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Papers: 30 Jan 2021 - 5 Feb 2021

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Morphine acts on spinal dynorphin neurons to cause itch through disinhibition.

Morphine-induced itch is a very common and debilitating side effect that occurs in laboring women who receive epidural analgesia and in patients who receive spinal morphine for relief of perioperative pain. Although antihistamines are still widely prescribed for the treatment of morphine-induced itch, their use is controversial because the cellular basis for morphine-induced itch remains unclear. Here, we used animal models and show that neuraxial morphine causes itch through neurons and not mast cells. In particular, we found that spinal dynorphin (Pdyn) neurons are both necessary and sufficient for morphine-induced itch in mice. Agonism of the kappa-opioid receptor alleviated morphine-induced itch in mice and nonhuman primates. Thus, our findings not only reveal that morphine causes itch through a mechanism of disinhibition but also challenge the long-standing use of antihistamines, thereby informing the treatment of millions worldwide.

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Cognition in the Chronic Pain Experience: Preclinical Insights.

Acutely, pain is protective. It promotes escape from, and future avoidance of, noxious stimuli through strong and often lifetime associative memories. However, with persistent acute pain or when pain becomes chronic, these memories can promote negative emotions and poor decisions often associated with deleterious behaviors. In this review, we discuss how preclinical studies can provide insights into the relationship between cognition and chronic pain. We also discuss the concept of pain as a cognitive disorder and new strategies for treating chronic pain that emphasize inhibiting the formation of pain memories or promoting 'forgetting' of established pain memories.

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Innocuous pressure sensation requires A-type afferents but not functional ΡΙΕΖΟ2 channels in humans.

The sensation of pressure allows us to feel sustained compression and body strain. While our understanding of cutaneous touch has grown significantly in recent years, how deep tissue sensations are detected remains less clear. Here, we use quantitative sensory evaluations of patients with rare sensory disorders, as well as nerve blocks in typical individuals, to probe the neural and genetic mechanisms for detecting non-painful pressure. We show that the ability to perceive innocuous pressures is lost when myelinated fiber function is experimentally blocked in healthy volunteers and that two patients lacking Aβ fibers are strikingly unable to feel innocuous pressures at all. We find that seven individuals with inherited mutations in the mechanoreceptor PIEZO2 gene, who have major deficits in touch and proprioception, are nearly as good at sensing pressure as healthy control subjects. Together, these data support a role for Aβ afferents in pressure sensation and suggest the existence of an unknown molecular pathway for its detection.

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Association of Headache With School Functioning Among Children and Adolescents in the United States.

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Allocation of National Institutes of Health Funding by Disease Category in 2008 and 2019.

Prior research suggests an association between burden of disease and National Institutes of Health (NIH) funding. The allocation of NIH funding should reflect, to some extent, the health needs of the population, along with other factors.

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Antidepressants for musculoskeletal pain.

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Efficacy and safety of antidepressants for the treatment of back pain and osteoarthritis: systematic review and meta-analysis.

To investigate the efficacy and safety of antidepressants for back and osteoarthritis pain compared with placebo.

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Heightened pain facilitation rather than impaired pain inhibition distinguishes those with moderate/severe disability in work-related neck pain.

To better understand the mechanisms underpinning work-related neck pain, this cross-sectional and single-blinded study compared somatosensory profiles among sonographers with varied neck disability levels. Based on K-mean cluster analysis of scores on the neck disability index (NDI), participants were classified into no (NDI≤8%, n=31, reference group), mild (NDI=10%-20%, n=43) or moderate/severe (NDI≥22%, n=18) disability groups. Data were collected on bodily pain distribution and severity and psychological measures including depression, anxiety, pain-catastrophizing and fear-avoidance beliefs using validated scales. Participants attended one session of quantitative sensory testing performed according to a standardized protocol, including local and remote thermal and mechanical pain thresholds, temporal summation of pain (TSP), conditioned pain modulation (CPM) and an exercise-induced analgesia (EIA) paradigm. Compared to participants with no and mild disability, those with moderate/severe disability showed more widespread pain, cold and mechanical hyperalgesia at a remote non-painful site and significantly higher TSP. Participants with mild disability demonstrated significantly higher TSP than those with no disability. These group differences were attenuated after adjusting for depression or anxiety, indicating these psychological factors may mediate the somatosensory changes associated with neck disability. Group differences were not found for CPM or EIA. These findings suggest that heightened pain facilitation, rather than impaired pain inhibition may underpin nociplastic pain in participants with moderate/severe disability, and it may be associated with depression and anxiety. Clinicians should be aware that individuals with work-related neck pain presenting with moderate/severe disability display distinct somatosensory features and tailor management strategies accordingly.

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Selective targeting of peripheral cannabinoid receptors prevents behavioral symptoms and sensitization of trigeminal neurons in mouse models of migraine and medication overuse headache.

Migraine affects ∼15% of the world's population greatly diminishing their quality of life. Current preventative treatments are effective in only a subset of migraine patients, and while cannabinoids appear beneficial in alleviating migraine symptoms, central nervous system (CNS) side effects limit their widespread use. We developed peripherally-restricted cannabinoids (PRCBs) that relieve chronic pain symptoms of cancer and neuropathies, without appreciable CNS side effects or tolerance development. Here we determined PRCB effectiveness in alleviating hypersensitivity symptoms in mouse models of migraine and medication overuse headache (MOH). Chronic glyceryl trinitrate (GTN, 10 mg/kg) administration led to increased sensitivity to mechanical stimuli, and increased expression of phosphorylated protein kinase A (p-PKA), neuronal nitric oxide synthase (nNOS), and transient receptor potential ankyrin 1 (TRPA1) proteins in trigeminal ganglia. PRCB pretreatment, but not posttreatment, prevented behavioral and biochemical correlates of GTN-induced sensitization. Low pH- and allyl isothiocyanate-activated currents in acutely isolated trigeminal neurons were reversibly attenuated by PRCB application. Chronic GTN treatment significantly enhanced these currents. Chronic sumatriptan treatment also led to development of allodynia to mechanical and cold stimuli which was slowly reversible after sumatriptan discontinuation. Subsequent challenge with a previously ineffective low-dose GTN (0.1-0.3 mg/kg) revealed latent behavioral sensitization and increased expression of p-PKA, nNOS, and TRPA1 proteins in trigeminal ganglia. PRCB pretreatment prevented all behavioral and biochemical correlates of allodynia and latent sensitization. Importantly, chronic PRCB treatment alone did not produce any behavioral or biochemical signs of sensitization. These data validate peripheral cannabinoid receptors as potential therapeutic targets in migraine and MOH.

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Maintaining musculoskeletal health using a behavioural therapy approach: a population-based randomised controlled trial (the MAmMOTH Study).

Cognitive-behavioural therapy (CBT) has been shown to be effective in the management of chronic widespread pain (CWP); we now test whether it can onset among adults at high risk.

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Potential for increased prevalence of neuropathic pain after the COVID-19 pandemic.

Although coronavirus disease 2019 (COVID-19) most commonly manifests with acute respiratory symptoms, one very common symptom of COVID-19 is pain. As COVID-19 often causes peripheral or central neurological complications, it is anticipated that a number of the chronic pain complications of COVID-19 will be neuropathic. This review first examines the most common viral infections responsible for neurological complications including neuropathic pain. These encompass herpes zoster, HIV, poliovirus, enteroviruses, and several tropical viruses. Neurological complications of COVID-19 including in particular Guillain-Barré syndrome, myelitis, and stroke are reviewed with regards to their potential risk of chronic neuropathic pain. Prospective longitudinal cohorts of patients should be implemented to evaluate the exact risk of neuropathic pain after COVID-19.

