la atención al paciente con cefalea para garantizar una asistencia adecuada y homogénea a nivel nacional.

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Targeting 5-HT receptors and Kv7 channels in PFC to attenuate chronic neuropathic pain in rats using a spared nerve injury model.

Chronic pain remains a disabling disease with limited therapeutic options. Pyramidal neurons in the prefrontal cortex (PFC) express excitatory G-coupled 5-HT receptors (5-HTR) and their effector system, the inhibitory Kv7 ion channel. While recent publications show these cells innervate brainstem regions important for regulating pain, the cellular mechanisms underlying the transition to chronic pain are not well understood. The present study examined whether local blockade of 5-HTR or enhanced Kv7 ion channel activity in the PFC would attenuate mechanical allodynia associated with spared nerve injury (SNI) in rats. Following SNI, we show that inhibition of PFC 5-HTRs with M100907 or opening of PFC Kv7 channels with retigabine reduced mechanical allodynia. Parallel proteomic and RNAScope experiments evaluated 5-HTR/Kv7 channel protein and mRNA. Our results support the role of 5-HTRs and Kv7 channels in the PFC in the maintenance of chronic pain.

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Paeonol inhibits chronic constriction injury-induced astrocytic activation and neuroinflammation in rats via the HDAC/miR-15a pathway.

Neuropathic pain affects millions of people in the worldwide, but the major therapeutics perform limited effectiveness. Paeonol (PAE) is widely distributed in Paeonis albiflora, and has manifested anti-inflammatory and antioxidative effects in multiple diseases. The present study aims to elucidate the effect of Paeonol (PAE) on neuropathic pain (NP) and the potential targets. Chronic constriction injury model was established to mimic NP in vivo in rats. The expression of GFAP, HDAC2, AHDAC3, Ac-H3K9, Histone-H3, Ac-H4K12, Histone-H4, TNF-α, IL-1β, and IL-6 was assessed by real-time polymerase chain reaction, western blot, and/or enzyme-linked immunosorbent assay kits. Ultimately, results indicated that intervention of PAE significantly blocked neuroinflammation and astrocytic activation via blocking HDAC/miR-15a signaling in CCI rats. These data revealed PAE is a novel therapeutic target for the treatment of neuropathic pain.

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A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide for treating diabetic-related peripheral neuropathic pain.

Peripheral neuropathy is a common complication of diabetes. The management of the associated neuropathic pain remains difficult to treat.

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Chronic pain, psychological distress, and quality of life in males with Duchenne muscular dystrophy.

To describe chronic pain in Duchenne muscular dystrophy (DMD) from children's/adolescents' perspectives, explore patient variables associated with self-reported pain, and examine the relationship between chronic pain, psychological functioning, and health-related quality of life (HRQoL).

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Serum lipid profile in migraine and its association with clinical characteristics.

Migraine is one of the most prevalent and disabling conditions worldwide. Dyslipidemia has become an issue of great importance recently in migraine patients. There is still no consensus on the relationship between specific lipid levels with clinical characteristics of migraine and patients' demographic features. In this study, we investigated each serum lipid level in migraine patients and correlated it with migraine and patients' characteristics to understand the contribution of these factors together.

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Child and adolescent psychiatry staff’s knowledge on pain management.

To assess the level of child and adolescent psychiatric staff's knowledge regarding pain management, to determine group differences between the medically more educated (physicians, nurses) and the less educated (psychologists, educators, special therapists) and to investigate the influence of gender, age, or professional experience as well as staff's own pain experiences.

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Evaluating the relationship between right-to-left shunt and white matter hyperintensities in migraine patients: A systematic review and meta-analysis.

White matter hyperintensities (WMHs) have been observed with greater frequency in patients with migraine and are thought to be associated with impaired cognition and function. The relationship between WMHs and right-to-left shunt (RLS) in migraine patients is unknown. We performed a systematic review to determine if there is an association between RLS and WMHs in patients with migraine.

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B1 and/or B2? That is the question.

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The Significance of Pain Drawing as a Screening Tool for Cervicogenic Headache and Associated Symptoms in Chronic Fatigue.

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a broad spectrum of symptoms, including headache. A simple, yet powerful tool – the pain drawing identifies essential aspects such as pain distribution. The aim with this study was to 1) evaluate the significance of pain drawing as a screening tool for cervicogenic headache using a predefined C2 pain pattern, 2) assess whether there was an association between dizziness/imbalance and a C2 pain pattern, and 3) compare subgroups according to the pain drawing with respect to pain characteristics and quality of life.

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Expression of NF-κB-associated lncRNAs in different types of migraine.

NF-κB partakes in the pathophysiology of neurologic conditions. We quantified levels of NF-κB-associated genes in 119 patients with migraine versus healthy controls.

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Bidirectional Association Between Fibromyalgia and Migraine Among Probands and Unaffected Non-Twin Siblings: A Nationwide Population-Based Study.

This study explored the bidirectional relationship between fibromyalgia and migraine among probands with either of the two disorders and their unaffected siblings.

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Fibromyalgia: Associations Between Fat Infiltration, Physical Capacity, and Clinical Variables.

Obesity is a risk factor for the development of fibromyalgia (FM) and generally most studies report increased Body Mass Index (BMI) in FM. Obesity in FM is associated with a worse clinical presentation. FM patients have low physical conditioning and obesity further exacerbates these aspects. Hitherto studies of FM have focused upon a surrogate for overall measure of fat content, ie, BMI. This study is motivated by that ectopic fat and adipose tissues are rarely investigated in FM including their relationships to physical capacity variables. Moreover, their relationships to clinical variables including are not known. Aims were to 1) compare body composition between FM and healthy controls and 2) investigate if significant associations exist between body composition and physical capacity aspects and important clinical variables.

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Multidimensional pain phenotypes after Traumatic Brain Injury.

