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Papers: 2 Jan 2021 - 8 Jan 2021

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A neuroimaging biomarker for sustained experimental and clinical pain.

Sustained pain is a major characteristic of clinical pain disorders, but it is difficult to assess in isolation from co-occurring cognitive and emotional features in patients. In this study, we developed a functional magnetic resonance imaging signature based on whole-brain functional connectivity that tracks experimentally induced tonic pain intensity and tested its sensitivity, specificity and generalizability to clinical pain across six studies (total n = 334). The signature displayed high sensitivity and specificity to tonic pain across three independent studies of orofacial tonic pain and aversive taste. It also predicted clinical pain severity and classified patients versus controls in two independent studies of clinical low back pain. Tonic and clinical pain showed similar network-level representations, particularly in somatomotor, frontoparietal and dorsal attention networks. These patterns were distinct from representations of experimental phasic pain. This study identified a brain biomarker for sustained pain with high potential for clinical translation.

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Pain modulatory network is influenced by sex and age in a healthy state and during osteoarthritis progression in rats.

Old age and female sex are risk factors for the development of osteoarthritis (OA) and chronic pain. We investigated the effects of sex and age on pain modulatory networks in a healthy state and during OA progression. We used functional MRI to determine the effects of sex and age on periaqueductal gray functional connectivity (PAG FC) in a healthy state (pre-OA) and during the early and late phases of monosodium iodoacetate-induced OA in rats. We then examined how sex and age affect longitudinal changes in PAG FC in OA. In a healthy state, females exhibited more widespread PAG FC than males, and this effect was exaggerated with aging. Young males had moderate PAG FC changes during the early phase but recruited additional brain regions, including the rostral anterior cingulate cortex (ACC), during the late phase. Young females exhibited widespread PAG FC in the early phase, which includes connections to insula, caudal ACC, and nucleus accumbens (NAc). Older groups had strong PAG FC with fewer regions in the early phase, but they recruited additional brain regions, including NAc, in the late phase. Overall, our findings show that PAG FC is modulated by sex and age in a healthy state. A widespread PAG network in the early phase of OA pain may contribute to the transition from acute to chronic OA pain and the increased risk of developing chronic pain for females. Enhanced PAG FC with the reward system may represent a potential mechanism underlying chronic OA pain in elderly patients.

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The Jak/STAT pathway: A focus on pain in rheumatoid arthritis.

Pain is a manifestation of rheumatoid arthritis (RA) that is mediated by inflammatory and non-inflammatory mechanisms and negatively affects quality of life. Recent findings from a Phase 3 clinical trial showed that patients with RA who were treated with a Janus kinase 1 (Jak1) and Janus kinase 2 (Jak2) inhibitor achieved significantly greater improvements in pain than those treated with a tumor necrosis factor blocker; both treatments resulted in similar changes in standard clinical measures and markers of inflammation. These findings suggest that Jak1 and Jak2 inhibition may relieve pain in RA caused by inflammatory and non-inflammatory mechanisms and are consistent with the overarching involvement of the Jak-signal transducer and activator of transcription (Jak/STAT) pathway in mediating the action, expression, and regulation of a multitude of pro- and anti-inflammatory cytokines. In this review, we provide an overview of pain in RA, the underlying importance of cytokines regulated directly or indirectly by the Jak/STAT pathway, and therapeutic targeting of the Jak/STAT pathway in RA. As highlighted herein, multiple cytokines directly or indirectly regulated by the Jak/STAT pathway play important roles in mediating various mechanisms underlying pain in RA. Having a better understanding of these mechanisms may help clinicians make treatment decisions that optimize the control of inflammation and pain.

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Brain Responses to Noxious Stimuli in Patients With Chronic Pain: A Systematic Review and Meta-analysis.

Functional neuroimaging is a valuable tool for understanding how patients with chronic pain respond to painful stimuli. However, past studies have reported heterogenous results, highlighting opportunities for a quantitative meta-analysis to integrate existing data and delineate consistent associations across studies.

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Ictal and interictal brain activation in episodic migraine: Neural basis for extent of allodynia.

In some patients, migraine attacks are associated with symptoms of allodynia which can be localized (cephalic) or generalized (extracephalic). Using functional neuroimaging and cutaneous thermal stimulation, we aimed to investigate the differences in brain activation of patients with episodic migraine (n = 19) based on their allodynic status defined by changes between ictal and interictal pain tolerance threshold for each subject at the time of imaging. In this prospective imaging study, differences were found in brain activity between the ictal and interictal visits in the brainstem/pons, thalamus, insula, cerebellum and cingulate cortex. Significant differences were also observed in the pattern of activation along the trigeminal pathway to noxious heat stimuli in no allodynia vs. generalized allodynia in the thalamus and the trigeminal nucleus but there were no activation differences in the trigeminal ganglion. The functional magnetic resonance imaging (fMRI) findings provide direct evidence for the view that in migraine patients who are allodynic during the ictal phase of their attacks, the spinal trigeminal nucleus and posterior thalamus become hyper-responsive (sensitized)-to the extent that they mediate cephalic and extracephalic allodynia, respectively. In addition, descending analgesic systems seem as "switched off" in generalized allodynia.

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Does aerobic exercise training alter responses to opioid analgesics in individuals with chronic low back pain?: a randomized controlled trial.

We tested whether aerobic exercise training altered morphine analgesic responses or reduced morphine dosages necessary for adequate analgesia. Chronic back pain patients were randomized to an 18-session aerobic exercise intervention (n = 38) or usual activity control (n = 45). Before and after the intervention, participants underwent three laboratory sessions (double-blinded, crossover) to assess effects of saline placebo, i.v. morphine (0.09 mg/kg), and i.v. naloxone (12 mg) on low back pain and evoked heat pain responses. Differences in evoked and back pain measures between the placebo and morphine conditions indexed morphine analgesia, with pre-post intervention changes the primary outcome. Endogenous opioid (EO) analgesia was indexed by differences in evoked and low back pain measures between the naloxone and placebo conditions. A Sex X Intervention interaction on the analgesic effects of morphine on VAS back pain intensity was observed (p = .046), with a similar trend for evoked pain threshold (p = .093). Male exercisers showed reduced morphine analgesia pre-post intervention whereas male controls showed increased analgesia (with no differences in females). Of clinical significance were findings that relative to the control group, aerobic exercise produced analgesia more similar to that observed after receiving ≈7 mg morphine pre-intervention (p's < .045). Greater pre-post intervention increases in EO function (from any source) were significantly associated with larger pre-post intervention decreases in morphine analgesia (p's < .046). The overall pattern of findings suggest that regular aerobic exercise has limited direct effects on morphine responsiveness, reducing morphine analgesia in males only.

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Developing clinical prediction models for non-recovery in older patients seeking care for back pain: the BACE prospective cohort study.

Back pain is a leading cause of disability worldwide and is common in older adults. No clinical prediction models for poor long-term outcomes have been developed in older patients with back pain. This study aimed to develop and internally validate three clinical prediction models for non-recovery in this population. A prospective cohort study in general practice was conducted (BACE, Netherlands), including 675 patients >55 years with a new episode of care for back pain. Three definitions of non-recovery were used combining 6- and 12-month follow-up data: 1) persistent back pain; 2) persistent disability; 3) perceived non-recovery. Sample size calculation resulted in a maximum of 14 candidate predictors that were selected from back pain prognostic literature and clinical experience. Multivariable logistic regression was used to develop the models (backward selection procedure). Models' performance was evaluated with explained variance (Nagelkerke's R2), calibration (Hosmer-Lemeshow test), and discrimination (AUC) measures. The models were internally validated in 250 bootstrapped samples to correct for over-optimism. All three models displayed good overall performance during development and internal validation (i.e. R2>30%; AUC>0.77). The model predicting persistent disability performed best, showing good calibration, discrimination (AUC 0.86, 95%CI 0.83-0.89; optimism-adjusted AUC 0.85), and explained variance (R2 49%, optimism-adjusted R2 46%). Common predictors in all models were: age, chronic duration, disability, a recent back pain episode, and patients' recovery expectations. Spinal morning stiffness and pain during spinal rotation were included in two out of three models. These models should be externally validated before being used in a clinical primary care setting.

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The Mysteries of Capsaicin-Sensitive Afferents.