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Parabrachial complex processes dura inputs through a direct trigeminal ganglion-to-parabrachial connection.

Migraines cause significant disability and contribute heavily to healthcare costs. Irritation of the meninges' outermost layer (the dura mater), and trigeminal ganglion activation contribute to migraine initiation. Maladaptive changes in central pain-processing regions are also important in maintaining pain. The parabrachial complex (PB) is a central region that mediates chronic pain. PB receives diverse sensory information, including a direct input from the trigeminal ganglion. We hypothesized that PB processes inputs from the dura. Using electrophysiology recordings from single units in anesthetized rats we identified 58 neurons in lateral PB that respond reliably and with short latency to electrical dura stimulation. After injecting tracer into PB, anatomical examination reveals retrogradely labeled cell bodies in the trigeminal ganglion. Neuroanatomical tract-tracing revealed a population of neurons in the trigeminal ganglion that innervate the dura and project directly to PB. These findings indicate that PB is strategically placed to process dura inputs and suggest that it is directly involved in the pathogenesis of migraine headaches.

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Trends in peptide drug discovery.

Since the introduction of insulin almost a century ago, more than 80 peptide drugs have reached the market for a wide range of diseases, including diabetes, cancer, osteoporosis, multiple sclerosis, HIV infection and chronic pain. In this Perspective, we summarize key trends in peptide drug discovery and development, covering the early efforts focused on human hormones, elegant medicinal chemistry and rational design strategies, peptide drugs derived from nature, and major breakthroughs in molecular biology and peptide chemistry that continue to advance the field. We emphasize lessons from earlier approaches that are still relevant today as well as emerging strategies such as integrated venomics and peptide-display libraries that create new avenues for peptide drug discovery. We also discuss the pharmaceutical landscape in which peptide drugs could be particularly valuable and analyse the challenges that need to be addressed for them to reach their full potential.

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Grey matter brain alterations in temporomandibular disorder tested in a population cohort and three clinical samples.

Temporomandibular pain (TMD) is a frequent symptom comprising pain around the mandibular jaw with a high dependence on stressors. Chronic pain has been associated with changes of the brains grey matter volume (GMV), but previous studies on GMV alterations associated with TMD have yielded contradictory results. This might be caused by divergent samples and study methods. We here tested GMV alterations using voxel based morphometry in three clinical samples (summing up to 47 TMD patients) and a population sample with 57 participants who indicated facial pain for the last 6 months. The GMV of pain patients was compared against age-matched and gender-matched participants without chronic pain (60 for the clinical sample comparison and 381 for the cohort sample comparison) who underwent the same assessments as the patient group (MRI measurements and data evaluation using CAT12). In a region of interest analysis, only the clinical samples showed an effect of decreased GMV in the anterior medial cingulate cortex reaching into the medial prefrontal cortex, known to be especially vulnerable for chronic pain grey matter volume reduction. The analysis of the population-based sample did not reveal relevant GMV differences. Overall, an important question remains as to whether most inconsistent results from VBM-studies in chronic pain are related to chance results facilitated by small sample size and selection of patient samples.

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TRESK background potassium channel modifies the TRPV1-mediated nociceptor excitability in sensory neurons.

TWIK-related spinal cord potassium channel (TRESK) background potassium channels have a key role in controlling resting membrane potential and excitability of sensory neurons. A frameshift mutation leading to complete loss of TRESK function has been identified in members of a family suffering from migraine with aura. In the present study, we examined the role of TRESK channels on nociceptor function in mice.

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The ACTTION Guide to Clinical Trials of Pain Treatments, part II: mitigating bias, maximizing value.

Summaries of the articles included in part II of the ACTTION Guide to Clinical Trials of Pain Treatments are followed by brief overviews of methodologic considerations involving precision pain medicine, pragmatic clinical trials, real world evidence, and patient engagement in clinical trials.

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Essential statistical principles of clinical trials of pain treatments.

This article presents an overview of fundamental statistical principles of clinical trials of pain treatments. Statistical considerations relevant to phase 2 proof of concept and phase 3 confirmatory randomized trials investigating efficacy and safety are discussed, including (1) research design; (2) endpoints and analyses; (3) sample size determination and statistical power; (4) missing data and trial estimands; (5) data monitoring and interim analyses; and (6) interpretation of results. Although clinical trials of pharmacologic treatments are emphasized, the key issues raised by these trials are also directly applicable to clinical trials of other types of treatments, including biologics, devices, nonpharmacologic therapies (eg, physical therapy and cognitive-behavior therapy), and complementary and integrative health interventions.

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Effect of topical analgesia on desensitization following 8% topical capsaicin application.

To prevent pain associated with 8% capsaicin application, pretreatment with local anesthetics, such as EMLA (eutectic mixture of lidocaine 2.5% and prilocaine 2.5%), is considered an option. However, there is contradicting evidence regarding the effects of local analgesia on capsaicin-induced desensitization. In session 1, two skin areas in each forearm of 24 healthy volunteers were randomized to 2-hour pretreatment with EMLA/placebo cream. After pretreatment, 8% capsaicin patches were applied for 3 hours in one placebo and one EMLA pretreated area, obtaining the following four areas: Capsaicin+EMLA, Capsaicin+Placebo, EMLA alone, and Placebo. Pain intensity scores were assessed during the 3-h application of capsaicin. Warmth detection, heat pain sensitivity, and micro-vascular reactivity were measured after the removal of capsaicin. After 24 hours, in session 2, all tests were repeated followed by histamine application in each area to examine itch intensity and neurogenic flare. Overall, EMLA caused significant reductions in capsaicin-induced pain compared with placebo (p=0.007) and enhanced the capsaicin-induced increase in superficial blood perfusion immediately after the 3-hour capsaicin application (p<0.01). Regardless of pretreatment, capsaicin induced heat hyperalgesia immediately after the application (p<0.001). 24 h post application, heat pain sensitivity was normalized. However, WDT increased significantly (p<0.001). Capsaicin tended to reduce the itch intensity and significantly reduced the neurogenic flare (p<0.05) induced by histamine compared with EMLA alone. The findings suggest that pre-treatment with topical analgesic cream reduces application site pain without interfering with the 8% topical capsaicin-induced desensitization. Perspective: Pretreatment with local anesthetic EMLA cream might be considered a good therapeutic option to reduce the pain associated with 8% capsaicin application currently used for treatment of neuropathic pain syndromes. This study also suggests the existence of a synergistic effect of capsaicin and EMLA on the process of neurogenic inflammation.

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Clinical outcome assessment in clinical trials of chronic pain treatments.

Clinical outcome assessments (COAs) measure outcomes that are meaningful to patients in clinical trials and are critical for determining whether a treatment is effective. The objectives of this study are to (1) describe the different types of COAs and provide an overview of key considerations for evaluating COAs, (2) review COAs and other outcome measures for chronic pain treatments that are recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) or other expert groups, and (3) review advances in understanding pain-related COAs that are relevant to clinical trials. The authors reviewed relevant articles, chapters, and guidance documents from the European Medicines Agency and U.S. Food and Drug Administration. Since the original core set of outcome measures were recommended by IMMPACT 14 years ago, several new advancements and publications relevant to the measurement or interpretation of COAs for chronic pain trials have emerged, presenting new research opportunities. Despite progress in the quality of measurement of several outcome domains for clinical trials of chronic pain, there remain some measurement challenges that require further methodological investigation.