More than 50% of individuals develop chronic pain following traumatic brain injury (TBI). Research suggests that a significant portion of post-TBI chronic pain conditions is neuropathic in nature, yet the relationship between neuropathic pain, psychological distress, and somatosensory function following TBI is not fully understood. This study evaluated neuropathic pain symptoms, psychological and somatosensory function, and psychosocial factors in individuals with TBI (TBI, = 38). A two-step cluster analysis was used to identify phenotypes based on the Neuropathic Pain Symptom Inventory and Beck's Anxiety Inventory scores. Phenotypes were then compared on pain characteristics, psychological and somatosensory function, and psychosocial factors. Our analyses resulted in two different neuropathic pain phenotypes: (1) Moderate neuropathic pain severity and anxiety scores (MNP-AS, = 11); and (2) mild or no neuropathic pain symptoms and anxiety scores (LNP-AS, = 27). Furthermore, the MNP-AS group exhibited greater depression, PTSD, pain severity, and affective distress scores than the LNP-AS group. In addition, thermal somatosensory function (difference between thermal pain and perception thresholds) was significantly lower in the MNP-AS compared to the LNP-AS group. Our findings suggest that neuropathic pain symptoms are relatively common after TBI and are not only associated with greater psychosocial distress but also with abnormal function of central pain processing pathways.

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R399E, a mutated form of Growth and Differentiation Factor 5, for disease modification of osteoarthritis.

To preclinically characterize a mutant form of growth and differentiation factor 5 (GDF5, R399E) with reduced osteogenic properties, as a potential disease-modifying osteoarthritis (OA) drug.

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“The Pain Doesn’t Have to Control You.” A Qualitative Evaluation of Three Pain Clinics Teaching Nonopioid Pain Management Strategies.

To explore factors related to effectiveness of nonpharmacological treatment for opioid-dependent patients suffering with chronic pain.

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Multiple sclerosis and migraine: Links, management and implications.

Multiple sclerosis (MS) is a chronic inflammatory disease leading to multifocal neuronal demyelination and axonal damage in the central nervous system (CNS). MS symptoms vary widely but typically do not include headaches. A large spectrum of headaches manifestations was reported as comorbidities in MS and results in additional disability. Migraine, tension-type headache and cluster headache are the most frequently reported primary headache syndromes in patients with MS (pwMS). Secondary causes of headache should be excluded (cerebral vein thrombosis, CNS or systemic infection, cervical and/or cranial trauma, headaches associated with psychiatric disorders, medication overuse headache, etc.) in this particular population. A careful medical history and general and neurological examinations and sometimes further investigations may be needed to rule out secondary headache syndromes. In pwMS, the headache could be an adverse effect of the disease-modifying therapies or a complication of pain medication overuse prescribed to relieve other causes of pain related to MS (neuropathic pain, mechanical pain, pain associated with spasticity, etc.). Migraine-type headache occurs in pwMS more frequently than in the general population. It can precede the disease onset, be associated with relapses, or appear during the MS course. A predominance of brainstem inflammatory lesions is described on magnetic resonance imaging (MRI) in MS patients with migraine. The relationship between both conditions remains unclear. Migraine and MS occur in the same demographic groups with similar background factors, including gender, hormonal status, and psychological features (anxiety, depression, stress). An early diagnosis and adequate treatment of migraine in MS patients are important to improve their quality of life. In this review, we focus on the relationship between MS and Migraine, discuss the differential diagnoses of migraine in pwMS, and describe its management in this particular context.

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People at a persistent pain service can walk it, but some struggle to talk about it: Reliability, detectable difference and clinically important difference of the six-minute walk test.

The six-minute walk test (6MWT) is a commonly used measure of functional capacity. This study is the first to investigate the test-retest reliability, minimal detectable difference (MDD) and the minimal clinically important difference (MCID) for people attending a persistent pain service. Relationships between change in 6MWT performance and change in self-reported physical, functional and psychological outcome measures were also explored.

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Muscle quantitative MRI as a novel biomarker in hereditary transthyretin amyloidosis with polyneuropathy: a cross-sectional study.

The development of reproducible and sensitive outcome measures has been challenging in hereditary transthyretin (ATTRv) amyloidosis. Recently, quantification of intramuscular fat by magnetic resonance imaging (MRI) has proven as a sensitive marker in patients with other genetic neuropathies. The aim of this study was to investigate the role of muscle quantitative MRI (qMRI) as an outcome measure in ATTRv.

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MiR-672-5p-Mediated Upregulation of REEP6 in Spinal Dorsal Horn Participates in Bortezomib-Induced Neuropathic Pain in Rats.

Evidence shows that miRNAs are deeply involved in nervous system diseases, but whether miRNAs contribute to the bortezomib (BTZ)-induced neuropathic pain remains unclear. We aimed to investigate whether miRNAs contribute to bortezomib (BTZ)-induced neuropathic pain and explore the related downstream cascades. The level of miRNAs in the spinal dorsal horn was explored using miRNA microarray and PCR. MiR-672-5p was significantly downregulated in dorsal horn neurons in the rats with BTZ treatment. Intrathecal injection of miR-672-5p agomir blunted the increase of the amplitude and frequency of sEPSCs in dorsal horn neurons and mechanical allodynia induced by BTZ. In addition, the knockdown of miR-672-5p by intrathecal injection of antagomir increased the amplitude and frequency of sEPSCs in dorsal horn neurons and decreased the mechanical withdrawal threshold in naïve rats. Furthermore, silico analysis and the data from subsequent assays indicated that REEP6, a potential miR-672-5p-regulating molecule, was increased in the spinal dorsal horn of rats with BTZ-induced neuropathic pain. Blocking REEP6 alleviated the mechanical pain behavior induced by BTZ, whereas overexpressing REEP6 induced pain hypersensitivity in naïve rats. Importantly, we further found that miR-672-5p was expressed in the REEP6-positive cells, and overexpression or knockdown of miR-672-5p reversely regulated the REEP6 expression. Bioinformatics analysis and double-luciferase reporter assay showed the existence of interaction sites between REEP6 mRNA and miR-672-5p. Overall, our study demonstrated that miR-672-5p directly regulated the expression of REEP6, which participated in the neuronal hyperexcitability in the spinal dorsal horn and neuropathic pain following BTZ treatment. This signaling pathway may potentially serve as a novel therapeutic avenue for chemotherapeutic-induced mechanical hypersensitivity.