A fundamental subdivision of nociceptive sensory neurons is named after their unique sensitivity to capsaicin, the pungent ingredient in hot chili peppers: these are the capsaicin-sensitive afferents. The initial excitation by capsaicin of these neurons manifested as burning pain sensation is followed by a lasting refractory state, traditionally referred to as "capsaicin desensitization," during which the previously excited neurons are unresponsive not only to capsaicin but a variety of unrelated stimuli including noxious heat. The long sought-after capsaicin receptor, now known as TRPV1 (transient receptor potential cation channel, subfamily V member 1), was cloned more than two decades ago. The substantial reduction of the inflammatory phenotype of knockout mice has spurred extensive efforts in the pharmaceutical industry to develop small molecule TRPV1 antagonists. However, adverse effects, most importantly hyperthermia and burn injuries, have so far prevented any compounds from progressing beyond Phase 2. There is increasing evidence that these limitations can be at least partially overcome by approaches outside of the mainstream pharmaceutical development, providing novel therapeutic options through TRPV1. Although ablation of the whole TRPV1-expressing nerve population by high dose capsaicin, or more selectively by intersectional genetics, has allowed researchers to investigate the functions of capsaicin-sensitive afferents in health and disease, several "mysteries" remain unsolved to date, including the molecular underpinnings of "capsaicin desensitization," and the exact role these nerves play in thermoregulation and heat sensation. This review tries to shed some light on these capsaicin mechanisms.

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The changing states of fibromyalgia in patients with axial spondyloarthritis: results from BSRBR-AS.

To identify factors associated with fibromyalgia (FM) development and recovery in patients with axial spondyloarthritis (axSpA).

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Prevalence of chronic pain after spinal cord injury: a systematic review and meta-analysis.

The reported prevalence of chronic pain after spinal cord injury (SCI) varies widely due, in part, to differences in the taxonomy of chronic pain. A widely used classification system is available to describe subcategories of chronic pain in SCI, but the prevalence of chronic pain in SCI based on this system is unknown.

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Long-term efficacy and safety of erenumab in migraine prevention: results from a 5-year, open-label treatment phase of a randomized clinical trial.

Although erenumab has demonstrated significant reduction in migraine frequency and improved quality of life in studies lasting 3-12 months, little is known about long-term therapy.

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Age differences in cognitive-affective processes in adults with chronic pain.

Chronic pain is associated with significant physical and psychological impairments across the adult lifespan. However, there is a relative gap in knowledge on individual differences that predict pain-related functioning. The current study highlights one important source of individual variation: age.

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Are some patient-perceived migraine triggers simply early manifestations of the attack?

To study the agreement between self-reported trigger factors and early premonitory symptoms amongst a group of migraineurs in both spontaneous and pharmacologically provoked attacks.

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Cannabidiol Use for Fibromyalgia: Prevalence of Use and Perceptions of Effectiveness in a Large Online Survey.

Cannabidiol (CBD) is widely advertised as helpful for chronic pain management but research is limited. Using a cross-sectional, anonymous survey, we examined patterns of naturalistic CBD use among individuals with fibromyalgia (FM) and other chronic pain conditions. Our objective was to better understand rates of CBD use, reasons for use and discontinuation, communication with healthcare professionals about CBD, and perceptions of CBD effectiveness and safety among people with FM. After excluding incomplete surveys, our study population consisted of N = 2701 participants with fibromyalgia, primarily in the United States. Overall, 38.1% reported never using CBD, 29.4% reported past CBD use, and 32.4% reported current CBD use. Past-year cannabis use was strongly associated with past or current CBD use. Those using CBD typically did so due to inadequate symptom relief, while those not using CBD typically cited safety concerns as their reason for not using CBD. Two-thirds of participants disclosed CBD use to their physician, although only 33% asked for physician advice on using CBD. Participants used CBD for numerous FM-related symptoms (most commonly pain), and generally reported slight to much improvement across symptom domains. Around half of participants reported side effects, which were typically minor. Our findings are limited by selection bias and our cross-sectional design, which prevents causal associations. In conclusion, CBD use is common among individuals with FM and many individuals using CBD report improvements across numerous FM-related symptoms. Our findings highlight the need for additional rigorous studies to better understand CBD's potential for FM management. Perspective: This article indicates that that CBD use is common among people with fibromyalgia, and the results suggest that many derive benefit from using CBD across multiple symptoms domains. Clinicians should discuss CBD use with fibromyalgia patients, and future studies are needed to rigorously assess CBD's therapeutic value for fibromyalgia symptoms.

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CXCL12-mediated monocyte transmigration into brain perivascular space leads to neuroinflammation and memory deficit in neuropathic pain.

Emerging clinical and experimental evidence demonstrates that neuroinflammation plays an important role in cognitive impairment associated with neuropathic pain. However, how peripheral nerve challenge induces remote inflammation in the brain remains largely unknown. The circulating leukocytes and plasma C-X-C motif chemokine 12 (CXCL12) and brain perivascular macrophages (PVMs) were analyzed by flow cytometry, Western blotting, ELISA, and immunostaining in spared nerve injury (SNI) mice. The memory function was evaluated with a novel object recognition test (NORT) in mice and with Montreal Cognitive Assessment (MoCA) in chronic pain patients. The classical monocytes and CXCL12 in the blood, PVMs in the perivascular space, and gliosis in the brain, particularly in the hippocampus, were persistently increased following SNI in mice. Using the transgenic CCR2 and CX3CR1 mice, we discovered that at least some of the PVMs were recruited from circulating monocytes. The SNI-induced increase in hippocampal PVMs, gliosis, and memory decline were substantially prevented by either depleting circulating monocytes via intravenous injection of clodronate liposomes or blockade of CXCL12-CXCR4 signaling. On the contrary, intravenous injection of CXCL12 at a pathological concentration in naïve mice mimicked SNI effects. Significantly, we found that circulating monocytes and plasma CXCL12 were elevated in chronic pain patients, and both of them were closely correlated with memory decline. CXCL12-mediated monocyte recruitment into the perivascular space is critical for neuroinflammation and the resultant cognitive impairment in neuropathic pain.

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Mast cells in the paraventricular nucleus participate in visceral hypersensitivity induced by neonatal maternal separation.

Early-life stress (ELS) is a high-risk factor for the development of chronic visceral pain in adulthood. Emerging evidence suggests that mast cells play a key role in the development of visceral hypersensitivity through interaction with neurons. The sensitization of corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) plays a pivotal role in the pathogenesis of visceral pain. However, the precise mechanism by which mast cells and CRF neurons interact in the PVN in the pathogenesis of visceral hypersensitivity remains elusive. In the present study, we used neonatal maternal separation (MS), an ELS model, and observed that neonatal MS induced visceral hypersensitivity and triggered PVN mast cell activation in adult rats, which was repressed by intra-PVN infusion of the mast cell stabilizer disodium cromoglycate (cromolyn). Wild-type (WT) mice but not mast cell-deficient Kit mice that had experienced neonatal MS exhibited chronic visceral hypersensitivity. MS was associated with an increase in the expression of proinflammatory mediators, the number of CRF cells and CRF protein in the PVN, which was prevented by intra-PVN infusion of cromolyn. Furthermore, we demonstrated that intra-PVN infusion of the mast degranulator compound 48/80 significantly induced mast cell activation, resulting in proinflammatory mediator release, CRF neuronal sensitization, and visceral hypersensitivity, which was suppressed by cromolyn. Overall, our findings demonstrated that neonatal MS induces the activation of PVN mast cells, which secrete numerous proinflammatory mediators that may participate in neighboring CRF neuronal activity, ultimately directly inducing visceral hypersensitivity in adulthood.

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The Combination of Preoperative Pain, Conditioned Pain Modulation, and Pain Catastrophizing Predicts Postoperative Pain 12 Months After Total Knee Arthroplasty.

Approximately 20% of knee osteoarthritis patients undergoing total knee arthroplasty (TKA) report chronic postoperative pain. Studies suggest that preoperative variables such as impaired descending pain control, catastrophizing, function, and neuropathic pain-like symptoms may predict postoperative pain 12 months after TKA, but the combined prediction value of these factors has not been tested. The current prospective cohort study aimed to combine preoperative risk factors to investigate the predictive value for postoperative pain 12 months after TKA.

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Effect of erenumab on functional outcomes in patients with episodic migraine in whom 2-4 preventives were not useful: results from the LIBERTY study.

To evaluate the effect of erenumab on patient-reported, functional outcomes in patients with episodic migraine (EM) in whom 2-4 preventives were not useful from the Phase 3b LIBERTY study.

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A Pilot Trial of Collaborative Care with Motivational Interviewing to Reduce Opioid Risk and Improve Chronic Pain Management.

Opioid use and chronic pain are prevalent in the veteran population. Collaborative Care enhances coordination between patients and their care teams and Motivational Interviewing (MI) is a communication style designed to facilitate behavior change. This study evaluated the use of Collaborative Care with MI (CCMI) with patients with chronic pain and high-risk prescription opioid use.