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The µ-δ opioid heteromer masks Latent Pain Sensitization in neuropathic and inflammatory pain in male and female mice.

The episodic nature of chronic pain can be studied in the rodent model of latent pain sensitization. After remission, central sensitization is opposed by activation of opioid receptors. At the behavioral level, latent pain sensitization is unmasked when pain hypersensitivity is reinstated by opioid receptor (OR) antagonism. Previous studies have focused on inflammatory pain and male rodents. Whether latent pain sensitization occurs in models of chemotherapy-induced neuropathic pain in female and male mice is unknown. The first aim of this study was to investigate whether μ- and δ-OR suppress latent pain sensitization in our model of chemotherapy-induced neuropathic pain in both sexes. Mounting evidence suggests that μ-and δ-ORs form a heteromer and that the heteromer modulates pain sensitivity. Potential implications of the μ-δ OR heteromer in latent pain sensitization have not been fully explored due to a lack of tools to effectively modulate the heteromer. To specifically target the μ-δ OR heteromer, we used a specific interfering peptide blocking the heteromerization. The second aim of this study was to investigate whether disruption of the μ-δOR heteromer, after remission, reinstates pain hypersensitivity. After remission from cisplatin-induced neuropathic pain, antagonism of µOR and δOR reinstates pain hypersensitivity in both sexes. After remission from cisplatin-induced neuropathic pain and postoperative pain, disruption of the μ-δOR heteromer reinstates pain hypersensitivity in both sexes. Taken together our findings suggest that the μ-δOR heteromer plays a crucial role in remission in various pain models and may represent a novel therapeutic target to prevent the relapse to pain and the transition to chronic pain.

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A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes.

G protein-coupled receptors (GPCRs) are traditionally known for signaling at the plasma membrane, but they can also signal from endosomes after internalization to control important pathophysiological processes. In spinal neurons, sustained endosomal signaling of the neurokinin 1 receptor (NKR) mediates nociception, as demonstrated in models of acute and neuropathic pain. An NKR antagonist, Spantide I (Span), conjugated to cholestanol (Span-Chol), accumulates in endosomes, inhibits endosomal NKR signaling, and causes prolonged anti-nociception. However, the extent to which the Chol-anchor influences long-term location and activity is poorly understood. Herein, we used fluorescent correlation spectroscopy and targeted biosensors to characterize Span-Chol over time. The Chol-anchor increased local concentration of probe at the plasma membrane. Over time we observed an increase in NKR binding affinity and more potent inhibition of NKR-mediated calcium signaling. Span-Chol, but not Span, caused a persistent decrease in NKR recruitment of β-arrestin and receptor internalization to early endosomes. Using targeted biosensors, we mapped the relative inhibition of NKR signaling as the receptor moved into the cell. Span selectively inhibited cell surface signaling, whereas Span-Chol partitioned into endosomal membranes and blocked endosomal signaling. In a preclinical model of pain, Span-Chol caused prolonged antinociception (>9 h), which is attributable to a three-pronged mechanism of action: increased local concentration at membranes, a prolonged decrease in NKR endocytosis, and persistent inhibition of signaling from endosomes. Identifying the mechanisms that contribute to the increased preclinical efficacy of lipid-anchored NKR antagonists is an important step toward understanding how we can effectively target intracellular GPCRs in disease.

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Design and conduct of confirmatory chronic pain clinical trials.

The purpose of this article is to provide readers with a basis for understanding the emerging science of clinical trials and to provide a set of practical, evidence-based suggestions for designing and executing confirmatory clinical trials in a manner that minimizes measurement error. The most important step in creating a mindset of quality clinical research is to abandon the antiquated concept that clinical trials are a method for capturing data from clinical practice and shifting to a concept of the clinical trial as a measurement system, consisting of an interconnected set of processes, each of which must be in calibration for the trial to generate an accurate and reliable estimate of the efficacy (and safety) of a given treatment. The status quo of inaccurate, unreliable, and protracted clinical trials is unacceptable and unsustainable. This article gathers aspects of study design and conduct under a single broad umbrella of techniques available to improve the accuracy and reliability of confirmatory clinical trials across traditional domain boundaries.

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The effect of handedness on mental rotation of hands: a systematic review and meta-analysis.

Body-specific mental rotation is thought to rely upon internal representations of motor actions. Handedness is a source of distinctly different motor experience that shapes the development of such internal representations. Yet, the influence of handedness upon hand mental rotation has never been systematically evaluated. Five databases were searched for studies evaluating hand left/right judgement tasks in adults. Two independent reviewers performed screening, data extraction, and critical appraisal. Eighty-seven datasets were included, with 72 datasets pooled; all had unclear/high risk of bias. Meta-analyses showed that right-handers were faster, but not more accurate, than left-handers at hand mental rotation. A unique effect of handedness was found on performance facilitation for images corresponding to the dominant hand. Meta-analyses showed that right-handers were quicker at identifying images of right hands than left hands-a dominance advantage not evident in left-handers. Differing hand representations (more lateralised hand dominance in right-handers) likely underpin these findings. Given potential differences between hand preference and motor performance, future research exploring their distinct contributions to mental rotation is warranted.

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Differential expression of GluN2 NMDA receptor subunits in the dorsal horn of male and female rats.

N-methyl-D-aspartate receptors (NMDARs) are excitatory ionotropic glutamate receptors expressed throughout the CNS, including in the spinal dorsal horn. The GluN2 subtypes of NMDAR subunit, which include GluN2A, GluN2B, and GluN2D in the dorsal horn, confer NMDARs with structural and functional variability, enabling heterogeneity in synaptic transmission and plasticity. Despite essential roles for NMDARs in physiological and pathological pain processing, the distribution and function of these specific GluN2 isoforms across dorsal horn laminae remain poorly understood. Surprisingly, there is a complete lack of knowledge of GluN2 expression in female rodents. We, therefore, investigated the relative expression of specific GluN2 variants in the dorsal horn of lumbar (L4/L5) spinal cord from both male and female rats. In order to detect synaptic GluN2 isoforms, we used pepsin antigen-retrieval to unmask these highly cross-linked protein complexes. We found that GluN2B and GluN2D are preferentially localized to the pain-processing superficial regions of the dorsal horn in males, while only GluN2B is predominantly localized to the superficial dorsal horn of female rats. The GluN2A subunit is diffusely localized to neuropil throughout the dorsal horn of both males and females, while GluN2B and GluN2D immunolabelling are found both in the neuropil and on the soma of dorsal horn neurons. Finally, we identified an unexpected enhanced expression of GluN2B in the medial division of the superficial dorsal horn, but in males only. These sex-specific localization patterns of GluN2-NMDAR subunits across dorsal horn laminae have significant implications for the understanding of divergent spinal mechanisms of pain processing.

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Design, Structural Optimization, and Characterization of the First Selective Macrocyclic Neurotensin Receptor Type 2 Non-opioid Analgesic.

Neurotensin (NT) receptor type 2 (NTS2) represents an attractive target for the development of new NT-based analgesics. Here, we report the synthesis and functional characterization of the first constrained NTS2-selective macrocyclic NT analog. While most chemical optimization studies rely on the NT(8-13) fragment, we focused on NT(7-12) as a scaffold to design NTS2-selective macrocyclic peptides. Replacement of Ile by Leu, and Pro/Pro by allylglycine residues followed by cyclization via ring-closing metathesis led to macrocycle , which exhibits good affinity for NTS2 (50 nM), high selectivity over NTS1 (>100 μM), and improved stability compared to NT(8-13). profiling in rats reveals that macrocycle produces potent analgesia in three distinct rodent pain models, without causing the undesired effects associated with NTS1 activation. We further provide evidence of its non-opioid antinociceptive activity, therefore highlighting the strong therapeutic potential of NTS2-selective analogs for the management of acute and chronic pain.