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Acute and chronic pain management in patients with sickle cell disease in the modern era: A comprehensive review.

Sickle cell disease (SCD) is the most common inherited red blood cell (RBC) disorder worldwide, resulting in chronic hemolytic anemia, vaso-occlusion, tissue hypoxia, and ultimately end organ damage. The hallmark of the disease is manifested by vaso-occlusive crisis (VOC) resulting in acute on chronic pain, and the most common cause for presentation to the emergency department and hospital admission. The management of pain for patients with SCD in the U.S. has historically been socially and politically complex with most patients experiencing pain on a daily basis but not seeking immediate medical attention. The pathophysiology of acute and chronic pain in SCD is multifactorial and complex. Here, we describe factors contributing to acute and chronic pain in SCD and management strategies.

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Peripheral mechanisms of chronic pain.

Acutely, pain serves to protect us from potentially harmful stimuli, however damage to the somatosensory system can cause maladaptive changes in neurons leading to chronic pain. Although acute pain is fairly well controlled, chronic pain remains difficult to treat. Chronic pain is primarily a neuropathic condition, but studies examining the mechanisms underlying chronic pain are now looking beyond afferent nerve lesions and exploring new receptor targets, immune cells, and the role of the autonomic nervous system in contributing chronic pain conditions. The studies outlined in this review reveal how chronic pain is not only confined to alterations in the nervous system and presents findings on new treatment targets and for this debilitating disease.

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Changes in brain connectivity linked to multisensory processing of pain modulation in migraine with acupuncture treatment.

Migraine without aura (MWoA) is a major neurological disorder with unsatisfactory adherence to current medications. Acupuncture has emerged as a promising method for treating MWoA. However, the brain mechanism underlying acupuncture is yet unclear. The present study aimed to examine the effects of acupuncture in regulating brain connectivity of the key regions in pain modulation. In this study, MWoA patients were recruited and randomly assigned to 4 weeks of real or sham acupuncture. Resting-state functional magnetic resonance imaging (fMRI) data were collected before and after the treatment. A modern neuroimaging literature meta-analysis of 515 fMRI studies was conducted to identify pain modulation-related key regions as regions of interest (ROIs). Seed-to-voxel resting state-functional connectivity (rsFC) method and repeated-measures two-way analysis of variance were conducted to determine the interaction effects between the two groups and time (baseline and post-treatment). The changes in rsFC were evaluated between baseline and post-treatment in real and sham acupuncture groups, respectively. Clinical data at baseline and post-treatment were also recorded in order to determine between-group differences in clinical outcomes as well as correlations between rsFC changes and clinical effects. 40 subjects were involved in the final analysis. The current study demonstrated significant improvement in real acupuncture vs sham acupuncture on headache severity (monthly migraine days), headache impact (6-item Headache Impact Test), and health-related quality of life (Migraine-Specific Quality of Life Questionnaire). Five pain modulation-related key regions, including the right amygdala (AMYG), left insula (INS), left medial orbital superior frontal gyrus (PFCventmed), left middle occipital gyrus (MOG), and right middle cingulate cortex (MCC), were selected based on the meta-analysis on brain imaging studies. This study found that 1) after acupuncture treatment, migraine patients of the real acupuncture group showed significantly enhanced connectivity in the right AMYG/MCC-left MTG and the right MCC-right superior temporal gyrus (STG) compared to that of the sham acupuncture group; 2) negative correlations were established between clinical effects and increased rsFC in the right AMYG/MCC-left MTG; 3) baseline right AMYG-left MTG rsFC predicts monthly migraine days reduction after treatment. The current results suggested that acupuncture may concurrently regulate the rsFC of two pain modulation regions in the AMYG and MCC. MTG and STG may be the key nodes linked to multisensory processing of pain modulation in migraine with acupuncture treatment. These findings highlighted the potential of acupuncture for migraine management and the mechanisms underlying the modulation effects.

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Thermal Antinociceptive Responses to Alcohol in DBA/2 J and C57BL/6 J Inbred Male and Female Mouse Strains.

The phenomenon of alcohol analgesia and tolerance can facilitate misuse and lead to the development of alcohol use disorder (AUD). Numerous alcohol-induced behaviors are genetically influenced; however, it is unknown if alcohol analgesia has a genetic contribution. Rodent studies have shown that alcohol responses differ vastly between two widely studied inbred strains of mice, C57BL/6J (B6) and DBA/2J (D2). Here, we used B6 and D2 mice as an initial behavioral genetic analysis of acute alcohol-induced antinociception.

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Antiretroviral Therapy for HIV Infection Induced-Neuropathic Pain, A Narrative Review.

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS). AIDS is a human disease in which there is a systematic failure of the immune system, thereby leading to severe opportunistic infections. HIV is treated with antiretroviral therapy (ART), which helps in preventing the virus from replicating in the body. ART also enables the immune system to repair itself and restrict further injury. Nevertheless, the long-term use of ART leads to multiple neurological complications (e.g.neuropathic pain). Neuropathic pain (NP) arises if the nervous system is damaged or not working correctly. NP is is characterized by pain in both hands and feet and can hinder the quality of life (QOL) as it is always linked to impaired cognition, anxiety, depression, loss of function, among others.

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Novel Formulation Approaches Used for the Management of Osteoarthritis: A Recent Review.