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A widening gap between boys and girls in musculoskeletal complaints, while growing up from age 11 to age 20 – The PIAMA Birth Cohort Study.

The adolescent years represent a key period for the development of musculoskeletal complaints (MSC) and the differences between boys and girls. We evaluated the prevalence and course of MSC and factors associated with MSC while growing up from age 11 to age 20.

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Characteristics of pain in patients with pituitary adenomas: a cross-sectional study.

This study determines the prevalence and particularities of headache and pain with neuropathic characteristics (NC) in a large French group of patients with pituitary adenoma (PA).

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Bimodal Imaging of Mouse Peripheral Nerves with Chlorin Tracers.

Almost 17 million Americans have a history of cancer, a number expected to reach over 22 million by 2030. Cancer patients often undergo chemotherapy in the form of antineoplastic agents such as -platin and paclitaxel. Though effective, these agents can induce debilitating side effects; the most common neurotoxic effect, chemotherapy-induced peripheral neuropathy (CIPN), can endure long after treatment ends. Despite the widespread and chronic nature of the dysfunction, no tools exist to quantitatively measure chemotherapy-induced peripheral neuropathy. Such a tool would not only benefit patients but their stratification could also save significant financial and social costs associated with neuropathic pain. In our first step toward addressing this unmet clinical need, we explored a novel dual approach to localize peripheral nerves: Cerenkov luminescence imaging (CLI) and fluorescence imaging (FI). Our approach revolves around the targeting and imaging of voltage-gated sodium channel subtype Na1.7, highly expressed in peripheral nerves from both harvested human and mouse tissues. For the first time, we show that Hsp1a, a radiolabeled Na1.7-selective peptide isolated from spec. Peru, can serve as a targeted vector for delivering a radioactive sensor to the peripheral nervous system. , we observe high signal-to-noise ratios in the sciatic nerves of animals injected with fluorescently labeled Hsp1a and radiolabeled Hsp1a. Moreover, confocal microscopy on fresh nerve tissue shows the same high ratios of fluorescence, corroborating our results. This study indicates that fluorescently labeled and radiolabeled Hsp1a tracers could be used to identify and demarcate nerves in a clinical setting.

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The potential of lasmiditan in migraine.

Lasmiditan, a highly selective 5-hydroxytryptamine receptor 1F (5-HT) agonist, is the first drug in its class and is lacking triptan-like vasoactive properties. The US Food and Drug Administration (FDA) has recently approved lasmiditan for the acute treatment of migraine in adults based on positive results of two pivotal phase III trials, which showed a significant difference to placebo in the proportion of patients achieving total migraine freedom within 2 h. More patients with lasmiditan achieved headache freedom and, in addition, freedom from the most bothersome symptom, that is, photophobia, than with placebo. Treatment-related side effects seem to be related to the rapid penetration of the drug into the brain and include dizziness, paresthesia and drowsiness, mostly of mild to moderate intensity. Interim results from an ongoing long-term phase III trial suggest a decrease in the frequency of adverse events after multiple lasmiditan use. Lasmiditan is a promising acute anti-migraine therapy, in particular for patients with cardiovascular risk factors, contraindications, or unwanted side effects to triptans.

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The Long-Term Impact of Whiplash Injuries on Patient Symptoms and the Associated Degenerative Changes Detected Using MRI: A Prospective 20-Year follow-up Study Comparing Patients with Whiplash-Associated Disorders with Asymptomatic Subjects.

A longitudinal, 20-year comparative study of patients with whiplash-associated disorders (WAD).

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Sensory Processing in People With and Without Tendinopathy: A Systematic Review With Meta-analysis of Local, Regional, and Remote Sites in Upper- and Lower-Limb Conditions.

To synthesize results of somatosensory processing tests in people with upper- and lower-limb tendinopathy, compared to controls.

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Presynaptic Inhibition of Pain and Touch in the Spinal Cord: From Receptors to Circuits.

Sensory primary afferent fibers, conveying touch, pain, itch, and proprioception, synapse onto spinal cord dorsal horn neurons. Primary afferent central terminals express a wide variety of receptors that modulate glutamate and peptide release. Regulation of the amount and timing of neurotransmitter release critically affects the integration of postsynaptic responses and the coding of sensory information. The role of GABA (γ-aminobutyric acid) receptors expressed on afferent central terminals is particularly important in sensory processing, both in physiological conditions and in sensitized states induced by chronic pain. During the last decade, techniques of opto- and chemogenetic stimulation and neuronal selective labeling have provided interesting insights on this topic. This review focused on the recent advances about the modulatory effects of presynaptic GABAergic receptors in spinal cord dorsal horn and the neural circuits involved in these mechanisms.

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Functional Coupling of Slack Channels and P2X3 Receptors Contributes to Neuropathic Pain Processing.

The sodium-activated potassium channel Slack (K1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (I) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing of neuropathic pain. However, mechanisms underlying the regulation of Slack activity in this context are poorly understood. Using whole-cell patch-clamp recordings we found that Slack-mediated I in sensory neurons of mice is reduced after peripheral nerve injury, thereby contributing to neuropathic pain hypersensitivity. Interestingly, Slack is closely associated with ATP-sensitive P2X3 receptors in a population of sensory neurons. In vitro experiments revealed that Slack-mediated I may be bidirectionally modulated in response to P2X3 activation. Moreover, mice lacking Slack show altered nocifensive responses to P2X3 stimulation. Our study identifies P2X3/Slack signaling as a mechanism contributing to hypersensitivity after peripheral nerve injury and proposes a potential novel strategy for treatment of neuropathic pain.

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Associations between biased threat interpretations, fear and avoidance of pain and pain-linked disability in adolescent chronic pain patients.

Biased interpretations of ambiguous bodily threat situations characterise youth with chronic pain, and have been associated with functional disability for this population. Despite predictions by the fear-avoidance model of chronic pain, that fear and avoidance of pain explain the association between threat perceptions and disability, this has not yet been explored in youth with chronic pain. The current study aimed to address this gap by investigating these proposed relationships, in addition to the association between bodily threat interpretations and daily aspects of disability (as well as social, and emotional impairments).

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β-endorphin at the intersection of pain and cancer progression: Preclinical evidence.

We examined the association between endogenous opioid β-endorphin, cancer progression and pain in a transgenic mouse model of breast cancer, with a rat C3(1) simian virus 40 large tumor antigen fusion gene (C3TAg). C3TAg mice develop ductal epithelial atypia at 8 weeks, progression to intra-epithelial neoplasia at 12 weeks, and invasive carcinoma with palpable tumors at 16 weeks. Consistent with invasive carcinoma at 4 months of age, C3TAg mice demonstrate a significant increase in hyperalgesia compared to younger C3TAg or control FVBN mice without tumors. Our data show that the growing tumor contributes to circulating β-endorphin. As an endogenous ligand of mu opioid receptor, β-endorphin has analgesic activity. Paradoxically, we observed an increase in pain in transgenic breast cancer mice with significantly high circulating and tumor-associated β-endorphin. Increased circulating β-endorphin correlates with increasing tumor burden. β-endorphin induced the activation of mitogenic and survival-promoting signaling pathways, MAPK/ERK 1/2, STAT3 and Akt, observed by us in human MDA-MB-231 cells suggesting a role for β-endorphin in breast cancer progression and associated pain.

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Age-related molecular changes in the lumbar dorsal root ganglia of mice: Signs of sensitization, and inflammatory response.

Aging is a major risk factor for numerous painful, inflammatory, and degenerative diseases including disc degeneration. A better understanding of how the somatosensory nervous system adapts to the changing physiology of the aging body will be of great significance for our expanding aging population. Previously, we reported that chronological aging of mouse lumbar discs is pathological and associated with behavioral changes related to pain. It is established that with age and degeneration the lumbar discs become inflammatory and innervated. Here we analyze the aging lumbar dorsal root ganglia (DRGs) and spinal cord dorsal horn (SCDH) in mice between 3 and 24 months of age for age-related somatosensory adaptations. We observe that as mice age there are signs of peripheral sensitization, and response to inflammation at the molecular and cellular level in the DRGs. From 12 months onwards the mRNA expression of vasodilator and neurotransmitter, (CGRP); stress (and survival) marker, ; and neurotrophic factor, , increases linearly with age in the DRGs. Further, while the mRNA expression of neuropeptide, precursor of Substance P, did not change at the transcriptional level, TAC1 protein expression increased in 24-month-old DRGs. Additionally, elevated expression of NFκB subunits, and , but not inflammatory mediators, , in the DRGs suggest peripheral nerves are responding to inflammation, but do not increase the expression of inflammatory mediators at the transcriptional level. These results identify a progressive, age-related shift in the molecular profile of the mouse somatosensory nervous system and implicates nociceptive sensitization and inflammatory response.