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The Early Impact of COVID-19 on Chronic Pain: A Cross-Sectional Investigation of a Large Online Sample of Individuals with Chronic Pain in the United States, April to May, 2020.

Individuals with chronic pain are uniquely challenged by the COVID-19 pandemic, as increased stress may exacerbate chronic pain, and there are new barriers to receiving chronic pain treatment. In light of this, using a large online sample in the United States, we examined 1) the early impact of COVID-19 on pain severity, pain interference, and chronic pain management; and 2) variables associated with perceived changes in pain severity and pain interference.

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National Estimates of Chronic Musculoskeletal Pain and Its Treatment in Children, Adolescents and Young Adults in the United States: Data from the 2007-2015 NAMCS.

To portray physician office visits by young Americans with chronic musculoskeletal pain; to describe clinical management in this group; and to explore factors associated with prescribed treatments.

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Headache during COVID-19: Lessons for all, implications for the International Classification of Headache Disorders.

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Effectiveness of a structured group intervention based on pain neuroscience education for patients with fibromyalgia in primary care: a multicenter randomized open-label controlled trial.

There has been increased interest in pain neuroscience education (PNE) as a therapeutic approach for the management of fibromyalgia (FM).

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Beyond Therapy Types: Mindful Self-Compassion and the Future of Process-Based Therapy for Chronic Pain.

This journal recently published a paper by Palao et al., (2021) entitled "Mindful Self-Compassion Program for Chronic Pain Patients: A Randomized Controlled Trial." In their study the authors compare a treatment including mindfulness and self-compassion methods (MSC) with conventional cognitive behavioral therapy (CBT). They recruited people with long standing chronic pain plus significant anxiety or depression (N = 123).

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Is opioid therapy for chronic noncancer pain associated with a greater risk of all-cause mortality compared to non-opioid analgesics? A systematic review of propensity score matched observational studies.

The many risks associated with opioid therapy for chronic noncancer pain (CNCP) have led to questions about use. This is particularly relevant for risk of increased mortality. However, underlying medical conditions of those using opioids may influence mortality findings due to confounding by indication. Similarly, non-opioid analgesics are also associated with an increased risk of mortality, too.

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How Might We Screen for Psychological Factors in People With Pelvic Pain? An e-Delphi Study.

Persistent pelvic pain is a complex condition often influenced by psychological factors that can alter treatment outcomes. These factors are potentially modifiable; however, currently there is no instrument to screen for them in these individuals. The purpose of this study was to determine (1) which psychological factors should be screened in individuals with persistent pelvic pain and (2) the most appropriate statements to represent these psychological factors.

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Mechanisms of recovery after neck-specific or general exercises in patients with cervical radiculopathy.

The mechanisms of action that facilitate improved outcomes after conservative rehabilitation are unclear in individuals with cervical radiculopathy (CR). This study aims to determine the pathways of recovery of disability with different exercise programs in individuals with CR.

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The effect of acute-experimental pain models on offset analgesia.

Offset analgesia (OA) is characterized by a disproportionately large decrease in pain perception after a slight decrease in noxious stimulation. In patients with ongoing pain, this response is reduced. The effect is pronounced in painful body areas. The influence of acute pain has not been sufficiently investigated. The aim of this study was to investigate the influence of two experimental acute pain models, measured within the area of acute pain and on the non-affected opposite side, thereby considering the possible somatotopic nature of OA.

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Temporal association of pain catastrophizing and pain severity across the perioperative period: a cross-lagged panel analyses following total knee arthroplasty.

While numerous studies show that preoperative pain catastrophizing is a risk factor for pain following total knee arthroplasty (TKA), little is known regarding the temporal course of the association between perioperative pain catastrophizing and pain severity. The present study investigated temporal changes and their dynamic associations between pain catastrophizing and pain severity before and after TKA.

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Towards health equity for people experiencing chronic pain and social marginalization.

For people who experience social inequities and structural violence, pain and related care are inexorably linked to experiences of injustice and stigma. The purpose of this study was to examine in greater depth the experiences of pain and discrimination and stigma across diverse marginalized communities in order to recommend equity-oriented healthcare approaches.

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Exploratory study into the relationship between the symptoms of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) and fibromyalgia (FM) using a quasiexperimental design.

To explore the relationship between symptoms of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) and fibromyalgia (FM). The hypothesis predicated that there would be no significant differences between the group's symptom experience.

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Altered central pain processing in fibromyalgia-A multimodal neuroimaging case-control study using arterial spin labelling.

Fibromyalgia is characterized by chronic pain and a striking discrepancy between objective signs of tissue damage and severity of pain. Function and structural alterations in brain areas involved in pain processing may explain this feature. Previous case-control studies in fibromyalgia focused on acute pain processing using experimentally-evoked pain paradigms. Yet, these studies do not allow conclusions about chronic, stimulus-independent pain. Resting-state cerebral blood flow (rsCBF) acquired by arterial spin labelling (ASL) may be a more accurate marker for chronic pain. The objective was to integrate four different functional and structural neuroimaging markers to evaluate the neural correlate of chronic, stimulus-independent pain using a resting-state paradigm. In line with the pathophysiological concept of enhanced central pain processing we hypothesized that rsCBF is increased in fibromyalgia in areas involved in processing of acute pain. We performed an age matched case-control study of 32 female fibromyalgia patients and 32 pain-free controls and calculated group differences in rsCBF, resting state functional connectivity, grey matter volume and cortical thickness using whole-brain and region of interest analyses. We adjusted all analyses for depression and anxiety. As centrally acting drugs are likely to interfere with neuroimaging markers, we performed a subgroup analysis limited to patients not taking such drugs. We found no differences between cases and controls in rsCBF of the thalamus, the basal ganglia, the insula, the somatosensory cortex, the prefrontal cortex, the anterior cingulum and supplementary motor area as brain areas previously identified to be involved in acute processing in fibromyalgia. The results remained robust across all neuroimaging markers and when limiting the study population to patients not taking centrally acting drugs and matched controls. In conclusion, we found no evidence for functional or structural alterations in brain areas involved in acute pain processing in fibromyalgia that could reflect neural correlates of chronic stimulus-independent pain.

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Diet and companionship modulate pain via a serotonergic mechanism.

Treatment of severe chronic and acute pain in sickle cell disease (SCD) remains challenging due to the interdependence of pain and psychosocial modulation. We examined whether modulation of the descending pain pathway through an enriched diet and companionship could alleviate pain in transgenic sickle mice. Mechanical and thermal hyperalgesia were reduced significantly with enriched diet and/or companionship. Upon withdrawal of both conditions, analgesic effects observed prior to withdrawal were diminished. Serotonin (5-hydroxytryptamine, 5-HT) was found to be increased in the spinal cords of mice provided both treatments. Additionally, 5-HT production improved at the rostral ventromedial medulla and 5-HT accumulated at the dorsal horn of the spinal cord of sickle mice, suggesting the involvement of the descending pain pathway in the analgesic response. Modulation of 5-HT and its effect on hyperalgesia was also investigated through pharmaceutical approaches. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, showed a similar anti-nociceptive effect as the combination of diet and companionship. Depletion of 5-HT through p-chlorophenylalanine attenuated the anti-hyperalgesic effect of enriched diet and companionship. More significantly, improved diet and companionship enhanced the efficacy of a sub-optimal dose of morphine for analgesia in sickle mice. These findings offer the potential to reduce opioid use without pharmacological interventions to develop effective pain management strategies.