Background The osteoarthritis (OA) causes economic, social, and health difficulties to the patients. Approximately 10% to 15% of all persons above the age of 60 have some degree of OA. OA is more common in women than in males. Diagnosed OA prevalence varies widely among EU member states, from 2.8% in Romania to 18.3% in Hungary. Introduction Osteoarthritis (OA) is a slow-progressing, non-inflammatory disorder. This disorder ultimately destroys articular cartilage and other joint components. The main symptoms are stiffness, pain, loss of flexibility, swelling, and bone spurs. Many risk factors, both modifiable and non-modifiable, have been associated with osteoarthritis (OA), including obesity and lack of exercise, genetic susceptibility, bone density, work-related damage, and trauma. Method Hydrogels, micro and nano-sized particles, and novel topical gels are among the most common examples. Hydrogels are cross-linked polymers with 3-D architecture that can hold water and expand like living tissue. The Micro-carriers, and nano-based drug delivery systems provide several advantages and may demonstrate prolonged release, controlled release, and higher joint half-life. Result OA-induced male Lewis rats were injected with celecoxib-loaded PEA microspheres to assess in vivo biocompatibility and degradation. According to the findings of this research, PEA microspheres loaded with celecoxib may be employed as safe delivery of drug with self-regulating behavior for the pain treatment related to knee osteoarthritis. Conclusion The concept of novel drug delivery systems has shown tangible benefits as a new avenue for precise, safe, and high-quality drug delivery for OA treatment. Currently, herbal drugs are also used in osteoarthritis treatment due to their potency and fewer side effects in contrast to synthetic drugs. The herbo-synthetic approach is a new concept for the delivery of both herbal and synthetic drugs together to exploit their individual beneficial effects while reducing undesirable side effects.

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Healthcare professionals’ perspectives on the use of medicinal cannabis to manage chronic pain: a systematic search and narrative review.

Chronic pain is a global public health problem that negatively impacts individuals' quality of life and imposes a substantial economic burden on societies. The use of medicinal cannabis (MC) is often considered by patients to help manage chronic pain as an alternative or supplement to more conventional treatments, given enabling legalisation in a number of countries. However, healthcare professionals involved in providing guidance for patients related to MC are often doing so in the absence of strong evidence and clinical guidelines. Therefore, it is crucial to understand their perspectives regarding the clinical use and relevance of MC for chronic pain. As little is known about attitudes of HCPs with regard to MC use for chronic pain specifically, the aim of this review was to identify and synthesise the published evidence on this topic.

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Investigation on how dynamic effective connectivity patterns encode the fluctuating pain intensity in chronic migraine.

Chronic migraine is characterised by persistent headaches for >15 days per month; the intensity of the pain is fluctuating over time. Here, we explored the dynamic interplay of connectivity patterns between regions known to be related to pain processing and their relation to the ongoing dynamic pain experience. We recorded EEG from 80 sessions (20 chronic migraine patients in 4 separate sessions of 25 min). The patients were asked to continuously rate the intensity of their endogenous headache. On different time-windows, a dynamic causal model (DCM) of cross spectral responses was inverted to estimate connectivity strengths. For each patient and session, the evolving dynamics of effective connectivity were related to pain intensities and to pain intensity changes by using a Bayesian linear model. Hierarchical Bayesian modelling was further used to examine which connectivity-pain relations are consistent across sessions and across patients. The results reflect the multi-facetted clinical picture of the disease. Across all sessions, each patient with chronic migraine exhibited a distinct pattern of pain intensity-related cortical connectivity. The diversity of the individual findings are accompanied by inconsistent relations between the connectivity parameters and pain intensity or pain intensity changes at group level. This suggests a rejection of the idea of a common neuronal core problem for chronic migraine.

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Scores of peripheral neuropathic pain predicting long-term mortality in patients with type 2 diabetes: A retrospective cohort study.

Diabetic peripheral neuropathic pain (DPNP) is a prevalent chronic complication in patients with diabetes. Using a questionnaire is helpful for DPNP screening in outpatients. In this retrospective cohort, we aimed to examine whether DPNP diagnosed based on scoring questionnaires could predict long-term mortality in outpatients with type 2 diabetes.

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Content and delivery of pre-operative interventions for patients undergoing total knee replacement: a rapid review.

Total knee replacement (TKR) is a common operation typically performed for end-stage knee osteoarthritis. Patients awaiting TKR often have poor health-related quality of life. Approximately 20% of patients experience persistent pain post-TKR. Pre-operative TKR interventions could improve pre- and post-operative outcomes, but future research is required to inform their design. This review aimed to identify and synthesize recent literature on the content and delivery of pre-operative TKR interventions to help guide future research and clinical practice.

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Disease- and headache-specific microRNA signatures and their predicted mRNA targets in peripheral blood mononuclear cells in migraineurs: role of inflammatory signalling and oxidative stress.

Migraine is a primary headache with genetic susceptibility, but the pathophysiological mechanisms are poorly understood, and it remains an unmet medical need. Earlier we demonstrated significant differences in the transcriptome of migraineurs' PBMCs (peripheral blood mononuclear cells), suggesting the role of neuroinflammation and mitochondrial dysfunctions. Post-transcriptional gene expression is regulated by miRNA (microRNA), a group of short non-coding RNAs that are emerging biomarkers, drug targets, or drugs. MiRNAs are emerging biomarkers and therapeutics; however, little is known about the miRNA transcriptome in migraine, and a systematic comparative analysis has not been performed so far in migraine patients.

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Polyphenolic grape stalk and coffee extracts attenuate spinal cord injury-induced neuropathic pain development in ICR-CD1 female mice.

More than half of spinal cord injury (SCI) patients develop central neuropathic pain (CNP), which is largely refractory to current treatments. Considering the preclinical evidence showing that polyphenolic compounds may exert antinociceptive effects, the present work aimed to study preventive effects on SCI-induced CNP development by repeated administration of two vegetal polyphenolic extracts: grape stalk extract (GSE) and coffee extract (CE). Thermal hyperalgesia and mechanical allodynia were evaluated at 7, 14 and 21 days postinjury. Then, gliosis, ERK phosphorylation and the expression of CCL2 and CX3CL1 chemokines and their receptors, CCR2 and CX3CR1, were analyzed in the spinal cord. Gliosis and CX3CL1/CX3CR1 expression were also analyzed in the anterior cingulate cortex (ACC) and periaqueductal gray matter (PAG) since they are supraspinal structures involved in pain perception and modulation. GSE and CE treatments modulated pain behaviors accompanied by reduced gliosis in the spinal cord and both treatments modulated neuron-glia crosstalk-related biomolecules expression. Moreover, both extracts attenuated astrogliosis in the ACC and PAG as well as microgliosis in the ACC with an increased M2 subpopulation of microglial cells in the PAG. Finally, GSE and CE prevented CX3CL1/CX3CR1 upregulation in the PAG, and modulated their expression in ACC. These findings suggest that repeated administrations of either GSE or CE after SCI may be suitable pharmacologic strategies to attenuate SCI-induced CNP development by means of spinal and supraspinal neuroinflammation modulation.

