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: Cost utility analysis is increasingly used by decision makers in patient management with chronic disease. Generic preference-based measures are used to evaluate disability and health-related quality of life (HRQoL).: To evaluate if Short Form Six Dimensions (SF-6Dv2) is correlated with specific current questionnaires used in chronic low back pain (CLBP) and if a predictive equation of SF-6Dv2 could be established.: Between October 2018 and January 2019, an online survey on CLBP was conducted. HRQoL was measured with two specific questionnaires, i.e. Oswestry Disability Index (ODI) and Roland-Morris Disability Questionnaire (RMDQ), and with the new version of the SF-6Dv2 as a generic preference-based measure.: 402 subjects completed at least two of the three HRQoL questionnaires. Mean (95% confidence interval) of SF-6Dv2, ODI or RMDQ were respectively 0.561 (0.553-0.569), 43.7 (42.1-45.2) and 10.3 (9.8-10.8). SF-6Dv2 was moderately correlated with ODI and RMDQ (r=-0.635 and r=-0.542, p<0.001). The best model to predict SF-6Dv2 explained 50.6% of variability and included ODI. The correlation between actual and predicted SF-6Dv2 was 0.71. Principal predictors were ODI, age and life satisfaction (0-10 cm).: This study demonstrated that SF-6Dv2 was moderately correlated with ODI and RMDQ and that ODI was a better predictor. There was a strong correlation between actual and predicted SF-6Dv2 from multivariate models. These results suggest that the model can be used in similar studies to estimate the SF-6Dv2 when it was not measured.
Learn More >To determine the risk factors for new neuropathic pain (NeP) after five years in healthy middle-aged and elderly volunteers.
Learn More >Digital technologies connect young people with health services and resources that support their self-care. The lack of accessible, reliable digital resources tailored to young people with persistent musculoskeletal pain is a significant gap in the health services in Australia. Recognizing the intense resourcing required to develop and implement effective electronic health (eHealth) interventions, the adaptation of extant, proven digital technologies may improve access to pain care with cost and time efficiencies.
Learn More >To assess the long-term analgesic effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex in patients with chronic pain syndrome.
Learn More >Central sensitization (CS) has been recently identified as a significant risk factor for persistent pain and patient dissatisfaction following total knee arthroplasty (TKA). However, it remains unclear as to whether the preoperative CS persists after the elimination of a nociceptive pain source by TKA, or how CS affects the quality of life after TKA.
Learn More >Heat shock protein 90 (Hsp90) is a ubiquitous signal transduction regulator, and Hsp90 inhibitors are in clinical development as cancer therapeutics. However, there have been very few studies on the impact of Hsp90 inhibitors on pain or analgesia, a serious concern for cancer patients. We previously found that Hsp90 inhibitors injected into the brain block opioid-induced anti-nociception in tail flick, paw incision, and HIV neuropathy pain. This study extended from that initial work to test the cancer-related clinical impact of Hsp90 inhibitors on opioid anti-nociception in cancer-induced bone pain (CIBP) in female BALB/c mice and chemotherapy-induced peripheral neuropathy (CIPN) in male and female CD-1 mice. Mice were treated with Hsp90 inhibitors (17-AAG, KU-32) by the intracerebroventricular, intrathecal, or intraperitoneal routes, and after 24 hours pain behaviors were evaluated following analgesic drug treatment. Hsp90 inhibition in the brain or systemically completely blocked morphine and oxymorphone anti-nociception in CIPN; this effect was partly mediated by decreased ERK and JNK MAPK activation and by increased protein translation, was not altered by chronic treatment, and Hsp90 inhibition had no effect on gabapentin anti-nociception. We also found that the Hsp90 isoform Hsp90α and the co-chaperone Cdc37 were responsible for the observed changes in opioid anti-nociception. In contrast, Hsp90 inhibition in the spinal cord or systemically partially reduced opioid anti-nociception in CIBP. These results demonstrate that Hsp90 inhibitors block opioid anti-nociception in cancer-related pain, suggesting that Hsp90 inhibitors for cancer therapy could decrease opioid treatment efficacy.