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Incorporating walking into cognitive behavioral therapy for chronic pain: safety and effectiveness of a personalized walking intervention.

We examined the effectiveness and safety of a walking program offered as part of cognitive behavioral therapy for chronic pain (CBT-CP). Participants were randomized to 10 weeks of CBT-CP, delivered either in person or by interactive voice response. Participants reported pedometer-measured step counts daily throughout treatment and received a weekly goal to increase their steps by 10% over the prior week's average. Walking-related adverse events (AEs) were assessed weekly. Participants (n = 125) were primarily male (72%), and white (80%) with longstanding pain (median: 11 years). There was no significant difference between treatment groups in rate of change in daily steps, but there was a significant increase in steps from baseline to treatment termination in the combined study sample (1648 steps (95% CI 1063-2225)). Participants classified as active doubled. AEs were mostly minor and temporary. Treatment was effective and safe whether the program was delivered in-person or remotely.Trial registration number: clinicaltrials.gov identifier: NCT01025752.

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Neuronal Correlates of Cognitive Control Are Altered in Women With Endometriosis and Chronic Pelvic Pain.

Endometriosis is a debilitating women's health condition and is the most common cause of chronic pelvic pain. Impaired cognitive control is common in chronic pain conditions, however, it has not yet been investigated in endometriosis. The aim of this study was to explore the neuronal correlates of cognitive control in women with endometriosis. Using a cross-sectional study design with data collected at a single time-point, event-related potentials were elicited during a cued continuous performance test from 20 women with endometriosis (mean age = 28.5 ± 5.2 years) and 20 age- and gender-matched controls (mean age = 28.5 ± 5.2 years). Event-related potential components were extracted and P3 component amplitudes were derived with temporal principal components analysis. Behavioral and ERP outcomes were compared between groups and subjective pain severity was correlated with ERP component amplitudes. No significant behavioral differences were seen in task performance between the groups (all > 0.094). Target P3b (all < 0.034) and SW (all < 0.040), and non-target early P3a (eP3a; all < 0.023) and late P3a (lP3a; all < 0.035) amplitudes were smaller for the endometriosis compared to the healthy control group. Lower non-target eP3a ( < 0.001), lP3a ( = 0.013), and SW ( = 0.019) amplitudes were correlated with higher pain severity scores. Findings suggest that endometriosis-associated chronic pelvic pain is linked to alterations in stimulus-response processing and inhibitory control networks, but not impaired behavioral performance, due to compensatory neuroplastic changes in overlapping cognitive control and pain networks.

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Antinociceptive Effects of Kappa-Opioid Receptor Agonists.

Preclinical models that assess "pain" in rodents typically measure increases in behaviors produced by a "pain stimulus." A large literature exists showing that kappa opioid receptor (KOR) agonists can decrease these "pain-stimulated behaviors" following many different pain stimuli. Despite showing apparent antinociceptive properties in these preclinical models, KOR agonists failed as analgesics in clinical trials. Recent studies that assessed decreases in behavior due to a pain stimulus show that KOR agonists are not effective in restoring these "pain-depressed behaviors" to normal levels, which agrees with the lack of effectiveness for KOR agonists in clinical trials. One current explanation for the failure of previous KOR agonists in clinical trials is that those agonists activated beta-arrestin signaling and that KOR agonists with a greater bias for G protein signaling will be more successful. However, neither G protein-biased agonists nor beta-arrestin-biased agonists are very effective in assays of pain-depressed behavior, which suggests that novel biased agonists may still not be effective analgesics. This review provides a concise account of the effectiveness of KOR agonists in preclinical models of pain-stimulated and pain-depressed behaviors following the administration of different pain stimuli. Based on the previous results, it may be appropriate to include both behaviors when testing the analgesic potential of KOR agonists.

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Biosensors Monitor Ligand-Selective Effects at Kappa Opioid Receptors.

The kappa opioid receptor (KOR) has emerged as a promising therapeutic target for pain and itch treatment. There is growing interest in biased agonists that preferentially activate select signaling pathways downstream of KOR activation on the cellular level due to their therapeutic promise in retaining the analgesic and antipruritic effects and eliminating the sedative and dysphoric effects of KOR signaling on the physiological level. The concept of ligand-selective signaling includes that biased ligands promote KOR to selectively recruit one transducer or regulator protein over another, introducing bias into the signaling cascade at the very receptor-proximal level. Measuring agonist effects directly at the receptor has remained challenging and previous studies have focused on inferring agonist-selective KOR engagement with G protein relative to β-arrestin based on downstream signaling readouts. Here we discuss novel strategies to directly assess ligand-selective effects on receptor activation using KOR-interacting biosensors. The conformation-specific cytoplasmic biosensors are disconnected from the endogenous signaling machinery and provide a direct receptor-proxy readout of ligand effects in living cells. Receptor-biosensor interaction is ligand concentration dependent and can be used to determine relative ligand potency and efficacy. In addition, the biosensors reveal the existence of two dimensions of agonist bias in the cellular context: Firstly, agonists can selectively produce discrete protein-engaged KOR states and secondly, agonists can differ in the precise subcellular location at which they activate KOR. We discuss the value and the limitations of using orthogonal receptor-interacting biosensors in the quest to understand functional selectivity amongst KOR agonists in the cellular context.

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Glycosylation of Ca3.2 Channels Contributes to the Hyperalgesia in Peripheral Neuropathy of Type 1 Diabetes.

Our previous studies implicated glycosylation of the Ca3.2 isoform of T-type Ca channels (T-channels) in the development of Type 2 painful peripheral diabetic neuropathy (PDN). Here we investigated biophysical mechanisms underlying the modulation of recombinant Ca3.2 channel by de-glycosylation enzymes such as neuraminidase (NEU) and PNGase-F (PNG), as well as their behavioral and biochemical effects in painful PDN Type 1. In our study we used whole-cell recordings of current-voltage relationships to confirm that Ca3.2 current densities were decreased ~2-fold after de-glycosylation. Furthermore, de-glycosylation induced a significant depolarizing shift in the steady-state relationships for activation and inactivation while producing little effects on the kinetics of current deactivation and recovery from inactivation. PDN was induced by injections of streptozotocin (STZ) in adult female C57Bl/6j wild type (WT) mice, adult female Sprague Dawley rats and Ca3.2 knock-out (KO mice). Either NEU or vehicle (saline) were locally injected into the right hind paws or intrathecally. We found that injections of NEU, but not vehicle, completely reversed thermal and mechanical hyperalgesia in diabetic WT rats and mice. In contrast, NEU did not alter baseline thermal and mechanical sensitivity in the Ca3.2 KO mice which also failed to develop painful PDN. Finally, we used biochemical methods with gel-shift analysis to directly demonstrate that N-terminal fragments of native Ca3.2 channels in the dorsal root ganglia (DRG) are glycosylated in both healthy and diabetic animals. Our results demonstrate that in sensory neurons glycosylation-induced alterations in Ca3.2 channels directly enhance diabetic hyperalgesia, and that glycosylation inhibitors can be used to ameliorate painful symptoms in Type 1 diabetes. We expect that our studies may lead to a better understanding of the molecular mechanisms underlying painful PDN in an effort to facilitate the discovery of novel treatments for this intractable disease.

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Association between response to triptans and response to erenumab: real-life data.

Triptans and erenumab are both migraine-specific agents acting on the calcitonin gene-related peptide pathway. Therefore, response to triptans might be associated with response to erenumab.

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The Relationship between Stressors and Pain-Related Clinical Outcomes in Pediatric Chronic Pain Patients.

Youth with chronic pain and youth who have experienced stressors are at risk for poor outcomes; however, little is known about the intersection of pain and stressors. This study aims to understand the prevalence of stressors among youth with chronic pain and the relationship between stressors and pain-related outcomes. Seven hundred and seventy youth with chronic pain aged 8-18 (M = 14.15 years, 70% female) reported pain characteristics, stressors, anxiety, disability, and quality of life. Most participants (82%) endorsed at least one stressor. A greater number of stressors was significantly related to greater anxiety and disability, and lower levels of quality of life. School stressors were significantly associated with functional disability; family, school, and peer stressors were significantly associated with anxiety and quality of life. Stressors are common in youth with chronic pain, and the presence of stressors is related to greater functional impairment. The results of this preliminary study using semi-structured clinical interviews suggest the importance of developing a validated measure that encompasses a wide variety of stressors for youth with pain. Future research on patient-reported stressors, relative intensity, and impact are needed.

