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Different pathophysiological mechanisms contribute to the pain development in osteoarthritis (OA). Sensitization mechanisms play an important role in the amplification and chronification of pain and may predict the therapeutic outcome. Stratification of patients according to their pain mechanisms could help to target pain therapy. This study aimed at developing an easy-to-use, bedside tool-kit to assess sensitization in patients with chronic painful knee OA or chronic pain after total knee replacement (TKR).In total, 100 patients were examined at the most affected knee and extra-segmentally by use of four standardized quantitative sensory testing parameters reflecting sensitization (mechanical pain threshold, mechanical pain sensitivity, dynamic mechanical allodynia, pressure pain threshold), a bedside testing battery of equivalent parameters including also temporal summation and conditioned pain modulation, and pain questionnaires. Machine learning techniques were applied to identify an appropriate set of bedside screening tools.Approximately half of the patients showed signs of sensitization (46%). Based on machine learning techniques a composition of tests consisting of three modalities were developed. The most adequate bedside tools to detect sensitization were pressure pain sensitivity (pain intensity at 4 ml pressure using a 10 ml blunted syringe), mechanical pinprick pain sensitivity (pain intensity of a 0.7 mm nylon-filament) over the most affected knee, and extra-segmental pressure pain sensitivity (pain threshold).This pilot study presents a first attempt to develop an easy-to-use bedside test to probe sensitization in patients with chronic OA knee pain or chronic pain after TKR. This tool may be used to optimize individualized, mechanism-based pain therapy.
Learn More >Normalization of the excitatory and inhibitory balance by increasing the levels of endogenous inhibitory neurotransmitters by blocking their reuptake is a promising therapeutic strategy for relieving chronic pain. Pharmacological blockade of spinal GABA transporter subtypes 1 and 3 (GAT1 and GAT3) has been reported to generate analgesic effects in animal models of neuropathic pain. Here we explored the synaptic mechanisms underlying their analgesic effects in the spinal dorsal horn. Whole-cell recordings were made from dorsal horn neurons in spinal slices with attached dorsal roots from adult mice, and the effects of GAT inhibitors on miniature and evoked postsynaptic currents were examined. Behaviorally, GAT inhibitors were intrathecally applied to assess their effects on mechanical hypersensitivity in mice developing neuropathic pain after partial sciatic nerve ligation. The GAT1 inhibitor NNC-711 reduced the frequency of mEPSCs and the amplitude of C-fiber-mediated EPSCs, and the GAT3 inhibitor SNAP-5114 reduced the amplitude of A- and C-fiber-mediated EPSCs. These effects were antagonized by the GABAB receptor antagonist CGP55845. Consistently, the analgesic effect of intrathecally injected NNC-711 and SNAP-5114 in mice developing mechanical hypersensitivity after partial sciatic nerve ligation was abolished by CGP55845. Thus, GAT1 and GAT3 inhibitors exert distinct GABAB receptor-mediated inhibitory effects on excitatory synaptic transmission in the spinal dorsal horn, which most likely contributes to their analgesic effects.
Learn More >Accumulating evidence suggests Gulf War illness (GWI) is characterised by autonomic nervous system dysfunction (higher heart rate [HR], lower heart rate variability [HRV]). Yoga – an ancient mind-body practice combining mindfulness, breathwork, and physical postures – is proposed to improve autonomic dysfunction yet this remains untested in GWI. We aimed to determine (i) whether HR and HRV improve among Veterans with GWI receiving either yoga or cognitive behavioural therapy (CBT) for pain; and (ii) whether baseline autonomic functioning predicts treatment-related pain outcomes across follow-up.
Learn More >Mental health disorders can occur in patients with pain conditions, and there have been reports of an increased risk of persistent pain after THA and TKA among patients who have psychological distress. Persistent pain may result in the prolonged consumption of opioids and other analgesics, which may expose patients to adverse drug events and narcotic habituation or addiction. However, the degree to which preoperative use of antidepressants or benzodiazepines is associated with prolonged analgesic use after surgery is not well quantified. QUESTION/PURPOSES: (1) Is the preoperative use of antidepressants or benzodiazepine medications associated with a greater postoperative use of opioids, NSAIDs, or acetaminophen? (2) Is the proportion of patients still using opioid analgesics 1 year after arthroplasty higher among patients who were taking antidepressants or benzodiazepine medications before surgery, after controlling for relevant confounding variables? (3) Does analgesic drug use decrease after surgery in patients with a history of antidepressant or benzodiazepine use? (4) Does the proportion of patients using antidepressants or benzodiazepines change after joint arthroplasty compared with before?