Learn More >Class B G protein-coupled receptors are highly therapeutically relevant but challenges remain in identifying suitable small-molecule drugs. The calcitonin-like receptor (CLR) in particular is linked to conditions such as migraine, cardiovascular disease, and inflammatory bowel disease. The CLR cannot act as a cell-surface receptor alone but rather must couple to one of three receptor activity-modifying proteins (RAMPs), forming heterodimeric receptors for the peptides adrenomedullin and calcitonin gene-related peptide. These peptides have extended binding sites across their receptors. This is one reason why there are few small-molecule ligands that can modulate these receptors. Here we describe small molecules that are able to positively modulate the signaling of the CLR with all three RAMPs but are not active at the related calcitonin receptor. These compounds were selected from a β-arrestin recruitment screen, coupled with rounds of medicinal chemistry to improve their activity. Translational potential is shown as the compounds can positively modulate cAMP signaling in a vascular cell line model. Binding experiments do not support an extracellular domain binding site; however, molecular modeling reveals potential allosteric binding sites in multiple receptor regions. These are the first small-molecule positive modulators described for the CLR:RAMP complexes.
Learn More >Calcitonin gene-related peptide (CGRP) is a neuropeptide that is involved in the transmission of pain. Drugs targeting CGRP or a CGRP receptor are efficacious in the treatment of migraine. The canonical CGRP receptor is a complex of a G protein-coupled receptor, the calcitonin-like receptor (CLR), with an accessory protein, receptor activity-modifying protein 1 (RAMP1). A second receptor, the AMY receptor, a complex of the calcitonin receptor with RAMP1, is a dual high-affinity receptor for CGRP and amylin. Receptor regulatory processes, such as internalization, are crucial for controlling peptide and drug responsiveness. Given the importance of CGRP receptor activity in migraine we compared the internalization profiles of both receptors for CGRP using novel fluorescent probes and a combination of live cell imaging, fixed cell imaging, and ELISA. This revealed stark differences in the regulation of each receptor with the AMY receptor unexpectedly showing little internalization.
Learn More >Cannabinoid receptor 1 (CB) is a key drug target for a number of diseases, including metabolic syndromes and neuropathic pain. Most of the typical cannabinoid ligands provoke psychotropic side effects that impair their therapeutic utility. As of today, it is not yet clearly known which structural features of cannabinoid ligands determine a preference toward specific signaling pathways. Distinct bioassays are typically used to elucidate signaling preferences. However, these are often based on different cell lines and use different principles and/or read-outs, which makes straightforward assessment of "ligand bias" difficult. Within this context, this study is the first to investigate ligand bias among synthetic cannabinoid receptor agonists (SCRAs) in as closely analogous conditions as possible, by applying a new functional complementation-based assay panel to assess the recruitment of Gα protein or β-arrestin2 to CB. In a panel of 21 SCRAs, chosen to cover a broad diversity in chemical structures, distinct, although often subtle, preferences toward specific signaling pathways were observed. Relative to CP55940, here considered as a "balanced" reference agonist, most of the selected SCRAs (e.g., 5F-APINACA, CUMYL-PEGACLONE, among others) displayed preferred signaling through the β-arrestin2 pathway, whereas MMB-CHMICA could serve as a potential "balanced" agonist. Interestingly, EG-018 was the only SCRA showing a significant (10-fold) preference toward G protein over β-arrestin2 recruitment. While it is currently unclear what this exactly means in terms of abuse potential and/or toxicity, the approach proposed here may allow construction of a knowledge base that in the end may allow better insight into the structure-"functional" activity relationship of these compounds. This may aid the development of new therapeutics with less unwanted psychoactive effects.
Learn More >This is a comprehensive review of the current literature on central neuropathic pain mechanisms that is secondary to spinal cord injury. It reviews recent and seminal findings on the pathophysiology, diagnosis, and treatment and compares treatment options and recommendations.
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