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Computational and Functional Mapping of Human and Rat α6β4 Nicotinic Acetylcholine Receptors Reveals Species-Specific Ligand-Binding Motifs.

Nicotinic acetylcholine receptors (nAChRs) are pharmacological targets for the treatment of neuropathic pain, and the α6β4 subtype has been identified as particularly promising. Rat α6β4 nAChRs are less sensitive to some ligands than the human homologue potentially complicating the use of rodent α6β4 receptors for screening therapeutic compounds. We used molecular dynamics simulations coupled with functional assays to study the interaction between α-conotoxin PeIA and α6β4 nAChRs and to identify key ligand-receptor interactions that contribute to species differences in α-conotoxin potency. Our results show that human and rat α6β4 nAChRs have distinct ligand-binding motifs and show markedly different sensitivities to α-conotoxins. These studies facilitated the creation of PeIA-5667, a peptide that shows 270-fold higher potency for rat α6β4 nAChRs over native PeIA and similar potency for the human homologue. Our results may inform the design of therapeutic ligands that target α6β4 nAChRs for the treatment of neuropathic pain.

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Familial and Genetic Influences on the Common Pediatric Primary Pain Disorders: A Twin Family Study.

The primary pain disorders of childhood are highly prevalent but have infrequently been studied collectively. Genetic influences have been suggested to be causally implicated. Surveys were sent to 3909 Australian twin families, assessing the lifetime prevalence of growing pains, migraine, headache, recurrent abdominal pain, low back pain, and persistent pain (not otherwise specified) in pediatric twins and their immediate family members. Comparisons between monozygous (MZ) and dizygous (DZ) twin pair correlations, concordances and odds ratios were performed to assess the contribution of additive genetic influences. Random-effects logistic regression modelling was used to evaluate relationships between twin individuals and their co-twins, mothers, fathers and oldest siblings with the subject conditions. Twin analyses of responses from 1016 families revealed significant influence of additive genetic effects on the presence of growing pains, migraine, and recurrent abdominal pain. The analyses for headache, low back pain, and persistent pain overall did not conclusively demonstrate that genetic influences were implicated more than shared environmental factors. Regression analyses demonstrated varying levels of significance in relationships between family members and twin individuals for the tested conditions, with strongest support for genetic influences in growing pains and migraine. These data, together with previously published association analyses, suggest common causal influences including genes.

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Factors Mediating Pain-Related Risk for Opioid Use Disorder.

Pain is a complex experience with far-reaching organismal influences ranging from biological factors to those that are psychological and social. Such influences can serve as pain-related risk factors that represent susceptibilities to opioid use disorder. This review evaluates various pain-related risk factors to form a consensus on those that facilitate opioid abuse. Epidemiological findings represent a high degree of co-occurrence between chronic pain and opioid use disorder that is, in part, driven by an increase in the availability of opioid analgesics and the diversion of their use in a non-medical context. Brain imaging studies in individuals with chronic pain that use/abuse opioids suggest abuse-related mechanisms that are rooted within mesocorticolimbic processing. Preclinical studies suggest that pain states have a limited impact on increasing the rewarding effects of opioids. Indeed, many findings indicate a reduction in the rewarding and reinforcing effects of opioids during pain states. An increase in opioid use may be facilitated by an increase in the availability of opioids and a decrease in access to non-opioid reinforcers that require mobility or social interaction. Moreover, chronic pain and substance abuse conditions are known to impair cognitive function, resulting in deficits in attention and decision making that may promote opioid abuse. A better understanding of pain-related risk factors can improve our knowledge in the development of OUD in persons with pain conditions and can help identify appropriate treatment strategies.

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Painful intervertebral disc degeneration and inflammation: from laboratory evidence to clinical interventions.

Low back pain (LBP), as a leading cause of disability, is a common musculoskeletal disorder that results in major social and economic burdens. Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration, a significant contributor to LBP. Inflammatory mediators also play an indispensable role in discogenic LBP. The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies. Here, an overview of the advances in inflammation-related pain in disc degeneration is provided, with a discussion on the role of inflammation in IVD degeneration and pain induction. Puncture models, mechanical models, and spontaneous models as the main animal models to study painful disc degeneration are discussed, and the underlying signaling pathways are summarized. Furthermore, potential drug candidates, either under laboratory investigation or undergoing clinical trials, to suppress discogenic LBP by eliminating inflammation are explored. We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.

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Treatment Preferences for Chronic Low Back Pain: Views of Veterans and Their Providers.

This study was conducted to characterize chronic low back pain (cLBP) and to identify treatment histories and preferences for cLBP management among Veterans and primary care providers within the Veterans Affairs (VA) healthcare system.

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Minocycline for Controlling Neuropathic Pain: A Systematic Narrative Review of Studies in Humans.

Minocycline is known to reduce microglial activation, suggesting that it may reduce neuropathic pain. We reviewed studies in humans that evaluated the effectiveness of minocycline in alleviating neuropathic pain.

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ISSLS PRIZE IN CLINICAL SCIENCE 2021: What are the risk factors for low back pain flares and does this depend on how flare is defined?

Although risk factors for new low back pain (LBP) episodes and acute-to-chronic transition have been identified, risk factors for flares of LBP remain largely unknown. This case-crossover study aimed to identify: (1) risk factors LBP flares and (2) whether risk factors differed when flare is defined by pain increase (pain-defined flare: PDF) or identified by participants according to a broader flare definition that considered emotions and coping (self-reported flare: SRF).

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A population-based survey for disabling headaches in Greece: Prevalence, burden and treatment preferences.

To estimate the prevalence, burden and current treatment of disabling primary headaches in a large sample of the Greek population aged 18-70 years old.

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Temporal Relationships Between Pain, Mood and Urinary Symptoms in Urologic Chronic Pelvic Pain Syndrome (UCPPS): A MAPP Network Study.

To determine the time-lagged, bidirectional relationships among clinical variables of pelvic pain, urinary symptoms, negative mood, non-pelvic pain and quality of life (QOL) in men and women with UCPPS, incorporating interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

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Sustained release buprenorphine effectively attenuates postoperative hypersensitivity in an incisional pain model in neonatal rats (Rattus norvegicus).

Despite the need for safe and effective postoperative analgesia in neonates, research regarding pain management in neonatal rodents is relatively limited. Here, we investigate whether sustained release buprenorphine (Bup SR) effectively attenuates thermal hypersensitivity in a neonatal rat model of incisional pain. Male and female postnatal day 3 Sprague Dawley rat pups (n = 34) were randomly assigned to one of four treatment groups: 1) saline (control), 0.1 mL, once subcutaneously (SC); 2) buprenorphine HCl (Bup HCl), 0.05 mg/kg, once SC; 3) low dose Bup SR (low-SR), 0.5 mg/kg, once SC; 4) high dose Bup SR (high-SR), 1 mg/kg, once SC. Pups were anesthetized with sevoflurane and a 0.5-cm long skin incision was made over the left lateral thigh. The underlying muscle was dissected and closed using surgical glue. Thermal hypersensitivity testing was performed at 24 h prior to surgery and subsequently at 1, 4, 8, 24, and 48 h post-surgery using an infrared diode laser. Thermal hypersensitivity was attenuated at 1 h post-surgery in the Bup HCl group, while it was attenuated through the entire postoperative period in both low-SR and high-SR groups. This data suggests that a single dose of low-SR (0.5 mg/kg) or high-SR (1 mg/kg) effectively attenuates thermal hypersensitivity for at least 8 h in neonatal rat pups.