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Can contagious itch be affected by positive and negative suggestions?

Contagious itch can be evoked by observing people scratching. Verbal suggestions about to-be-received itch can influence itch intensity, as shown by placebo research, but it is unknown whether this extends to contagious itch. The current study aimed to replicate prior findings that listening to scratching and rubbing sounds elicits contagious itch, and to investigate whether suggestions can modulate this process. Healthy participants (n = 140) received positive or negative suggestions about itch in response to the sounds (aimed to decrease or increase expected itch, respectively), or no specific suggestions as a control. Participants listened to a number of audio fragments with scratching and rubbing sounds. The amount of expected itch as well as itch sensation after each audio fragment were measured by self-report. Suggestions had no effect on the expected itch. Both rubbing and scratching sounds significantly elicited itch in all groups. Scratching sounds induced more itch than rubbing sounds exclusively in the control group. These findings indicate that short suggestions might be not effective enough to modify the expectations of people regarding contagious itch. Furthermore, suggestions modulate contagious itch to some degree, but not in the hypothesized direction. Potential similarities and differences in the neurobiological mechanisms of contagious itch and nocebo effects are discussed.

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The role of physiotherapy in fibromyalgia: Current and future perspectives.

Fibromyalgia is a chronic pain condition characterized by generalized musculoskeletal pain, hyperalgesia and allodynia, commonly associated with other symptoms such as fatigue, poor sleep quality, anxiety and depression. The clinical manifestations of this rheumatic disease have significant psychosocial and economic repercussions, with a substantial impact on health status, quality of life and social activities. Currently, recommendations for the management of fibromyalgia include patient education and non-pharmacological interventions, and among the indicated treatments, clinical guidelines include several physiotherapeutic resources, essential for individuals affected by this syndrome. Research in the physiotherapy field has demonstrated its effectiveness, but there is a need to update the literature. This study aims to identify the effectiveness of physiotherapy in the treatment of individuals with fibromyalgia. We performed a literature review looking for articles dated from March 2012 to March 2022 using the terms "fibromyalgia", "physiotherapy", "physical therapy", "rehabilitation" in different languages in various databases and their main information was read and collected and presented in a descriptive way. The effects of physiotherapy interventions are summarized in order to provide a reference for future research and clinical application. Research on non-pharmacological physiotherapy-oriented treatments has grown in recent years as an alternative for fibromyalgia treatment. This review allows fibromyalgia patients to receive appropriate physical therapy interventions to promote their health.

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An international open-label randomised trial comparing a two-step approach versus the standard three-step approach of the WHO analgesic ladder in patients with cancer.

Worldwide, cancer pain management follows the WHO three step analgesic ladder. Using weak opioids (e.g. codeine) at step two is debatable with low dose strong opioids potentially better, particularly in low and middle-income countries where weak opioids are expensive. We wanted to assess the efficiency, safety and cost of omitting step two of the WHO ladder.

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Metformin prevents morphine-induced apoptosis in rats with diabetic neuropathy: a possible mechanism for attenuating morphine tolerance.

Morphine is a drug of choice for the treatment of severe and chronic pain, but tolerance to the antinociceptive effect limits its use. The development of tolerance to morphine has recently been associated with neuronal apoptosis. In this study, our aim was to investigate the effects of metformin on morphine-induced neuronal apoptosis and antinociceptive tolerance in diabetic rats. Three days of cumulative dosing were administered to establish morphine tolerance in rats. The antinociceptive effects of metformin (50 mg/kg) and test dose of morphine (5 mg/kg) were considered at 30-min intervals by thermal antinociceptive tests. To induce diabetic neuropathy, streptozotocin (STZ, 65 mg/kg) was injected intraperitoneally. ELISA kits were used to measure caspase-3, bax, and bcl-2 levels from dorsal root ganglion (DRG) tissue. Semi-quantitative scoring system was used to evaluate apoptotic cells with the the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method. The findings suggest that co-administration of metformin with morphine to diabetic rats showed a significant increase in antinociceptive effect compared to morphine alone. The antinociceptive tests indicated that metformin significantly attenuated morphine antinociceptive tolerance in diabetic rats. In addition, metformin decreased the levels of apoptotic proteins caspase 3 and Bax in DRG neurons, while significantly increased the levels of antiapoptotic Bcl-2. Semi-quantitative scoring showed that metformin provided a significant reduction in apoptotic cell counts in diabetic rats. These data revealed that metformin demonstrated antiapoptotic activity in diabetic rat DRG neurons and attenuated morphine tolerance. The antiapoptotic activity of metformin probably plays a significant role in reducing morphine tolerance.

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The Role of Kappa-Opioid and Mu-Opioid Receptors in Pruritus: Peripheral and Central Itch Circuits.

Modern genetic approaches in animal models have unveiled novel itch-specific neural pathways, emboldening a paradigm in which drugs can be developed to selectively and potentially target itch in a variety of chronic pruritic conditions. In recent years, kappa-opioid receptors (KOR) and mu-opioid receptors (MOR) have been implicated in both the suppression and promotion of itch, respectively, by acting in both the peripheral and central nervous systems. The precise mechanisms by which agents that modulate these pathways to alleviate itch remains an active area of investigation. Notwithstanding this, a number of agents have demonstrated efficacy in clinical trials that influence both KOR and MOR signaling. Herein, we summarize a number of opioid receptor modulators in development and their promising efficacy across a number of chronic pruritic conditions, such as atopic dermatitis, uremic pruritus, and beyond.

