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: The aim of the study was to assess the development of widespread non-joint pain (WNP) in a cohort of patients with early rheumatoid arthritis (RA), the associated health-related quality of life (HRQoL), and clinical and demographic risk factors for WNP.: Incident cases with RA, from the Swedish population-based study Epidemiological Investigation of Rheumatoid Arthritis (EIRA), with a follow-up of at least 3 years, constituted the study population. WNP was defined as pain outside the joints in all four body quadrants and was assessed at the 3 year follow-up. Patients who reported WNP were compared to patients without WNP regarding HRQoL, measured by the Short Form-36, at 3 years, and clinical and demographic characteristics at the time of RA diagnosis.: A total of 749 patients constituted the study sample, of whom 25 were excluded after reporting already having severe pain before RA diagnosis. At the 3 year follow-up, 8% of the patients reported having WNP as well as statistically significant worse HRQoL. At the time of RA diagnosis, the patients with WNP had worse pain and pain-related features, while no difference was seen in the inflammatory parameters.: WNP occurs in a substantial subset of patients with RA, also early in the course of the disease, and the HRQoL for these patients is significantly reduced. Patients who develop WNP at 3 years are already distinguishable at the time of diagnosis by displaying more pronounced pain ratings together with an average level of inflammatory disease activity.
Learn More >This systematic review and meta-analysis examined relationships between low back pain (LBP)-related disability and pain beliefs, including pain catastrophizing, pain-related fear, self-efficacy, and back pain beliefs, in non-English-speaking populations. Additionally, the effects of selected cultural factors (i.e., language/geographic area) on the strength of relationships were examined.
Learn More >Evidence suggests that blunted reward responsiveness may account for poor clinical outcomes in both opioid use disorder (OUD) and chronic pain. Understanding how individuals with OUD and comorbid chronic pain (OUD+CP) respond to rewards is, therefore, of clinical interest because it may reveal a potential point of behavioral intervention.
Learn More >VVZ-149 is a small molecule that both inhibits the glycine transporter type 2 and the serotonin receptor 5 hydroxytryptamine 2 A. In a randomized, parallel-group, and double-blind trial (NCT02844725), we investigated the analgesic efficacy and safety of VVZ-149 Injections, which is under clinical development as a single-use injectable product for treating moderate to severe postoperative pain.
Learn More >Peripheral nerve injury induces long-term pro-inflammatory responses in spinal cord glial cells that facilitate neuropathic pain, but the identity of endogenous cells that resolve spinal inflammation has not been determined. Guided by single-cell RNA sequencing (scRNA-seq), we found that MRC1 spinal cord macrophages proliferated and upregulated the anti-inflammatory mediator Cd163 in mice following superficial injury (SI; nerve intact), but this response was blunted in nerve-injured animals. Depleting spinal macrophages in SI animals promoted microgliosis and caused mechanical hypersensitivity to persist. Conversely, expressing Cd163 in spinal macrophages increased Interleukin 10 expression, attenuated micro- and astrogliosis, and enduringly alleviated mechanical and thermal hypersensitivity in nerve-injured animals. Our data indicate that MRC1 spinal macrophages actively restrain glia to limit neuroinflammation and resolve mechanical pain following a superficial injury. Moreover, we show that spinal macrophages from nerve-injured animals mount a dampened anti-inflammatory response but can be therapeutically coaxed to promote long-lasting recovery of neuropathic pain.