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Pain Severity and Interference in Different Parkinson’s Disease Cognitive Phenotypes.

Chronic pain is prevalent in idiopathic Parkinson's disease (PD) with many individuals also experiencing cognitive deficits negatively impacting everyday life.

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Coenzyme Q10 supplementation for prophylaxis in adult patients with migraine-a meta-analysis.

To determine the effects of coenzyme Q10 (CoQ10) for reduction in the severity, frequency of migraine attacks and duration of headache in adult patients with migraine.

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Suicidal risk and resilience in juvenile fibromyalgia syndrome: a cross-sectional cohort study.

To characterize suicidality among youth with juvenile fibromyalgia syndrome (JFMS) receiving treatment from pediatric rheumatologists at a tertiary care center in order to determine the prevalence of suicidality in JFMS and to explore risk factors for persistent suicidal ideation.

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Relationships Between Pain, Life Stress, Sociodemographics, and Cortisol: Contributions of Pain Intensity and Financial Satisfaction.

The relationship between psychosocial stress and chronic pain is bidirectional. An improved understanding regarding the relationships among chronic pain, life stress, and ethnicity/race will inform identification of factors contributing to health disparities in chronic pain and improve health outcomes. This study aims to assess relationships between measures of clinical pain, life stress, sociodemographics, and salivary cortisol levels.

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Serum lipid abnormalities in migraine: A meta-analysis of observational studies.

The association of migraine with vascular comorbidities is long-established. The contribution of the "traditional" cardiovascular risk factors to this connection remains unclear.

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Temporomandibular disorders in patients with early rheumatoid arthritis and at-risk individuals in the Dutch population: a cross-sectional study.

To evaluate the prevalence of temporomandibular disorders (TMD) in patients with early rheumatoid arthritis (ERA) and individuals at-risk of RA.

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Invited Editorial, Pain Phenotypes in Chronic Pancreatitis: Beginning to Fine-tune our Approach to Treatment.

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Interleukin-10 Reduces Neurogenic Inflammation and Pain Behavior in a Mouse Model of Type 2 Diabetes.

Neurogenic inflammation is a major component of chronic neuropathic pain. Previously, we established the db/db mouse as an animal model of painful diabetic neuropathy (PDN) of type 2 diabetes. In the current study, we investigate the roles of interleukin (IL)-10, an anti-inflammatory cytokine, in the development of neurogenic inflammation and pain behavior in db/db mouse.

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Electrical stimulation of the posterior insula induces mechanical analgesia in a rodent model of neuropathic pain by modulating GABAergic signaling and activity in the pain circuitry.

The insula has emerged as a critical target for electrical stimulation since it influences pathological pain states. We investigated the effects of repetitive electrical stimulation of the insular cortex (ESI) on mechanical nociception, and general locomotor activity in rats subjected to chronic constriction injury (CCI) of the sciatic nerve. We also studied neuroplastic changes in central pain areas and the involvement of GABAergic signaling on ESI effects. CCI rats had electrodes implanted in the left agranular posterior insular cortex (pIC), and mechanical sensitivity was evaluated before and after one or five daily consecutive ESIs (15 min each, 60 Hz, 210 μs, 1 V). Five ESIs (repetitive ESI) induced sustained mechanical antinociception from the first to the last behavioral assessment without interfering with locomotor activity. A marked increase in Fos immunoreactivity in pIC and a decrease in the anterior and mid-cingulate cortex, periaqueductal gray and hippocampus were noticed after five ESIs. The intrathecal administration of the GABA receptor antagonist bicuculline methiodide reversed the stimulation-induced antinociception after five ESIs. ESI increased GAD65 levels in pIC but did not interfere with GABA, glutamate or glycine levels. No changes in GFAP immunoreactivity were found in this work. Altogether, the results indicate the efficacy of repetitive ESI for the treatment of experimental neuropathic pain and suggest a potential influence of pIC in regulating pain pathways partially through modulating GABAergic signaling.

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Predicting the Physical and Mental Health Status of Individuals with Chronic Musculoskeletal Pain from a Biopsychosocial Perspective: A Multivariate Approach.

Chronic pain is theoretically conceptualized from a biopsychosocial perspective. However, research into chronic pain still tends to focus on isolated, biological, psychological, or social variables. Simultaneous examination of these variables in the prediction of outcomes is important because communalities between predictors exist. Examination of unique contributions might help guide research and interventions in a more effective way.

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Patterns of Approach to Activity in 851 Patients with Severe Chronic Pain: Translation and Preliminary Validation of the 9-item Avoidance-Endurance Fast-Screen (AEFS) into Danish.

The Avoidance-Endurance Fast-Screen (AEFS) is a 9-item self-report questionnaire that classifies patients with back pain into four activity-related subgroups, based on the avoidance-endurance model (AEM) of pain. The objective of this study was to translate the AEFS into Danish and investigate its discriminative abilities in a large, diverse patient sample.

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Mast Cell-Specific MRGPRX2: a Key Modulator of Neuro-Immune Interaction in Allergic Diseases.

Atopic dermatitis (AD) and allergic asthma are complex disorders with significant public health burden. This review provides an overview of the recent developments on Mas-related G protein-coupled receptor-X2 (MRGPRX2; mouse counterpart MrgprB2) as a potential candidate to target neuro-immune interaction in AD and allergic asthma.

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Associations between frequent pain or headaches and neurobehavioral symptoms by gender and TBI severity.

: To investigate differences in frequent pain or headaches and associated neurobehavioral symptoms among men, women, and transgender individuals with and without a history of traumatic brain injury (TBI). : Community : English and Spanish-speaking adults (n = 2,862) with and without self-reported TBI : Cross-sectional study : Behavioral Assessment Screening Tool (BAST) subscales for Negative Affect, Substance Abuse, Executive Function, Fatigue, Impulsivity, and one item for experiencing "frequent pain or headache." : Women reported more pain than men. Women with a mild TBI (mTBI) more often reported frequent headaches/pain than woman in general or those with mTBI alone. Women reporting frequent headache/pain reported more negative affect and fatigue than men with comparable TBI history. Individuals identifying as transgender/other without TBI had higher negative affect and fatigue than both men and women without TBI. Individuals with mTBI and frequent headache/pain reported more executive function problems than those with mTBI without headache/pain. Pain and moderate/severe TBI were associated with more executive function problems in men and women, but more so for women. : Results suggest frequent headache/pain may differ between genders, particularly after mTBI. Pain, fatigue, executive function, and negative affect may be especially important in women's recovery from TBI.

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A long-term open-label safety study of galcanezumab in Japanese patients with migraine.

Because of the burden of migraine in Japan, there is a need for safe and effective preventive treatments. This study assessed the long-term safety and tolerability of galcanezumab in Japanese patients with episodic (EM) or chronic (CM) migraine.

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Synergistic interaction between trazodone and gabapentin in rodent models of neuropathic pain.

Neuropathic pain is a chronic debilitating condition caused by injury or disease of the nerves of the somatosensory system. Although several therapeutic approaches are recommended, none has emerged as an optimal treatment leaving a need for developing more effective therapies. Given the small number of approved drugs and their limited clinical efficacy, combining drugs with different mechanisms of action is frequently used to yield greater efficacy. We demonstrate that the combination of trazodone, a multifunctional drug for the treatment of major depressive disorders, and gabapentin, a GABA analogue approved for neuropathic pain relief, results in a synergistic antinociceptive effect in the mice writhing test. To explore the potential relevance of this finding in chronic neuropathic pain, pharmacodynamic interactions between low doses of trazodone (0.3 mg/kg) and gabapentin (3 mg/kg) were evaluated in the chronic constriction injury (CCI) rat model, measuring the effects of the two drugs both on evoked and spontaneous nociception and on general well being components. Two innate behaviors, burrowing and nest building, were used to assess these aspects. Besides exerting a significant antinociceptive effect on hyperalgesia and on spontaneous pain, combined inactive doses of trazodone and gabapentin restored in CCI rats innate behaviors that are strongly reduced or even abolished during persistent nociception, suggesting that the combination may have an impact also on pain components different from somatosensory perception. Our results support the development of a trazodone and gabapentin low doses combination product for optimal multimodal analgesia treatment.

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Hyperconnection and hyperperfusion of overlapping brain regions in patients with menstrual-related migraine: a multimodal neuroimaging study.