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Racial, Ethnic, and Socioeconomic Discrepancies in Opioid Prescriptions Among Older Patients With Cancer.

Minority race and lower socioeconomic status are associated with lower rates of opioid prescription and undertreatment of pain in multiple noncancer healthcare settings. It is not known whether these differences in opioid prescribing exist among patients undergoing cancer treatment.

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Refilling Opioid Prescriptions After Pediatric Orthopaedic Surgery: An Analysis of Incidence and Risk Factors.

Understanding which pediatric patients seek opioid refills is crucial as prescription opioid use in childhood is associated with an increased risk of future opioid misuse. Orthopaedic surgeons are optimally positioned to lead the charge in addressing the opioid epidemic. The aim of this study was to describe the incidence of and risk factors associated with requiring opioid refills after pediatric orthopaedic surgery in children.

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Pain Symptoms in Patients with Coronavirus Disease (COVID-19): A Literature Review.

On 11 March, 2020, the coronavirus disease (COVID-19) outbreak was declared as a global pandemic by the World Health Organization. It brought substantial physical and psychological burden on individuals and financial loss across countries. Patients with COVID-19 may exhibit various symptoms, such as fever, cough, dyspnea, muscle pain, sore throat, headache, chest pain, and abdominal pain, at 2-14 days after exposure to the novel coronavirus (severe acute respiratory syndrome [SARS]-CoV-2). Pain symptoms present important challenge to clinicians' diagnosis when treating COVID-19 patients with mild symptoms. Considering the increasing number of confirmed COVID-19 cases, the pain symptoms should be systematically summarized.

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Lactobacillus reuteri effects on maternal separation stress in newborn mice.

Probiotic Lactobacillus reuteri DSM 17938 (LR 17938) is beneficial to infants with colic. To understand its mechanism of action, we assessed ultrasonic vocalizations (USV) and brain pain/stress genes in newborn mice exposed to maternal separation stress.

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Neuropathic Pain in Children with Sickle Cell Disease: The Hidden Side of the Vaso-Occlusive Crisis.

The majority of hospitalizations of patients with sickle cell disease (SCD) are related to painful vaso-occlusive crises (VOCs). Although the pain of VOC is classically nociceptive, neuropathic pain (NP) has also been demonstrated in SCD patients. The aim of our study is to specify the prevalence of NP during VOCs in SCD children using a dedicated scale and to measure its characteristics. We performed a prospective study that included SCD children hospitalized for an acute VOC. The presence of NP was sought with the DN4 scale on the second and fourth days of hospitalization. A total of 54 SCD children were included in the study. Overall, 41% of the patients ( = 22) experienced neuropathic pain during the VOC, mostly at an early stage (Day 2). The median age, the sex ratio, the location of the pain, and the morphine consumption were similar for patients with and without NP. Our study shows that neuropathic pain is very common during VOCs in SCD children. The absence of identified risk factors should prompt us to be vigilant regardless of the patient's age, sex, and clinical presentation.

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The prevalence of migraine in Argentina: A reappraisal.

Argentina has one of the largest territories in the world, which spreads over a lengthy latitudinal span. Its population is mainly composed of a mixture of South American natives and the descendants of numerous waves of European immigrants. Results from a previous study suggested that the prevalence of migraine in Argentina is the lowest in the region. Here we aimed to reassess the prevalence of migraine in Argentina applying a more sensitive and specific screening tool.

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The impact of Covid-19-related distress on general health, oral behaviour, psychosocial features, disability and pain intensity in a cohort of Italian patients with temporomandibular disorders.

This study aimed to understand the impact of COVID-19 distress on psychological status, features of central sensitization and facial pain severity in people with temporomandibular disorders (TMDs). In this prospective cohort study, 45 adults (19 chronic, 26 acute/subacute TMD) were recruited prior to the COVID-19 outbreak. Baseline assessment took place before the outbreak while a follow-up was performed immediately after the lockdown period. Multiple variables were investigated including age, gender, perceived life quality, sleep quality, anxiety and depression, coping strategies, central sensitization, pain intensity, pain-related disability and oral behaviour. COVID Stress Scales (CSS) were applied at follow-up to measure the extent of COVID-related distress. CSS were significantly higher in those with chronic TMDs compared to those with acute/subacute TMDs (p<0.05). In people with chronic TMD, the variation in anxiety and depression from baseline to follow-up was significantly correlated with scores on the CSS (r = 0.72; p = 0.002). Variations of the central sensitization inventory (r = 0.57; p = 0.020) and graded chronic pain scale (r = 0.59; p = 0.017) were significantly correlated with scores on the CSS. These initial findings indicate that people with chronic TMD were more susceptible to COVID-19 distress with deterioration of psychological status, worsening features of central sensitization and increased chronic facial pain severity. These findings reinforce the role of stress as a possible amplifier of central sensitization, anxiety, depression, chronic pain and pain-related disability in people with TMDs. Trial Registration: ClinicalTrials.gov ID: NCT03990662.

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Underuse of Behavioral Treatments for Headache: a Narrative Review Examining Societal and Cultural Factors.

Migraine affects over 40 million Americans and is the world's second most disabling condition. As the majority of medical care for migraine occurs in primary care settings, not in neurology nor headache subspecialty practices, healthcare system interventions should focus on primary care. Though there is grade A evidence for behavioral treatment (e.g., biofeedback, cognitive behavioral therapy (CBT), and relaxation techniques) for migraine, these treatments are underutilized. Behavioral treatments may be a valuable alternative to opioids, which remain widely used for migraine, despite the US opioid epidemic and guidelines that recommend against them. Identifying and removing barriers to the use of headache behavioral therapy could help reduce the disability as well as the personal and social costs of migraine. These techniques will have their greatest impact if offered in primary care settings to the lower socioeconomic status groups at greatest risk for migraine. We review the societal and cultural challenges that impose barriers to optimal use of non-pharmacological treatment services. These barriers include insufficient knowledge of migraine/headache behavioral treatments and insufficient availability of clinicians trained in non-pharmacological treatment delivery; limited access in underserved communities; financial burden; and stigma associated with both headache and mental health diagnoses and treatment. For each barrier, we discuss potential approaches to minimizing its effect and thus enhancing non-pharmacological treatment utilization.Case ExampleA 25-year-old graduate student with a prior history of headaches in college is attending school in the evenings while working a full-time job. Now, his headaches have significant nausea and photophobia. They are twice weekly and are disabling enough that he is unable to complete homework assignments. He does not understand why the headaches occur on Saturdays when he pushes through all week to get through his examinations that take place on Friday evenings. He tried two different migraine preventive medications, but neither led to the 50% reduction in headache days his doctor had hoped for. His doctor had suggested cognitive behavioral therapy (CBT) before initiating the medications, but he had been too busy to attend the appointments, and the challenges in finding an in-network provider proved difficult. Now with the worsening headaches, he opted for the CBT and by the fifth week had already noted improvements in his headache frequency and intensity.

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“Holding-Cuddling” and Sucrose for Pain Relief During Venepuncture in Newborn Infants: A Randomized, Controlled Trial (CÂSA).