Learn More >The concept of inflammatory back pain (IBP) describes a cohort of patients with chronic back pain (CBP) who have distinct clinical characteristics, rather than being a diagnosis in and of itself. IBP is a common and important feature of axial spondyloarthritis (axSpA) but this is not the only differential. This review examines the utility of IBP in both primary and secondary care settings.
Learn More >Biopsychosocial factors above and beyond pathoanatomical changes likely contribute to the severity of chronic low back pain. A pro-nociceptive endogenous pain modulatory balance (↓inhibition and ↑facilitation) may be an important contributor to chronic low back pain severity and physical function; however, additional research is needed to address this possibility. The objective of this study was to determine whether quantitative sensory tests of endogenous pain inhibition and facilitation prospectively predict movement-evoked pain and cLBP severity self-reported on a validated questionnaire.
Learn More >The Short-Term Kinetics of sICAM-1 after Induction of Acute Experimental Pain in Healthy Volunteers.
Intercellular adhesion molecule-1 (ICAM-1) mediates extravasation of leukocytes, releasing proinflammatory cytokines or endogenous opioids in the inflamed tissue. Thus, ICAM-1 is a crucial component of peripheral antinociception. Previously, we demonstrated a significant correlation between the soluble form of ICAM (sICAM-1) in serum and pain intensity reported by chronic pain patients. The present study examines the role and kinetics of sICAM-1 in experimentally induced acute pain. Three groups of 10 subjects were exposed to 10 min of high (capsaicin-enhanced) or low-intensity heat pain or cold pain, respectively. Thermal stimuli were induced using a device for quantitative sensory testing. Topical capsaicin significantly increased heat pain intensity without the risk of thermal tissue damage. Pain intensity was recorded every minute during testing. sICAM-1 concentrations in serum were determined by ELISA before, immediately after, and 60 min after test termination. Among all experimental groups, sICAM-1 significantly decreased immediately after pain induction. After 60 min, sICAM-1 concentrations returned towards initial values. Interestingly, a linear correlation was found between the extent of sICAM-1 changes and the initial concentrations. Whereas high initial values led to a distinct decrease of sICAM-1, low concentrations tended to increase. There was no statistically significant correlation between levels or alterations of serum sICAM-1 and pain intensity reported by the test subjects. In contrast to our previous findings in chronic pain patients, the present results show that sICAM-1 values do not correlate with the intensity of acute experimental pain. However, we were able to detect short-term changes of sICAM-1 after induction of nociceptive thermal stimuli, suggesting that this marker is part of a demand-oriented homeostatically controlled system.
Learn More >Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of morbidity and the main cause of dose reductions and discontinuations in cancer treatment. Preclinical evidence indicates that activation of the Wallerian-like degeneration pathway driven by SARM1 is responsible for axonopathy in CIPN. SARM1 is the central driver of an evolutionarily conserved program of axonal degeneration downstream of chemical, inflammatory, mechanical or metabolic insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathies of the peripheral and central nervous systems. Small molecule SARM1 inhibitors have the potential to prevent axonal degeneration in peripheral and central axonopathies and to provide a transformational disease-modifying treatment for these disorders. Using a biochemical assay for SARM1 NADase we identified a novel series of potent and selective irreversible isothiazole inhibitors of SARM1 enzymatic activity that protected rodent and human axons in vitro. In sciatic nerve axotomy (SNA), we observed that these irreversible SARM1 inhibitors decreased a rise in nerve cADPR and plasma neurofilament light chain (NfL) released from injured sciatic nerves in vivo. In a mouse paclitaxel model of CIPN we determined that Sarm1 KO mice prevented loss of axonal function, assessed by sensory nerve action potential (SNAP) amplitudes of the tail nerve, in a gene dosage-dependent manner. In that CIPN model, the irreversible SARM1 inhibitors prevented loss of intraepidermal nerve fibers induced by paclitaxel and provided partial protection of axonal function assessed by SNAP amplitude and mechanical allodynia.
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