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The objective of this study was to describe patterns in monthly migraine days (MMD) and tablet utilization, and to estimate health-related quality of life (HRQoL) measures in patients treated as needed (PRN) with rimegepant 75 mg over 52-weeks.
Learn More >Randomized trial of three IVIg doses for treating chronic inflammatory demyelinating polyneuropathy.
Intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy usually starts with a 2.0 g/kg induction dose followed by 1.0 g/kg maintenance doses every 3 weeks. No dose-ranging studies with intravenous immunoglobulin maintenance therapy have been published. The Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) study was a prospective, double-blind, randomised, parallel-group, multicentre, phase III study investigating the efficacy and safety of 10% liquid intravenous immunoglobulin (panzyga®) in patients with active chronic inflammatory demyelinating polyneuropathy. Patients were randomised 1:2:1 to receive the standard intravenous immunoglobulin induction dose and then either 0.5, 1.0 or 2.0 g/kg maintenance doses every 3 weeks. The primary endpoint was the response rate in the 1.0 g/kg group, defined as an improvement ≥ 1 point in adjusted Inflammatory Neuropathy Cause and Treatment score at Week 6 versus baseline and maintained at Week 24. Secondary endpoints included dose response and safety. This trial was registered with EudraCT (Number 2015-005443-14) and clinicaltrials.gov (NCT02638207). Between August 2017 and September 2019, the study enrolled 142 patients. All 142 were included in the safety analyses. As no post infusion data were available for three patients, 139 were included in the efficacy analyses, of whom 121 were previously on corticosteroids. The response rate was 80% (55/69 patients) (95% confidence interval: 69-88%) in the 1.0 g/kg group, 65% (22/34; confidence interval: 48-79%) in the 0.5 g/kg group, and 92% (33/36; confidence interval 78-97%) in the 2.0 g/kg group. While the proportion of responders was higher with higher maintenance doses, logistic regression analysis showed that the effect on response rate was driven by a significant difference between the 0.5 and 2.0 g/kg groups, whereas the response rates in the 0.5 and 2.0 g/kg groups did not differ significantly from the 1.0 g/kg group. Fifty-six percent of all patients had an adjusted Inflammatory Neuropathy Cause and Treatment score improvement 3 weeks after the induction dose alone. Treatment-related adverse events were reported in 16 (45.7%), 32 (46.4%) and 20 (52.6%) patients in the 0.5, 1.0 and 2.0 g/kg dose groups, respectively. The most common adverse reaction was headache. There were no treatment-related deaths. Intravenous immunoglobulin 1.0 g/kg was efficacious and well tolerated as maintenance treatment for patients with chronic inflammatory demyelinating polyneuropathy. Further studies of different maintenance doses of intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy are warranted.
Learn More >Mechanotransduction is a biological phenomenon where mechanical stimuli are converted to biochemical responses. A model system for studying mechanotransduction are the chondrocytes of articular cartilage. Breakdown of this tissue results in decreased mobility, increased pain, and reduced quality of life. Either disuse or overloading can disrupt cartilage homeostasis, but physiological cyclical loading promotes cartilage homeostasis. To model this, we exposed SW1353 cells to cyclical mechanical stimuli, shear and compression, for different durations of time (15 and 30 min). By utilizing liquid chromatography-mass spectroscopy (LC-MS), metabolomic profiles were generated detailing metabolite features and biological pathways that are altered in response to mechanical stimulation. In total, 1457 metabolite features were detected. Statistical analyses identified several pathways of interest. Taken together, differences between experimental groups were associated with inflammatory pathways, lipid metabolism, beta-oxidation, central energy metabolism, and amino acid production. These findings expand our understanding of chondrocyte mechanotransduction under varying loading conditions and time periods. This article has an associated First Person interview with the first author of the paper.
Learn More >The precise underlying mechanisms of migraine remain unknown. Although we have previously shown acute orofacial pain evoked changes within the brainstem of individuals with migraine, we do not know if these brainstem alterations are driven by changes in higher cortical regions. The aim of this investigation is to extend our previous investigation to determine if higher brain centers display altered activation patterns and connectivity in migraineurs during acute orofacial noxious stimuli.