Oral sucrose is commonly used to provide analgesia to neonates during painful procedures, such as venepuncture. The additional benefits of reducing pain during venepuncture when oral sucrose is combined with nonpharmacological strategies have not been extensively studied. This randomized controlled trial compared the efficacy of oral sucrose with nonnutritive sucking vs. oral sucrose with nonnutritive sucking plus "holding-cuddling" for pain management during venepuncture in term infants from birth to 3 months of life. Seventy-eight infants were equally randomized to receive 24% oral sucrose with nonnutritive sucking (control group) or 24% oral sucrose with nonnutritive sucking plus "holding-cuddling" (being held in a secure, cuddling position; experimental group) before venepuncture. Behavioral response to pain was measured by the 0-10 ranking scale "acute pain for neonates (APN)" at 30 and 60 s after venepuncture. Within the study sample, APN scores were ≥ 2 for 32/68 (47%) infants. "Holding-cuddling" did not significantly reduce mean APN scores at 30 and 60 s, but the rate of infants experiencing a high pain score (APN ≥ 8) at 60 s after the venepuncture was significantly lower in the experimental group compared to controls [4/34 vs. 12/34 ( = 0.04)]. Venepuncture is a painful procedure in newborn and young infants. The implementation of behavioral strategies in association with oral sucrose may mitigate pain during this procedure. This trial was registered at http://clinicaltrials.gov/ (NCT number 02803723).

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Thalamocortical Connectivity in Experimentally-Induced Migraine Attacks: A Pilot Study.

In this study we used nitroglycerin (NTG)-induced migraine attacks as a translational human disease model. Static and dynamic functional connectivity (FC) analyses were applied to study the associated functional brain changes. A spontaneous migraine-like attack was induced in five episodic migraine (EM) patients using a NTG challenge. Four task-free functional magnetic resonance imaging (fMRI) scans were acquired over the study: baseline, prodromal, full-blown, and recovery. Seed-based correlation analysis (SCA) was applied to fMRI data to assess static FC changes between the thalamus and the rest of the brain. Wavelet coherence analysis (WCA) was applied to test time-varying phase-coherence changes between the thalamus and salience networks (SNs). SCA results showed significantly FC changes between the right thalamus and areas involved in the pain circuits (insula, pons, cerebellum) during the prodromal phase, reaching its maximal alteration during the full-blown phase. WCA showed instead a loss of synchronisation between thalami and SN, mainly occurring during the prodrome and full-blown phases. These findings further support the idea that a temporal change in thalamic function occurs over the experimentally induced phases of NTG-induced headache in migraine patients. Correlation of FC changes with true clinical phases in spontaneous migraine would validate the utility of this model.

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The role of social isolation in physical and emotional outcomes among patients with chronic pain.

Social isolation negatively impacts early-disease processes and long-term health. Individuals with chronic pain are more vulnerable to social isolation, which exacerbates symptoms. It is currently unclear whether: 1. group-based programs for chronic pain improve social isolation, 2. improvements in social isolation account for improvements in outcomes. This study involved secondary data analysis of participants in a 10-week mind-body physical activity program. We examined whether social isolation improved during treatment, and whether such improvements accounted for improvements in emotional and physical functioning.

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Central Nervous Activity during Implicit Processing of Emotional Face Expressions in Fibromyalgia Syndrome.

Fibromyalgia syndrome (FMS) is characterized by chronic widespread pain accompanied by symptoms like fatigue, insomnia, depression, anxiety and cognitive impairments. In addition to central nervous pain sensitization, emotional dysregulation may be involved in FMS pathogenesis. This study investigated central nervous correlates of affective and attentional processing in FMS using an implicit task.

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Interventional Modalities to Treat Complex Regional Pain Syndrome.

Complex regional pain syndrome (CRPS) is a debilitating pain condition that often requires a multidisciplinary approach including medication, physical therapy, occupational therapy, psychological therapy, and interventional procedures to restore the patient's quality of life. This article reviews the interventional treatments for pain resulting from CRPS.

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The Benefits and Harms of Botulinum Toxin-A in the Treatment of Chronic Pelvic Pain Syndromes: A Systematic Review by the European Association of Urology Chronic Pelvic Pain Panel.

Patients with chronic pelvic pain syndrome (CPPS) may have pain refractory to conventional management strategies. Botulinum toxin A (BTX-A) is a potential therapeutic option.

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Pain localization in cluster headache patients: Onset, peak, and radiation.

To describe differences in pain locations for onset, peak, and radiation aspects of cluster headache (CH) attacks.

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The Migraine-Anxiety Comorbidity Among Migraineurs: A Systematic Review.

Migraine is recognized as a neurological condition that is often associated with comorbid psychiatric symptoms such as anxiety, depression, bipolar disorder and/or panic disorder. Though some studies have demonstrated the link between migraine and anxiety disorders, there are no systematic reviews that have been published in this area to summarize the evidence. The aim of the present study is to systematically review the literature associated with comorbidity of migraine and anxiety disorders among migraineurs compared to non-migraineurs. The present systematic review included population-based, cohort and cross-sectional studies if they were reporting the frequency of migraine with either anxiety or depression as diagnosed by a medical practitioner according to the International Classification of Headache Disorders (ICHD-2/3). Eight eligible studies from 2060 relevant citations were included in the review. All participants were migraine patients from both primary care and outpatient settings, as well as tertiary headache and anxiety centers, and were compared to non-migraineurs. The results of the systematic review showed that there is a strong and consistent relationship between migraine and anxiety. The co-morbidity of co-occurrence for migraine and anxiety has an average OR of 2.33 (2.20-2.47) among the prevalence and cross sectional studies and an average RR of 1.63 (1.37-1.93) for two cohort studies; The major limitations of included studies were small sample sizes and a lack of adjusting of confounding factors. The results highlight the need for inclusion of an anxiety screening tool during initial assessments of migraine patients by medical practitioners and/or physicians and may explain why some anxiolytic medications work better than others for migraine mitigation.

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Comprehensive Review of Topical Analgesics for Chronic Pain.

Topical analgesics are a non-opioid option for the treatment of chronic pain conditions including neuropathic pain, musculoskeletal pain, and osteoarthritis. There are many topical medications available; however their efficacy is variable. This article reviews the various topical analgesics, their mechanisms of action, and their efficacy.

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Comparison of murine behavioral and physiologic responses after forced exercise by electrical shock vs. manual prodding.

What is the central question of this study? Forced treadmill exercise using electrical shock is the most common technique in rodent exercise studies. Here we examined how using electrical shock during forced treadmill exercise effects behavioral and physiological responses compared to a novel non-electrical shock technique. What is the main finding and its importance? Mice that underwent forced running using a novel technique involving gentle prodding to induce running showed 1) higher locomotor activity, 2) less anxiety-like behavior, and 3) altered exercise-induced muscle pain immediately after exercise compared to mice that underwent traditional treadmill running induced by electrical shock.

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Daily associations between sleep and pain in patients with chronic musculoskeletal pain.