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Quantifying the intensity of adverse events with ibuprofen and oxycodone: an observational cohort study.

To quantify the frequency and intensity of adverse events (AEs), commonly known as side effects, experienced by children receiving either ibuprofen or oxycodone for pain management following an acute fracture. Secondary objectives were to quantify functional outcome impairment and describe demographic and clinical characteristics associated with AEs.

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No preconscious attentional bias towards itch in healthy individuals.

Rapidly attending towards potentially harmful stimuli to prevent possible damage to the body is a critical component of adaptive behavior. Research suggests that individuals display an attentional bias, i.e., preferential allocation of attention, for consciously perceived bodily sensations that signal potential threat, like itch or pain. Evidence is not yet clear whether an attentional bias also exists for stimuli that have been presented for such a short duration that they do not enter the stream of consciousness. This study investigated whether a preconscious attentional bias towards itch-related pictures exists in 127 healthy participants and whether this can be influenced by priming with mild itch-related stimuli compared to control stimuli. Mild itch was induced with von Frey monofilaments and scratching sounds, while control stimuli where of matched modalities but neutral. Attentional bias was measured with a subliminal pictorial dot-probe task. Moreover, we investigated how attentional inhibition of irrelevant information and the ability to switch between different tasks, i.e., cognitive flexibility, contribute to the emergence of an attentional bias. Attentional inhibition was measured with a Flanker paradigm and cognitive flexibility was measured with a cued-switching paradigm. Contrary to our expectations, results showed that participants attention was not biased towards the itch-related pictures, in facts, attention was significantly drawn towards the neutral pictures. In addition, no effect of the itch-related priming was observed. Finally, this effect was not influenced by participants' attentional inhibition and cognitive flexibility. Therefore, we have no evidence for a preconscious attentional bias towards itch stimuli. The role of preconscious attentional bias in patients with chronic itch should be investigated in future studies.

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Mechanism-Based Pharmacological Treatment for Chronic Non-cancer Pain in Adolescents: Current Approaches and Future Directions.

Chronic non-cancer pain in pediatrics is a widespread phenomenon that affects about 20% of adolescents (10-19 years old). Although interdisciplinary pain treatment programs, which often include pharmacological treatment, have emerged as the standard of care in management of this patient population, evidence regarding an optimal treatment is lacking. The efficacy and safety profiles of pharmacological treatments used to help adolescents suffering from chronic non-cancer pain remain understudied. This lack of evidence may increase polypharmacy and the risk of drug interactions and adverse events. This review examines evidence for the use of pharmacological treatments prescribed to treat chronic pain in adolescents (10-19 years old), with a focus on mechanism-based pharmacology. The objectives of this review are to: (a) review the evidence for mechanism-based pharmacological treatments for chronic non-cancer pain in adolescents and (b) describe the pharmacological agents that are commonly prescribed to manage chronic pain in adolescents, including dosage information, mechanism, and potential adverse effects. Pharmacological treatments should be used carefully with adolescents, ideally within an interdisciplinary treatment program that will incorporate physical rehabilitation, integrative medicine/active mind-body techniques, psychology, and global efforts to normalize daily activities.

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Converting Adults with Sickle Cell Disease from Full Agonist Opioids to Buprenorphine: A Reliable Method with Safety and Early Evidence of Reduced Acute Care Utilization.

Buprenorphine, a novel opioid with complex pharmacology, is effective for treating pain and is qualitatively safer than high dose full agonist opioid therapy; but transitioning to buprenorphine can be technically complex and carries some risk of precipitated withdrawal. We report our clinic's experience converting 36 patients with sickle cell disease from full agonist opioids to buprenorphine using a method developed in the past ten years. Thirty of these patients were induced using a standard outpatient protocol and six were induced during medical admissions. Typically, patients were on high-dose chronic opioid therapy with inadequate response; often with very high acute care utilization. Unlike prior case series, the method of induction, dosing, and management of withdrawal are detailed, as are post-induction adverse events. There were seven adverse events in the first three days following standard induction, two of which were judged to be definitely related to the induction but none with any lasting sequelae. At six months follow-up, five participants had discontinued buprenorphine (16.67%), and overall acute care visits dropped from a mean of 10.50 (SD 11.35) in the six months pre-induction to 2.89 (SD 3.40) in the six months post induction. In an appropriately interdisciplinary care setting, buprenorphine shows promise as a safe alternative to chronic opioid therapy with early evidence of benefit for high utilizing patients with SCD. This article is protected by copyright. All rights reserved.

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Sedation and analgesia from prolonged pain and stress during mechanical ventilation in preterm infants: is dexmedetomidine an alternative to current practice?

Mechanical ventilation is an uncomfortable and potentially painful intervention. Opioids, such as morphine and fentanyl, are used for analgesia and sedation but there is uncertainty whether they reduce pain in mechanically ventilated infants. Moreover, there may be short-term and long-term adverse consequences such as respiratory depression leading to prolonged mechanical ventilation and detrimental long-term neurodevelopmental effects. Despite this, opioids are widely used, possibly due to a lack of alternatives.Dexmedetomidine, a highly selective alpha-2-adrenergic agonist with analgesic and sedative effects, currently approved for adults, has come into use in newborn infants. It provides analgesia and simulates natural sleep with maintenance of spontaneous breathing and upper airway tone. Although data on pharmacokinetics-pharmacodynamics in preterm infants are scant, observational studies report that using dexmedetomidine in conjunction with opioids/benzodiazepines or on its own can reduce the cumulative exposure to opioids/benzodiazepines. As it does not cause respiratory depression, dexmedetomidine could enable quicker weaning and extubation. Dexmedetomidine has also been suggested as an adjunct to therapeutic hypothermia in hypoxic ischaemic encephalopathy and others have used it during painful procedures and surgery. Dexmedetomidine infusion can cause bradycardia and hypotension although most report clinically insignificant effects.The increasing number of publications of observational studies and clinical use demonstrates that dexmedetomidine is being used in newborn infants but data on safety and efficacy are scant and not of high quality. Importantly, there are no data on long-term neurodevelopmental impact on preterm or term-born infants. The acceptance of dexmedetomidine in routine clinical practice must be preceded by clinical evidence. We need adequately powered and well-designed randomised controlled trials investigating whether dexmedetomidine alone or with opioids/benzodiazepines in infants on mechanical ventilation reduces the need for opioids/benzodiazepine and improves neurodevelopment at 24 months and later as compared with the use of opioids/benzodiazepines alone.