Menstrual-related migraine (MRM) results in moderate to severe intensity headaches accompanied by physical and emotional disability over time in women. Neuroimaging methodologies have advanced our understanding of migraine; however, the neural mechanisms of MRM are not clearly understood.

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Spinal mechanisms contributing to the development of pain hypersensitivity induced by sphingolipids in the rat.

Earlier studies show that endogenous sphingolipids can induce pain hypersensitivity, activation of spinal astrocytes, release of proinflammatory cytokines and activation of TRPM3 channel. Here we studied whether the development of pain hypersensitivity induced by sphingolipids in the spinal cord can be prevented by pharmacological inhibition of potential downstream mechanisms that we hypothesized to include TRPM3, σ and NMDA receptors, gap junctions and D-amino acid oxidase.

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Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy.

Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes which have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol-O-methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1 and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone and methadone and for OPRM1 and COMT for clinical use.

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Effects of α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator on BDNF, NKCC1 and KCC2 Expression in the Hippocampus following Lipopolysaccharide-induced Allodynia and Hyperalgesia in a Mouse Model of Inflammatory Pain.

Hyperalgesia and allodynia are frequent symptoms of inflammatory pain. Neuronal excitability induced by brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) cascade has a role in the modulation of inflammatory pain. The effects of 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline8-sulfonamide (TQS), an α7 nicotinic acetylcholine receptor positive allosteric modulator (nAChR PAM), on hippocampal BDNF, cation-chloride cotransporters, NKCC1 and KCC2, expression in inflammatory pain are not known. The objective of the study was to determine the effects of TQS on BDNF, NKCC1, and KCC2 expression in the hippocampus following lipopolysaccharide (LPS)-induced allodynia and hyperalgesia in a mouse model of inflammatory pain.

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Association of symptom severity, pain and other behavioral and medical comorbidities with diverse measures of functioning among adults with post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is an often disabling mental disorder whose management typically focuses on reducing PTSD symptoms. Chronic pain and other comorbidities that commonly accompany PTSD symptoms may also be independently associated with disability. Using data from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions, we examined the independent association of PTSD symptom severity, pain interference, non-PTSD psychiatric and substance use disorders (SUD), and medical illnesses with each of four domains of function: mental health-related quality of life and physical functioning assessed with the Mental Health Composite Score (MCS) and Physical Function Score (PFS) of the Short Form-12; perceived social support from the Interpersonal Support and Evaluation List-12 (ISEL-12); and self-reported past year employment. Among 1779 individuals representing 11 million U.S. adults who met the Diagnostic and Statistical Manual-5 (DSM-5) criteria for Past Year PTSD, the MCS (41.2; SD 12.5), PFS (44.8; SD 13.2) and ISEL-12 (33.6; SD 7.2) indicated substantial disability when compared to population norms, and only 63.6% were employed. Multiple regression showed the MCS had a modest negative association with PTSD symptoms, pain interference, psychiatric multimorbidity and medical comorbidity although not with SUD. PFS and employment had significant negative associations with pain interference and medical comorbidity. ISEL-12 had a weak negative association with PTSD symptoms and non-PTSD psychiatric comorbidity. Common comorbidities thus significantly influence disability associated with PTSD, often more strongly than PTSD symptoms. PTSD treatment may require integrative multimorbidity management beyond a focus on PTSD symptoms.

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Green Flags and headache: A concept study using the Delphi method.

The aim of this study was to collect and rate Green Flags, that is, symptoms or pieces of information indicating that a patient is more likely to suffer from a primary than from a secondary headache.

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Number of Chronic Nighttime Insomnia Symptoms and Risk of Chronic Widespread Pain and Pain-Related Disability: The HUNT Study.

To examine the association between the number of chronic nighttime insomnia symptoms and the risk of chronic widespread pain (CWP) and pain-related disability.

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Change in Pain Status and Subsequent Opioid and Marijuana Use Among Long-Term Adult Survivors of Childhood Cancer.

We evaluated pain status change and associations with subsequent opioid/marijuana use among 1208 adult survivors of childhood cancer. Pain status and opioid/marijuana were self-reported at baseline and follow-up evaluation (mean interval = 4.2 years). Over time, 18.7% of survivors endorsed persistent/increasing significant pain; 4.8% and 9.0% reported having used opioids and marijuana at follow-up. Persistent/increased (vs none/decreased) pain, persistent/increased (vs none/decreased) anxiety, and lack of health insurance increased odds of subsequent opioid use by 7.69-fold (95% confidence interval [CI] = 3.71 to 15.95), 2.55-fold (95% CI = 1.04 to 6.24), and 2.50-fold (95% CI = 1.07 to 5.82), respectively. Persistent/increased (vs none/decreased) depression increased odds of subsequent marijuana use by 2.64-fold (95% CI = 1.10 to 6.33).

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MINDflex Training for Cognitive Flexibility in Chronic Pain: A Randomized, Controlled Cross-Over Trial.

Impairments in executive functioning are prevalent in chronic pain conditions, with cognitive inflexibility being the most frequently reported. The current randomized, cross-over trial, piloted a computerized cognitive training (CCT) program based on Relational Frame Theory, targeting improvement in cognitive flexibility. At baseline, 73 chronic pain patients completed testing on pre-selected outcomes of executive functioning, alongside IQ measures. When tested three times over the course of 5 months, there was a drop-out rate of 40% at the third time point, leaving 44 patients who had data at all time points. The results showed that there was a substantial learning effect from the MINDFLEX training and a substantial time-dependent improvement on the primary outcomes of increased flexibility, but that this could not be tied to active training. In conclusion, this small study indicated a learning effect as well as improvement on primary outcomes. Based on the current results, a larger trial with improved feasibility of training is warranted.

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P2X7R-mediated autophagic impairment contributes to central sensitization in a chronic migraine model with recurrent nitroglycerin stimulation in mice.

Central sensitization is an important pathophysiological mechanism of chronic migraine (CM). According to our previous studies, microglial activation and subsequent inflammation in the trigeminal nucleus caudalis (TNC) contribute to the central sensitization. The P2X7 receptor (P2X7R) is a purinergic receptor expressed in microglia and participates in central sensitization in chronic pain, but its role in CM is unclear. Numerous studies have shown that P2X7R regulates the level of autophagy and that autophagy affects the microglial activation and inflammation. Recently, autophagy has been shown to be involved in neuropathic pain, but there is no information about autophagy in CM. Therefore, the current study investigated the role of P2X7R in CM and its underlying mechanism, focusing on autophagy regulation.

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7β-(3-Ethyl–crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro- Notonipetranone Attenuates Neuropathic Pain by Suppressing Oxidative Stress, Inflammatory and Pro-Apoptotic Protein Expressions.

7β-(3-Ethyl–crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro–notonipetranone (ECN), a sesquiterpenoid obtained from a natural source has proved to be effective in minimizing various side effects associated with opioids and nonsteroidal anti-inflammatory drugs. The current study focused on investigating the effects of ECN on neuropathic pain induced by partial sciatic nerve ligation (PSNL) by mainly focusing on oxidative stress, inflammatory and apoptotic proteins expression in mice. ECN (1 and 10 mg/kg, i.p.), was administered once daily for 11 days, starting from the third day after surgery. ECN post-treatment was found to reduce hyperalgesia and allodynia in a dose-dependent manner. ECN remarkably reversed the histopathological abnormalities associated with oxidative stress, apoptosis and inflammation. Furthermore, ECN prevented the suppression of antioxidants (glutathione, glutathione-S-transferase, catalase, superoxide dismutase, NF-E2-related factor-2 (Nrf2), hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase) by PSNL. Moreover, pro-inflammatory cytokines (tumor necrotic factor-alpha, interleukin 1 beta, interleukin 6, cyclooxygenase-2 and inducible nitric oxide synthase) expression was reduced by ECN administration. Treatment with ECN was successful in reducing the caspase-3 level consistent with the observed modulation of pro-apoptotic proteins. Additionally, ECN showed a protective effect on the lipid content of myelin sheath as evident from FTIR spectroscopy which showed the shift of lipid component bands to higher values. Thus, the anti-neuropathic potential of ECN might be due to the inhibition of oxidative stress, inflammatory mediators and pro-apoptotic proteins.

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Novel curcumin analog (Cis-Trans Curcumin) as ligand to adenosine receptors A and A: potential for therapeutics.