Patients with chronic pain commonly report sleep problems, and the evidence for a relationship between sleep disturbance and pain seems robust. The day-to-day associations between these constructs are less well studied, particularly with objective sleep measures such as actigraphy. Moreover, the concurrent presence of negative affective symptoms, as well as seasonality effects at extreme latitudes may complicate it further. Here, we studied 56 patients with chronic primary musculoskeletal pain conditions, contributing data in two separate 7-day data-collection periods during the summer and winter, respectively. The effect of self-reported sleep quality, and actigraphy measured sleep duration, efficiency and timing on next-day pain, as well as the effect of pain on the same sleep indices were estimated by generalised linear mixed regression models. The models were additionally adjusted for age, sex, education, data collection period, weekend, season and mental distress, with the latter two also specified as moderators. We observed a significant effect of pain as a predictor of next-night sleep quality (p = .003) and marginally of next-night sleep duration (p = .079). Conversely, sleep quality tentatively predicted next-day pain (p = .063). No other day-to-day associations were present. Mental distress was the strongest predictor of pain, but it did not modify the sleep-pain associations, nor did season. In conclusion pain, sleep quality and mental distress are closely related, underscoring the importance of encompassing this complexity in assessment and treatment of patients with chronic pain.

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Acupuncture ameliorates not only atopic dermatitis-like skin inflammation but also acute and chronic serotonergic itch possibly through blockade of 5-HT2 and 5-HT7 receptors in mice.

Acupuncture has been known to be effective for atopic dermatitis, especially ameliorating itch; however, its mechanisms are still unclear. The aim of this study was to test the anti-itch effects of acupuncture and to investigate its possible mechanisms. Acupuncture was performed at Gok-Ji (LI11) acupoints just before the injection of pruritogens in the mouse cheek model of acute itch and of MC903-induced atopic dermatitis displaying serotonergic chronic itch. Acupuncture significantly reduced acute itch triggered by compound 48/80, chloroquine, or especially serotonin. It also markedly reduced scratching behaviors evoked by the serotonin 5-HT2 receptor agonist α-methylserotonin and selective 5-HT7 receptor agonist LP 44. In addition, acupuncture treatment at LI11 had the preventive and therapeutic effects on persistent itch as well as the robust skin inflammation with epidermal thickening in mice with MC903-induced atopic dermatitis. It also considerably reduced the increased expression of 5-HT2A, 5-HT2B and 5-HT7 receptors in atopic dermatitis-like skin lesions in mice treated with MC903. Taken together, these findings highlight that acupuncture significantly ameliorates not only skin inflammation, but also acute and chronic serotonergic itch, possibly through blockade of serotonin 5-HT2 and 5-HT7 receptors.

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Donepezil attenuates the development of morphine tolerance in rats with cancer-induced bone pain: the role of cortical N-methyl-D-aspartate receptors.

Cancer-induced bone pain (CIBP), which is associated with poor quality of life, is most commonly treated using opioids. However, long-term use of morphine for analgesia induces tolerance and can diminish the treatment's effectiveness. The mechanisms that underlie morphine tolerance have been reported to be related to the inflammation of the nervous system and hyperactivation of N-methyl-D-aspartate receptors (NMDARs). Donepezil is an anti-inflammatory and neuroprotective drug that is thought to alleviate morphine tolerance. In this study, we aimed to investigate the effect of three different dosages of donepezil (1, 1.5 and 2 mg/kg) on morphine tolerance in rats with CIBP, and the possible involvement of donepezil-mediated NMDAR subunit 1 (NR1). We found that donepezil can prolong the analgesic efficacy of morphine and delay the development of chronic morphine tolerance. Furthermore, continuous morphine injection increased the expression of NR1, and this was suppressed by co-administration with donepezil using both western blotting and immunofluorescence. Our findings demonstrate that donepezil has the potential to attenuate morphine tolerance, possibly by inhibiting NR1 activity in the cortex.

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Real-Life Management Pathways for Chronic Peripheral Neuropathic Pain at Tertiary Pain Clinics in France.

Peripheral neuropathic pain (PNP) represents a major public health issue. Severe or refractory cases warrant tertiary multidisciplinary management, but little information is available about real-life care pathways. The primary objective of this cross-sectional, observational study was to investigate the pathways of patients with PNP consulting for the first time or followed for less than 1 year in French tertiary specialized pain clinics.

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Perfectly Tired: Perfectionism and Sleep in Adolescents With Chronic Pain.

Conceptual links between perfectionism and chronic pain have been proposed yet minimal empirical data exists. Poor sleep is associated with high levels of perfectionism and is common among youth with chronic pain. This study explores associations between perfectionism and sleep quality in adolescents with chronic pain while considering levels of functional disability.

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Nitric oxide and sickle cell disease-Is there a painful connection?

Sickle cell disease is the most common hemoglobinopathy and affects millions worldwide. The disease is associated with severe organ dysfunction, acute and chronic pain, and significantly decreased life expectancy. The large body of work demonstrating that hemolysis results in rapid consumption of the endogenous vasodilator nitric oxide, decreased nitric oxide production, and promotion of vaso-occlusion provides the basis for the hypothesis that nitric oxide bioavailability is reduced in sickle cell disease and that this deficit plays a role in sickle cell disease pain. Despite initial promising results, large clinical trials using strategies to increase nitric oxide bioavailability in sickle cell disease patients yielded no significant change in duration or frequency of acute pain crises. Further, recent investigations showed that sickle cell disease patients and mouse models have elevated baseline levels of blood nitrite, a reservoir for nitric oxide formation and a product of nitric oxide metabolism, regardless of pain phenotype. These conflicting results challenge the hypotheses that nitric oxide bioavailability is decreased and that it plays a significant role in the pathogenesis in sickle cell disease acute pain crises. Conversely, a large body of work demonstrates that nitric oxide, as a neurotransmitter, has a complex role in pain neurobiology, contributes to the development of central sensitization, and can mediate hyperalgesia in inflammatory and neuropathic pain. These results support an alternative hypothesis: one proposing that altered nitric oxide signaling may contribute to the development of neuropathic and/or inflammatory pain in sickle cell disease through its role as a neurotransmitter.

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Autobiographical Memory and Future Thinking Specificity and Content in Chronic Pain.

Chronic pain is associated with high levels of mental health issues and alterations in cognitive processing. Cognitive-behavioral models illustrate the role of memory alterations (e.g., autobiographical memory and future thinking) in the development and maintenance of chronic pain as well as in mental health disorders which frequently co-occur with chronic pain (e.g., anxiety and mood disorders). This study aims to expand our understanding of specific cognitive mechanisms underlying chronic pain which may in turn shed light on cognitive processes underlying pain-related psychological distress. Individuals ( = 84) who reported a history of chronic pain and individuals who reported no history of chronic pain ( = 102) were recruited from MTurk to complete an online survey including standardized measures of anxiety and depression and two sentence completion tasks that assessed autobiographical memory and future thinking specificity and content. Chi square analyses revealed that participants who endorsed experiencing chronic pain were significantly more likely to recall at least one painful and negative event and to imagine at least one anticipated painful event in their future. Two ANCOVAs were performed to examine the degree to which chronic pain endorsement influenced specificity in memory and future imagining. Individuals with a history of chronic pain and higher levels of depression symptom severity generated autobiographical memories with significantly less specificity; whereas, individuals with a history of chronic pain also generated future autobiographical events with significantly less specificity. In addition, individuals with a history of chronic pain were more likely to generate episodes related to pain when asked to recall the past or imagine the future. Further research is needed to improve our understanding of the etiology of autobiographical memory and future thinking specificity and content in the pathogenesis of mental health conditions in the context of chronic pain.

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Effect of Patient Characteristics on Clinical Outcomes More Than 12 Months Following Dorsal Root Ganglion Stimulation Implantation: A Retrospective Review.

Dorsal root ganglion (DRG) stimulation is an effective treatment option for lower extremity complex regional pain syndrome and other focal pain conditions. However, the patient characteristics that may predict long-term outcomes have not been defined.

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