Learn More >The mechanism underlying the high incidence of remifentanil-induced postoperative hyperalgesia is unclear. Also, no effective prevention method exists. Inflammatory pain-related studies showed that P2 × 4 purinergic receptors (P2X4Rs) in the dorsal horn of the spinal cord and dorsal root ganglia are essential for maintaining allodynia caused by inflammation. However, little is known about its role in opioid-induced hyperalgesia. This study aimed to determine the role of P2X4R and related signaling pathways in the remifentanil-induced postoperative hyperalgesia (RIH) model. The study simulated the remifentanil infusion and surgical incision during general anesthesia. The mRNA and protein expression level of P2X4R in rats with RIH model increased from 2 h to 48 h after the surgery. The administration of P2X4R inhibitors prevented the occurrence of RIH, resulting in a reduction in mechanical and thermal pain. Moreover, P2X4R was involved in RIH in male and female rats, indicating no sex-specific difference. P2X4R also increased the expression of AMPA receptor subunit GluA1 in a brain-derived neurotrophic factor (BDNF) / tyrosine receptor kinase B (TrkB) dependent manner. The results from whole-cell patch-clamp recording suggested that P2X4R also regulated AMPA receptor-mediated miniature excitatory postsynaptic currents and participated in the synaptic plasticity of spinal dorsal horn neurons. In summary, P2X4R was involved in AMPAR expression, electrophysiological function, and synaptic plasticity of spinal dorsal horn neurons through BDNF/TrkB signaling. This might be the mechanism underlying RIH, and hence inhibition of P2X4R might be a potential treatment strategy.
Learn More >Migraine, the third most common disease worldwide, is a well-known independent risk factor for subclinical focal deep white matter lesions (WML), even in young and otherwise individuals without cardiovascular risk factors. These white matter lesions are more commonly seen in migraine patients with transient neurological symptoms preceding their headaches, the so-called aura, and those with a high attack frequency. Despite their prevalence, the pathophysiology of migraine-related deep white matter hyperintensities remains poorly understood. Characteristic differences in their distribution when compared to common periventricular white matter lesions in the elderly that are related to chronic small vessel ischemic disease suggest a different underlying mechanism. Both ischemic and inflammatory mechanisms have been proposed, as there is increased cerebral vulnerability to ischemia in migraineurs, while there is also evidence for blood-brain-barrier disruption with associated release of pro-inflammatory substances during migraine attacks. An enhanced susceptibility to spreading depolarization, the electrophysiologic event underlying migraine, may be the underlying mechanism to cause repetitive episodes of cerebral hypoperfusion and neuroinflammation during migraine attacks. WML can negatively affect both physical and cognitive function, underscoring the public-health importance of migraine and suggesting that migraine is an important contributor to neurological deficits in the general population.
Learn More >The cytokine interleukin-31 has been implicated in the pathophysiology of multiple atopic disorderssuch asatopic dermatitis (AD), allergic rhinitisand airway hyperreactivity. In AD, IL-31 has been identified as one of the main 'drivers'of its cardinal symptom,pruritus. Here, we summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. T 2 cells play a central role in AD and release high levels ofT 2-associated cytokines including IL-31,thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch and neuronal outgrowth through activation ofthe heterodimeric receptor IL-31 receptor alpha (IL31RA)/Oncostatin M receptor (OSMRβ). IL31RA expression is found onhumanand murine dorsal root ganglia neurons, epithelial cells including keratinocytes as well asvarious innate immune cells. IL-31 is a critical cytokine involved in neuro-immune communication,which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31-downstream signalingmay be a beneficial approach for various inflammatory diseases including prurigo.However, as to whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory and pruritic disorders in the future.
Learn More >Symptomatic knee osteoarthritis (SKOA) is a chronic, disabling condition, requiring long-term pain management; over 800,000 SKOA patients in the USA use opioids chronically. We aim to characterize the societal economic burden of opioid use in this population.
Learn More >The clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed the key role of this axis in migraine pathogenesis. Three antibodies against CGRP – fremanezumab, galcanezumab and eptinezumab – and one antibody against the CGRP receptor, erenumab, are clinically approved therapeutics for the prevention of migraine. In addition, two small molecule CGRP receptor antagonists, ubrogepant and rimegepant, are approved for acute migraine treatment. Targeting either the CGRP ligand or receptor is efficacious for migraine treatment; however, a comparison of the mechanism of action of these therapeutic agents is lacking in the literature.
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