Learn More >Orofacial pain patients often report that the painful facial area is "swollen" without clinical signs – known as perceptual distortion (PD). The neuromodulatory effect of facilitatory repetitive transcranial magnetic stimulation (rTMS) on PD in healthy individuals was investigated, to provide further support that the primary somatosensory cortex (SI) is involved in facial PD. Participants were allocated to active (n=26) or sham (n=26) rTMS group in this case-control study. PD was induced experimentally by injecting local anesthesia (LA) in the right infraorbital region. PD was measured at baseline, 6 min after LA, immediately, 20 and 40 min after rTMS. Intermittent theta-burst stimulation (iTBS) as active rTMS and sham rTMS was applied to the face representation area of SI at 10 min after LA. The magnitude of PD was compared between the groups. The magnitude of PD significantly increased immediately after iTBS compared with sham rTMS (P=0.009). The PD was significantly higher immediately after iTBS compared to 6 min after LA (P=0.004) in the active rTMS group, but not in the sham rTMS group (P=0.054). iTBS applied to a somatotopic-relevant cortical region appears to facilitate facial PD further supporting the involvement of SI in the processing of one´s own face and PD. PERSPECTIVE: This study provides information on neural substrate responsible for processing of perceptual distortion of the face which is speculated to contribute to the chronification of orofacial pain. The findings of this study may aid in mechanism-based management of the condition in orofacial pain disorders and possibly other chronic pain states.
Learn More >Opioid analgesics are widely used to treat acute, postoperative, and chronic pain. However, opioid receptor activation can result in severe respiratory depression. In this study, we demonstrated that Tandospirone (TS), a selective serotonin-1A receptor partial agonist, is effective against opioid-induced respiratory depression. Fentanyl was used to establish a respiratory depression model in rodents. We observed the effects of TS on respiratory depression in rats by using plethysmographic recordings and arterial oxygen saturation. In addition, we evaluated the effects of TS on fentanyl-induced sedation and analgesia by using the loss of righting reflex (LORR) and hot-plate tests, respectively. Rats (n = 5) were treated with TS or saline 5 min prior to fentanyl administration. TS [2 mg/kg, intravenous (i.v.)] dose-dependently attenuated fentanyl-induced respiratory depression versus saline + fentanyl group. Furthermore, pre-treatment with TS (2 mg/kg, i.v.) increased arterial oxygen saturation to 76.5 ± 2.0% at 5 min after fentanyl injection, compared with 35.9 ± 2.5% in saline pre-treated rats (P < 0.001), whereas the time to induction of LORR (P > 0.99) and duration of LORR (P = 0.95) did not differ between the "TS + fentanyl" and "saline + fentanyl" group. The antinociceptive effect of fentanyl was not affected by the administration of TS (P = 0.99) in mice (n = 10). In conclusion, we found that TS, a novel non-benzodiazepine anxiolytic/antidepressant drug, could attenuate severe fentanyl-induced respiratory depression and did not affect the analgesic/sedative effect of fentanyl. The clinical application of TS could significantly improve pain management.
Learn More >Phosphorylation of N-methyl-D-aspartate receptor (NMDAR) is widely regarded as a vital modification of synaptic function. Various protein kinases are responsible for direct phosphorylation of NMDAR, such as cyclic adenosine monophosphate-dependent protein kinase A, protein kinase C, Ca/calmodulin-dependent protein kinase II, Src family protein tyrosine kinases, cyclin-dependent kinase 5, and casein kinase II. The detailed function of these kinases on distinct subunits of NMDAR has been reported previously and contributes to phosphorylation at sites predominately within the C-terminal of NMDAR. Phosphorylation underlies both structural and functional changes observed in chronic pain, and studies have demonstrated that inhibitors of kinases are significantly effective in alleviating pain behavior in different chronic pain models. In addition, the exploration of drugs that aim to disrupt the interaction between kinases and NMDAR is promising in clinical research. Based on research regarding the modulation of NMDAR in chronic pain models, this review provides an overview of the phosphorylation of NMDAR-related mechanisms underlying chronic pain to elucidate molecular and pharmacologic references for chronic pain management.
Learn More >To introduce cooled radiofrequency nerve ablation (C-RFA) as an alternative to managing symptomatically moderate to severe glenohumeral osteoarthritis (OA) in patients who have failed other conservative treatments and who are not surgical candidates or refuse surgery.
Learn More >Fibromyalgia (FM) is a condition characterized by chronic widespread pain whose pathogenesis is still not fully defined. Evidence based on structural and functional neuroimaging methods, electrophysiological, and morphological – skin biopsy – features demonstrated a central and peripheral nervous system involvement. A dysfunction in nociceptive inputs processing at the central level was highlighted as the primary cause of FM, but other data coming from different laboratories contributed to emphasize again the peripheral origin of FM. In fact, small fibers neuropathy (SFN) was observed in a large number of patients submitted to skin biopsy. The complex interaction between central and peripheral factors is opening a new scenario about the management of this neurological disorder. Whether proximal SFN is an initiating event leading to FM or is the consequence of stress-related insular hyper excitability remains unclear. Mild sufferance of peripheral afferents could function as a trigger for an exaggerated response of the so-called "salience matrix" in predisposed individuals. On the other side, the intriguing hypothesis rising from animal models could indicate that the cortical hyper function could cause peripheral small afferent damage. The research should go on the genetic origin of such peripheral and central abnormalities, the acquired facilitating factors, and the presence of different phenotypes in order to search for efficacious treatments, which are still lacking.
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