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Implementation of screening criteria for inflammatory bowel disease in patients with spondyloarthritis and its association with disease and endoscopic activity.

There is little literature on the implementation of screening criteria for inflammatory bowel disease (IBD) in patients with spondyloarthritis (SpA). This study aimed to apply IBD screening criteria in a group of patients with SpA without IBD diagnosis and correlate them to endoscopic findings and disease activity. A total of 82 patients with SpA were included. The IBD screening test and ileocolonoscopy with digital chromoendoscopy with magnification and histological analysis were performed. The data were analysed with Chi-square test/Fisher's exact test and multiple correspondence analysis. The major screening criteria found in 48.7% of the patients were associated with a history of infection (p = 0.037). Rectal bleeding was associated with the diagnosis of ankylosing spondylitis, acute inflammation, enthesitis and tissue architecture alteration in the ileum (p < 0.050). Diarrhoea was associated with a higher disease activity score (p = 0.02). Minor screening criteria were associated with painful inflammatory joint (p = 0.05), high disease activity score (p = 0.001) and high calprotectin levels (p = 0.050). Abdominal pain (36.9%) was associated with axial/peripheral compromise (p = 0.017), inflammatory back pain (p = 0.01), enthesitis (p = 0.021), higher disease activity score (p = 0.023) and acute ileum inflammation (p = 0.046). Diarrhoea of 4 weeks and abdominal pain were the most prevalent major and minor screening criteria, respectively, being related to early manifestations of inflammatory bowel compromise and higher disease activity score. This screening test grants a chance of opportune referral of SpA patients from rheumatology to gastroenterology.

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RETRACTION: Group-based multimodal exercises integrated with cognitive-behavioural therapy improve disability, pain and quality of life of subjects with chronic neck pain: a randomized controlled trial with one-year follow-up.

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Annals On Call – Do Cannabinoids Help Chronic Pain?

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Cooled Radiofrequency Ablation Provides Prolonged Pain Relief Compared to Traditional Radiofrequency Ablation: A Real-World, Large Retrospective Clinical Comparison from a Single Practice.

Genicular radiofrequency ablation is an established therapy for chronic knee pain. An analysis comparing different probe sizes and technologies has not yet been undertaken for this indication. This large retrospective, comparison study from a single-center comprehensive pain management practice aims to do that.

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The Role of the Autonomic Nervous System in Headache: Biomarkers and Treatment.

In this review, the role of the autonomic nervous system in tension-type headache and migraine is reviewed.

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Targeted muscle reinnervation: A narrative review of a novel tool for the management of neuropathic pathology in major lower extremity amputations.

The purpose of this narrative review is to provide the vascular surgery community with updated recommendations and information regarding the use of Targeted Muscle Reinnervation (TMR) for both the prevention and treatment of chronic pain and phantom limb pain occurring in patients after undergoing lower extremity amputation for peripheral artery disease.

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Living with gout. Experiences, impact and challenges of the disease. Qualitative study through focus groups.

To delve into the experiences of people living with gout regarding its causes and triggers, recommended treatments and therapeutic measures, and the impact of living with this problem.

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Non-Surgical Management of Chronic Pelvic Pain in Females.

The purpose of this paper is to review the most recent literature on non-surgical therapeutic options for chronic pelvic pain in females.

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Sleep deprivation and recovery sleep affect healthy male resident’s pain sensitivity and oxidative stress markers: The medial prefrontal cortex may play a role in sleep deprivation model.

Sleep is essential for the body's repair and recovery, including supplementation with antioxidants to maintain the balance of the body's redox state. Changes in sleep patterns have been reported to alter this repair function, leading to changes in disease susceptibility or behavior. Here, we recruited healthy male physicians and measured the extent of the effect of overnight sleep deprivation (SD) and recovery sleep (RS) on nociceptive thresholds and systemic (plasma-derived) redox metabolism, namely, the major antioxidants glutathione (GSH), catalase (CAT), malondialdehyde (MDA), and superoxide dismutase (SOD). Twenty subjects underwent morning measurements before and after overnight total SD and RS. We found that one night of SD can lead to increased nociceptive hypersensitivity and the pain scores of the Numerical Rating Scale (NRS) and that one night of RS can reverse this change. Pre- and post-SD biochemical assays showed an increase in MDA levels and CAT activity and a decrease in GSH levels and SOD activity after overnight SD. Biochemical assays before and after RS showed a partial recovery of MDA levels and a basic recovery of CAT activity to baseline levels. An animal study showed that SD can cause a significant decrease in the paw withdrawal threshold and paw withdrawal latency in rats, and after 4 days of unrestricted sleep, pain thresholds can be restored to normal. We performed proteomics in the rat medial prefrontal cortex (mPFC) and showed that 37 proteins were significantly altered after 6 days of SD. Current findings showed that SD causes nociceptive hyperalgesia and oxidative stress, and RS can restore pain thresholds and repair oxidative stress damage in the body. However, one night of RS is not enough for repairing oxidative stress damage in the human body.

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Potential therapeutics against neurological disorders: Natural products-based drugs.