All four of the adenosine receptor (AR) subtypes mediate pain and have been targeted by pharmacologists to generate new therapeutics for chronic pain. The vanilloid phytochemicals, which include curcumin, capsaicin, and gingerol, have been shown to alleviate pain. However, there is little to no literature on the interaction of vanilloid phytochemicals with ARs. In this study, photochemical methods were used to generate a novel isomer of curcumin (cis-trans curcumin or CTCUR), and the interactions of both curcumin and CTCUR with the two G-linked AR subtypes were studied. Competitive binding assays, docking analysis, and confocal fluorescence microscopy were performed to measure binding affinity; cell survival assays were used to measure toxicity; and cAMP assays were performed to measure receptor activation. Competitive binding results indicated that CTCUR binds to both AR A and AR A with K values of 5 µM and 7 µM, respectively, which is consistent with our docking results. Fluorescence microscopy data also shows binding for A and A. Cell survival results show that CTCUR and CUR are nontoxic at the tested concentrations in these cell lines. Overall, our results suggest that vanilloid phytochemicals may be slightly modified to increase interaction with G-ARs, and thereby can be further explored to provide a novel class of non-opioid antinociceptives.

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Sphenopalatine Ganglion Nerve Block for the Treatment of Migraine Headaches in the Pediatric Population.

Persistent headaches and migraines are common in pediatrics with various treatment options. The sphenopalatine ganglion (SPG) has been identified as communicating with the parasympathetic autonomic nervous system and pain receptors. In adults, SPG block is an established treatment but there is no published literature in pediatrics.

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Efficacy and Safety of Opioid Analgesics for the Management of Chronic Low Back Pain: An Evidence from Bayesian Network Meta-Analysis.

Chronic low back pain (CLBP) incurs huge costs owing to increased healthcare expenditure, disability, insurance, and work absenteeism. Opioid analgesics are commonly used for the management of CLBP.

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Mind-Body Interventions for Depressive Symptoms in Chronic Pain: A Systematic Review of Meta-Analyses.

Psychological comorbidities in chronic pain (CP) are common and contribute to adverse health outcomes and poor quality of life. Evidence-based guidance for the management of depressive symptoms in CP is limited, particularly for mind-body interventions.

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Is Epidural Injection of Sodium Chloride Solution a True Placebo or an Active Control Agent? A Systematic Review and Meta-Analysis.

Epidural injections have been extensively used since their description in 1901, and steroids since their first utilization in 1952. Multiple randomized controlled trials and systematic reviews have reached discordant conclusions regarding the effectiveness of sodium chloride solution and steroids in managing spinal pain. True placebo-controlled trials with the injection of an inactive substance to unrelated structures have been nonexistent. Consequently, the discussions continue to escalate, seemingly without proper discourse. In this review, we sought to assess the true placebo nature of saline and the effectiveness of steroids.

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Patterns of Long-Term Prescription Opioid Use Among Older Adults in the United States: A Study of Medicare Administrative Claims Data.

Long-term opioid therapy was prescribed with increasing frequency over the past decade. However, factors surrounding long-term use of opioids in older adults remains poorly understood, probably because older people are not at the center stage of the national opioid crisis.

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Declining Utilization and Inflation-Adjusted Expenditures for Epidural Procedures in Chronic Spinal Pain in the Medicare Population.

Despite epidurals being one of the most common interventional pain procedures for managing chronic spinal pain in the United States, expenditure analysis lacks assessment in correlation with utilization patterns.

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Impaired pain processing and its association with attention disturbance in patients with amyotrophic lateral sclerosis.

Cognitive dysfunction characterized by executive dysfunction and persistent attention function has been reported in patients with amyotrophic lateral sclerosis (ALS); however, it is unclear if this contributes to the pain processing deficits associated with the disease.

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Analysis of NOS Gene Polymorphisms in Relation to Cluster Headache and Predisposing Factors in Sweden.

Cluster headache is characterized by activation of the autonomic-trigeminal reflex. Nitric oxide can trigger headaches in patients, and nitric oxide signaling is known to be affected in cluster headache. Based on the hypothesis of nitric oxide being involved in cluster headache pathophysiology we investigated nitric oxide synthases as potential candidate genes for cluster headache. We analyzed eight variants in the three forms of nitric oxide synthase () genes, inducible (), endothelial () and neuronal (), and tested for association with cluster headache. Swedish cluster headache patients ( = 542) and controls ( = 581) were genotyped using TaqMan assays on an Applied Biosystems 7500 qPCR cycler. This is the largest performed genetic study on involvement in cluster headache so far. We found an association between cluster headache and one haplotype consisting of the minor alleles of rs2297518 and rs2779249 ( = 0.022). In addition, one of the analyzed variants, rs2682826, was associated with reported triptan use ( = 0.039). Our data suggest that genetic variants in genes do not have a strong influence on cluster headache pathophysiology, but that certain combinations of genetic variants in genes may influence the risk of developing the disorder or triptan use.

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Electroacupuncture effects on the P2X4R pathway in microglia regulating the excitability of neurons in the substantia gelatinosa region of rats with spinal nerve ligation.

Electroacupuncture (EA) has been used to treat neuropathic pain induced by peripheral nerve injury (PNI) by applying an electrical current to acupoints with acupuncture needles. However, the mechanisms by which EA treats pain remain indistinct. High P2X4 receptor (P2X4R) expression levels demonstrate a notable increase in hyperactive microglia in the ipsilateral spinal dorsal horn following PNI. In order to demonstrate the possibility that EA analgesia is mediated in part by P2X4R in hyperactive microglia, the present study performed mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests in male Sprague‑Dawley rats that had undergone spinal nerve ligation (SNL). The expression levels of spinal P2X4R were determined using reverse transcription‑quantitative PCR, western blotting analysis and immunofluorescence staining. Furthermore, spontaneous excitatory postsynaptic currents (sEPSCs) were recorded using whole‑cell patch clamp to demonstrate the effect of EA on synaptic transmission in rat spinal substantia gelatinosa (SG) neurons. The results of the present study demonstrated that EA increased the MWT and TWL and decreased overexpression of P2X4R in hyperactive microglia in SNL rats. Moreover, EA attenuated the frequency of sEPSCs in SG neurons in SNL rats. The results of the present study indicate that EA may mediate P2X4R in hyperactive spinal microglia to inhibit nociceptive transmission of SG neurons, thus relieving pain in SNL rats.

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Common health conditions in childhood and adolescence, school absence, and educational attainment: Mendelian randomization study.

Good health is positively related to children's educational outcomes, but relationships may not be causal. Demonstrating a causal influence would strongly support childhood and adolescent health as important for education policy. We applied genetic causal inference methods to assess the causal relationship of common health conditions at age 10 (primary/elementary school) and 13 (mid-secondary/mid-high school) with educational attainment at 16 and school absence at 14-16. Participants were 6113 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Exposures were symptoms of attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, asthma, migraines and BMI. Genetic liability for these conditions and BMI was indexed by polygenic scores. In non-genetic, multivariate-adjusted models, all health conditions except asthma and migraines were associated with poorer attainment and greater school absence. School absence substantially mediated effects of BMI (39.9% for BMI at 13) and migraines (72.0% at 10), on attainment with more modest mediation for emotional and neurodevelopmental conditions. In genetic models, a unit increase in standardized BMI at 10 predicted a 0.19 S.D. decrease (95% CI: 0.11, 0.28) in attainment at 16, equivalent to around a 1/3 grade lower in all subjects, and 8.7% more school absence (95% CI:1.8%,16.1%). Associations were similar at 13. Genetic liability for ADHD predicted lower attainment but not more absence. Triangulation across multiple approaches supports a causal, negative influence on educational outcomes of BMI and ADHD, but not of ASD, depression, asthma or migraine. Higher BMI in childhood and adolescence may causally impair educational outcomes.

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Gabapentin and Duloxetine Prevent Oxaliplatin- and Paclitaxel-Induced Peripheral Neuropathy by Inhibiting Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Phosphorylation in Spinal Cords of Mice.

Chemotherapy-induced peripheral neuropathy is a common factor in limiting therapy which can result in therapy cessation or dose reduction. Gabapentin, a calcium channel inhibitor, and duloxetine, a serotonin noradrenaline reuptake inhibitor, are used to treat a variety of pain conditions such as chronic low back pain, postherpetic neuralgia, and diabetic neuropathy. It has been reported that administration of gabapentin suppressed oxaliplatin- and paclitaxel-induced mechanical hyperalgesia in rats. Moreover, duloxetine has been shown to suppress oxaliplatin-induced cold allodynia in rats. However, the mechanisms by which these drugs prevent oxaliplatin- and paclitaxel-induced neuropathy remain unknown. Behavioral assays were performed using cold plate and the von Frey test. The expression levels of proteins were examined using western blot analysis. In this study, we investigated the mechanisms by which gabapentin and duloxetine prevent oxaliplatin- and paclitaxel-induced neuropathy in mice. We found that gabapentin and duloxetine prevented the development of oxaliplatin- and paclitaxel-induced cold and mechanical allodynia. In addition, our results revealed that gabapentin and duloxetine suppressed extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation in the spinal cord of mice. Moreover, PD0325901 prevented the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 activation in the spinal cord of mice. In summary, our findings suggest that gabapentin, duloxetine, and PD0325901 prevent the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 phosphorylation in mice. Therefore, inhibiting ERK1/2 phosphorylation could be an effective preventive strategy against oxaliplatin- and paclitaxel-induced neuropathy.