Neurodegenerative disorders, which are defined by the breakdown of neurons over time, are affecting an increasing number of people. Stroke, Alzheimer's, Parkinson's, Multiple Sclerosis, Migraine, and Amyotrophic Lateral Sclerosis are just a few examples of brain disorders that have no cure. Besides, there is a huge demand for drugs that can cure the diseases mentioned above because the majority of the medications we use to treat them only alleviate diseases. Different neurological disorders have responded satisfactorily to the pharmacological effects of medicinal plants. Despite the numerous multiple types of plants in the world, only a small number of them have been investigated for neurological disorders. As a result, there are many opportunities in this area for further research on plants and their bioactive chemicals. The search for natural therapeutic alternatives that promote faster healing and adverse effects avoidance has gained popularity in recent years. The aim of this mini-review is to explore some natural products that have strong therapeutic effects on neurodegenerative disorders such as Stroke, Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, Migraine, Amyotrophic Lateral Sclerosis, and others. We have also shown the safety of natural products to improve their appropriate usage in neurological disorders from recent literature.

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Elevated serum TLR4 level as a potential marker for postsurgical chronic pain in pediatric patients with different approaches to analgesia.

The perioperative period of any surgery is accompanied by immune suppression. The level of Toll-like receptor 4 (TLR4) is known to increase in inflammation and after nerve injury and contributes to the development of neuropathic pain. The interaction of TLRs in response to the effect of opioids results in paradoxical hyperalgesia. Regional anesthesia techniques are the standard of care for perioperative pain management in children.

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Contrasting the Expectations and Experiences Related to Mobile Health Use for Chronic Pain: Questionnaire Study.

Chronic pain is a prolonged condition that deteriorates one's quality of life. Treating chronic pain requires a multicomponent approach, and in many cases, there are no "silver bullet" solutions. Mobile health (mHealth) is a rapidly expanding category of solutions in digital health with proven potential in chronic pain management.

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Current Cannabidiol Safety: A Review.

Background- Marijuana, also known as cannabis, is the second most widely used illegal psychoactive substance smoked worldwide after tobacco, mainly due to the psychoactive effects induced by D-9-tetrahydrocannabinol (9-THC). Cannabidiol (CBD) is extracted from cannabis and may be used as an anti-inflammatory agent. Some patents on cannabidiol are discussed in this review. The cannabinoid is a non-psychoactive isomer of the more infamous tetrahydrocannabinol (THC); and is available in several administration modes, most known as CBD oil. Objectives- This study aims to provide an enhanced review of cannabidiol properties used in treating inflammation. This review also emphasises the current safety profile of cannabidiol. Method- Cannabis is also called Marijuana. It is the second most commonly used illegal psychoactive substance in the universe after tobacco. D-9-tetrahydrocannabinol (9-THC) present in cannabis produces psychoactive effects. Cannabidiol (CBD) extracted from cannabis is used for anti-inflammatory purposes. Cannabis smoking causes various types of cancer, such as lung, tongue, and jaw. The current review took literature from Google Scholar, PubMed, and Google Patents. Many clinical investigations are included in this review. Result- After analysing the literature on cannabis, it has been suggested that although cannabis is banned in some countries, it may be included in the treatment and mitigation of some diseases and symptoms like pain management, epilepsy, cancer, and anxiety disorder. Mild side effects were frequently observed in cannabis medications, which included infertility in females, liver damage, etc. Conclusion- Cannabis contains chemical compounds such as the cannabinoids delta-9-tetrahydrocannabinol (THC), a psychoactive substance, and non-psychoactive cannabidiol (CBD). Cannabidiol has been confirmed as an efficient treatment of epilepsy in several clinical trials, with one pure CBD product named Epidiolex. It is also used in treating anxiety and acne, as a pain reliever, and has anti-inflammatory properties.

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Bone marrow-derived mesenchymal stem cells alleviate paclitaxel-induced mechanical allodynia in rats.

Anticancer drug paclitaxel (PTX) frequently causes painful peripheral neuropathy; however, no medication has been shown to be effective in the treatment of this debilitating side effect. We aimed to investigate the efficacy of two different doses of allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) on PTX-induced mechanical allodynia and spinal cytokine levels and their localization to target tissues such as the spinal cord and sciatic nerve. After the development of mechanical allodynia with repeated PTX administration, two different doses of rat BM-MSCs, low or high (1 × 10 -5 × 10 ), were transplanted into rats and the evaluation continued for 30 days. Interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-10 levels in spinal cord samples of animals were analyzed by enzyme-linked immunosorbent assay. PTX-induced mechanical allodynia was relieved significantly 15 days after the transplantation of high-dose of BM-MSCs. Both MSCs doses were effective in alleviating allodynia, but the onset of effect was earlier with the high dose. High-dose of BM-MSCs significantly decreased spinal IL-1β and TNF-α levels compared to the PTX group. Fluorescent dye-labeled BM-MSCs were observed much more frequently in the sciatic nerve and spinal cord samples of the high-dose BM-MSCs transplanted group than in the low-dose group animals. In conclusion, we found that the antiallodynic effects of BM-MSCs appeared earlier when high-dose of cells were administered. We think that other mechanisms may play a role in the effects of MSCs, besides localization to damaged tissues and reducing spinal inflammatory cytokine levels. We show that BM-MSCs can be a novel approach in PTX-induced mechanical allodynia.

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Evidence-based perioperative pain management protocol for day case surgery in a resource limited setting: Systematic review.

Worldwide, there is an increasing trend of performing more complex operations in a day care setting, usually driven by economic considerations. Provision of appropriate pain relief is still inadequate in this setting. Poor pain control and adverse effects of opioids provided for pain control are common reasons for readmission, with human and economic consequences. The aim of this review was to develop evidence-based protocol for pain management of day surgery in a resource limited setting.

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Kratom: Substance of Abuse or Therapeutic Plant?

Kratom is the common term for Mitragyna speciosa and its products. Its major active compounds are mitragynine and 7-hydroxymitragynine. An estimated 2.1 million US residents used kratom in 2020, as a "legal high" and self-medication for pain, opioid withdrawal, and other conditions. Up to 20% of US kratom users report symptoms consistent with kratom use disorder. Kratom use is associated with medical toxicity and death. Causality is difficult to prove as almost all cases involve other psychoactive substances. Daily, high-dose use may result in kratom use disorder and opioid-like withdrawal on cessation of use. These are best treated with buprenorphine.

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