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Multi-channel hierarchy functional integration analysis between large-scale brain networks for migraine: An fMRI study.

Migraine is a chronic dysfunction characterized by recurrent pain, but its pathogenesis is still unclear. As a result, more and more methods have been focused on the study of migraine in recent years, including functional magnetic resonance imaging (fMRI), which is a mainstream technique for exploring the neural mechanisms of migraine. In this paper, we systematically investigated the fMRI functional connectivities (FCs) between large-scale brain networks in migraine patients from the perspective of multi-channel hierarchy, including static and dynamic FCs of group and individual levels, where the brain networks were obtained using group independent component analysis. Meanwhile, the corresponding topology properties of static and dynamic FCs networks in migraine patients were statistically compared with those in healthy controls. Furthermore, a graph metrics based method was used to detect the potential brain functional connectivity states in dynamic FCs at individual and group levels, and the corresponding topology properties and specificity of these brain functional connectivity states in migraine patients were explored compared with these in healthy controls. The results showed that the dynamic FCs and corresponding global topology properties among nine large-scale brain networks involved in this study have significant differences between migraine patients and healthy controls, while local topological properties and dynamic fluctuations were easily affected by window-widths. Moreover, the implicit dynamic functional connectivity patterns in migraine patients presented specificity and consistency under different window-widths, which suggested that the dynamic changes in FCs and topology structure between them played a key role in the brain functional activity of migraine. Therefore, it may be provided a new perspective for the clinical diagnosis of migraine.

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Recommended core outcome instruments for health-related quality of life, long-term control and itch intensity in atopic eczema trials: results of the HOME VII consensus meeting.

The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of domains for atopic eczema (AE) clinical trials. Previous consensus meetings have agreed on preferred instruments for clinician-reported signs (Eczema Area and Severity Index, EASI) and patient-reported symptoms (Patient-Oriented Eczema Measure, POEM). This paper reports consensus decisions from the HOME VII meeting.

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Current clinical practice in disabling and chronic migraine in the primary care setting: results from the European My-LIFE anamnesis survey.

Migraine is a prevalent and disabling headache disorder that affects more than 1.04 billion individuals world-wide. It can result in reduction in quality of life, increased disability, and high socio-economic burden. Nevertheless, and despite the availability of evidence-based national and international guidelines, the management of migraine patients often remains suboptimal, especially for chronic migraine (CM) patients.

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Upregulation of silent information regulator 1 alleviates mitochondrial dysfunction in the trigeminal nucleus caudalis in a rat model of chronic migraine.

Although the mechanism of chronic migraine is still unclear, more and more studies have shown that mitochondrial dysfunction plays a possible role in migraine pathophysiology. Silent information regulator 1 (SIRT1) plays a vital role in mitochondrial dysfunction in many diseases. However, there is no research on the role of SIRT1 in mitochondrial dysfunction of chronic migraine. The aim of this study was to explore the role of SIRT1 in mitochondrial dysfunction in chronic migraine. A rat model was established through repeated dural infusions of inflammatory soup for 7 days to simulate chronic migraine attacks. Cutaneous hyperalgesia caused by the repeated infusions of inflammatory soup was detected using the von Frey test. Then, we detected SIRT1 expression in the trigeminal nucleus caudalis. To explore the effect of SIRT1 on mitochondrial dysfunction in chronic migraine rats, we examined whether SRT1720, an activator of SIRT1, altered mitochondrial dysfunction in chronic migraine rats. Repeated infusions of inflammatory soup resulted in cutaneous hyperalgesia accompanied by downregulation of SIRT1. SRT1720 significantly alleviated the cutaneous hyperalgesia induced by repeated infusions of inflammatory soup. Furthermore, activation of SIRT1 markedly increased the expression of peroxisome proliferator-activated receptor gamma-coactivator 1-alpha, transcription factor A, nuclear respiratory factor 1 and nuclear respiratory factor 2 mitochondrial DNA and increased the ATP content and mitochondrial membrane potential. Our results indicate that SIRT1 may have an effect on mitochondrial dysfunction in chronic migraine rats. Activation of SIRT1 has a protective effect on mitochondrial function in chronic migraine rats.

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Inhibition of fibrotic changes in infrapatellar fat pad alleviates persistent pain and articular cartilage degeneration in monoiodoacetic acid-induced rat arthritis model.

We have reported that fibrotic changes in infrapatellar fat pad (IFP) after acute joint inflammation are closely associated with persistent pain in rats. In this study, to examine the effects of anti-fibrotic treatment on persistent pain, we used C-type natriuretic peptides (CNP) at the recovery phase after acute joint inflammation.

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The analgesic effect of intravenous lidocaine versus intrawound or epidural bupivacaine for postoperative opioid reduction in spine surgery: A systematic review and meta-analysis.

Pain management following spine surgery remains a challenge. The significant use of opioids may lead to opioid-related adverse events. These complications can increase perioperative morbidity and rapidly expend health care resources by developing chronic pain. Although intraoperative pain control for surgery has been studied in the literature, a thorough assessment of the effect in spine surgery is rarely reported. The objective of the present study was to examine the outcomes of intraoperative intravenous lidocaine and intrawound or epidural bupivacaine use in spine surgery.

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High-Dose Opioid Use Among Veterans with Unexplained Gastrointestinal Symptoms Versus Structural Gastrointestinal Diagnoses.

In a cohort of Veterans dually enrolled in the Department of Veterans Affairs (VA) and Medicare Part D, we sought to describe high-dose daily opioid use among Veterans with unexplained gastrointestinal (GI) symptoms and structural GI diagnoses and examine factors associated with high-dose use.

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A Fenofibrate Diet Prevents Paclitaxel-Induced Peripheral Neuropathy in Mice.

Paclitaxel-induced peripheral neuropathy (PIPN) is a major adverse effect of this chemotherapeutic agent that is used in the treatment of a number of solid malignancies. PIPN leads notably to burning pain, cold and mechanical allodynia. PIPN is thought to be a consequence of alterations of mitochondrial function, hyperexcitability of neurons, nerve fiber loss, oxidative stress and neuroinflammation in dorsal root ganglia (DRG) and spinal cord (SC). Therefore, reducing neuroinflammation could potentially attenuate neuropathy symptoms. Peroxisome proliferator-activated receptor-α (PPAR-α) nuclear receptors that modulate inflammatory responses can be targeted by non-selective agonists, such as fenofibrate, which is used in the treatment of dyslipidemia.

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Development and Content Validation of Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) in Adolescents and Adults with Moderate-to-Severe AD.

Most patient-reported outcome (PRO) instruments that measure atopic dermatitis (AD) symptoms do not have sufficient documented evidence of content validity to satisfy regulatory agency guidance for inclusion in product-labelling claims in the USA or Europe. The objective of this study was to develop a PRO instrument in accordance with regulatory agency guidance to assess daily AD symptoms during the course of therapy and to establish its content validity and psychometric properties.

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Cannabis Use and Low-Back Pain: A Systematic Review.

The potential use of cannabis and cannabinoid products for the treatment of low-back pain is an important area for investigation. As one of the leading reasons to visit a primary care provider, low-back pain results in a significant burden of disease in both the United States' economic and health care systems. Given the current opioid epidemic, it is important to seek novel analgesics and understand their efficacy for myriad pain conditions, including low-back pain. A systematic review was performed using multiple online databases to assess the association of cannabis use and low-back pain in the literature. A total of 124 articles were produced via our search methods, 73 abstracts in total were screened, 16 articles underwent full-text review, and 6 articles were included in qualitative synthesis. This systematic literature review reveals a lack of primary research investigating cannabis as a potential treatment of low-back pain and highlights the need for further investigation with well-designed clinical trials. There remain substantial political and legal barriers to performing such research. Although there is a considerable body of work on the usage of cannabinoid products for many medical conditions, including the treatment of chronic pain, more directed clinical research into their utility as an analgesic for low-back pain and related symptoms needs to be addressed.

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