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A number of studies have been published proposing various approaches to the treatment of neuropathic pain; however, to our knowledge, no attempts have been made to compare gabapentin and fentanyl in patients with lumbar radiculopathy. We evaluated the relative efficacy and safety of fentanyl matrix and gabapentin for the treatment of chronic neuropathic pain of radicular origin. The study was designed as a randomized blind multicentered parallel-group noninferiority trial. A total of 108 patients with moderate-to-severe pain (≥4 intensity on an 11-point numeric rating scale) were randomly prescribed either fentanyl matrix or gabapentin over a period of 56 days. In the primary analysis, the noninferiority of fentanyl matrix treatment was evaluated in relation to the efficacy of gabapentin based on the pain intensity difference (PID) at 56 days after the first dose of the drugs. Secondary endpoints included pain relief, improvement in functional status (the Korean-Oswestry Disability Index (K-ODI)), improvement in depressive symptoms (Korean-Beck Depression Index (K-BDI)) between the 28th and 56th day, and adverse events (AEs). Analysis of the primary efficacy endpoint established the noninferiority of fentanyl matrix compared with gabapentin, with no statistically significant difference observed in the PID after 56 days for the two treatment groups. Similarly, analysis of pain relief revealed no significant differences between the groups on days 28 and 56. There was no difference in the K-ODI and K-BDI between the groups during the study period. The overall incidence of at least one AE was similar for fentanyl matrix (67.3%) and gabapentin (69.6%). The most commonly reported AEs for patients treated with fentanyl matrix and gabapentin included dizziness (30.8% vs. 44.6%, respectively), somnolence (26.9% vs. 35.7%), and constipation (15.4% vs. 17.9%). This study demonstrated that the analgesic effect of fentanyl matrix is noninferior in comparison with gabapentin and supports the use of fentanyl matrix as an effective and safe treatment for moderate-to-severe chronic neuropathic pain. This trial is registered with NCT01127100.
Learn More >Type-A γ-aminobutyric (GABA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABA receptor modulators.
Learn More >Chronic widespread pain (CWP) is one of the most difficult pain conditions to treat due to an unknown etiology and a lack of innovative treatment design and effectiveness. Based upon preliminary findings within the fields of motivational psychology, integrative neuroscience, diaphragmatic breathing, and vagal nerve stimulation, we propose a new treatment intervention, motivational non-directive (ND) resonance breathing, as a means of reducing pain and suffering in patients with CWP. Motivational ND resonance breathing provides patients with a noninvasive means of potentially modulating five psychophysiological mechanisms imperative for endogenously treating pain and increasing overall quality of life.
Learn More >In 2016, a special interest group from the International Forum for the Study of Itch defined sensitive skin (SS) as a syndrome that manifests with the occurrence of unpleasant sensations (stinging, burning, pain, pruritus, and tingling sensations) after stimuli that should not cause a reaction, such as water, cold, heat, or other physical and/or chemical factors. The pathophysiology of sensitive skin is still poorly understood, but the symptoms described suggest inflammation and peripheral innervation. Only two publications have focused on sensitive skin transcriptomics. In the first study, the authors performed a microarray comparison of SS and non-sensitive skin (NSS) samples and showed differences in the expression of numerous genes in SS and NSS samples. Moreover, in the SS samples, two clusters of genes were identified, including upregulated and downregulated genes, compared to NSS samples. These results provide some interesting clues for the understanding of the pathophysiology of SS. The second study compared SS and NSS samples using RNA-seq assays. This method allowed the identification of long non-coding RNAs (lncRNAs) and differentially expressed mRNAs and provided a comprehensive profile in subjects with SS. The results showed that a wide range of genes may be involved in the pathogenesis of SS and suggested pathways that could be associated with them. In this paper, we discuss these two studies in detail and show how transcriptomic studies can help understand the pathophysiology of sensitive skin. We call for new transcriptomic studies on larger populations to be conducted before putative pathogenic mechanisms can be detected and analyzed to achieve a better understanding of this complex condition.
Learn More >This study examined the association between pain characteristics and the incidence of functional disability among community-dwelling older adults. This prospective cohort study included 4,365 older adults (mean age 74.7 years, 53.5% female) living in community settings. Pain characteristics, including severity and duration of pain, were assessed in participants who also underwent monthly follow-up assessment of functional disability for 24 months based on the national long-term care insurance system. Among the 4,365 participants, 2,149 (48.7%) reported pain, regardless of severity and duration. Of the 2,149 participants with pain, 950 (44.2%) reported moderate to severe pain and 1,680 (78.2%) reported chronic pain. Based on the univariate analyses, participants with moderate (hazard ratio [95% confidence interval]: 1.48 [1.05-2.09]) or severe (2.84 [1.89-4.27]) pain and chronic pain (1.50 [1.15-1.95]) showed significantly higher risk of disability incidence than did those without pain. After adjusting for covariates, severe pain remained a significant predictor (hazard ratio [95% confidence interval]: 1.66 [1.05-2.62]), but moderate (1.00 [0.69-1.47]) and chronic pain (1.04 [0.77-1.40]) did not. Our results established that moderate to severe pain or chronic pain affects functional disability; in particular, severe pain was independently associated with the incidence of disability. Subjective complaints of pain do not always correspond to physical causes; however, simplified questions regarding pain characteristics could be useful predictors of functional disability in community-dwelling older people.
Learn More >Despite the notable benefits of physical activity for chronic pain, a large proportion of patients with chronic pain report that they do not receive activity-related recommendations from their providers. Research suggests that patient factors such as weight and gender influence activity-related recommendations for chronic pain. Research also suggests that appraisals of the intensity and cause of pain may explain these weight and gender effects. We investigated the influence of patient weight and gender on observers' likelihood of recommending activity-related treatments for pain. We also explored the mediating effects of observers' ratings of pain severity and the extent to which pain was due to medical and lifestyle factors (pain attribution).
Learn More >The subjective nature of pain assessment and its large variance negatively affect patient-health care provider communication and reduce the assay sensitivity of pain clinical trials. Given the lack of an objective gold standard measure, identifying the source (true or error) of the within-subject variability of pain reports is a challenge. By assessing the within-subjects variability of pain and taste reports, alongside with interoceptive measures, the current study is aimed to investigate if the ability to reliably report bodily sensations is a cross-modal characteristic.
Learn More >Intravenous ketamine is often prescribed in severe neuropathic pain. Oral -methyl-D-aspartate receptor (NMDAR) antagonists might prolong pain relief, reducing the frequency of ketamine infusions and hospital admissions. This clinical trial aimed at assessing whether oral dextromethorphan or memantine might prolong pain relief after intravenous ketamine.
Learn More >Therapeutic virtual reality (VR) has emerged as an effective, drug-free tool for pain management, but there is a lack of randomized, controlled data evaluating its effectiveness in hospitalized patients. We sought to measure the impact of on-demand VR versus "health and wellness" television programming for pain in hospitalized patients.
Learn More >Research has indicated that calcitonin gene-related peptide (CGRP) receptor antagonists can be effective in the acute treatment of migraine. Six major drugs are included within this category: telcagepant, olcegepant, BI 44370, rimegepant (BMS-927711), MK3207, and ubrogepant. However, no previous studies have performed network meta-analyses to directly compare the effects of these drugs. In the present study, we assessed the therapeutic qualities of these six different drugs to inform further clinical research. We searched PubMed, Embase, Ovid MEDLINE, Web of Science, and the Cochrane Central Register for Controlled Trials for relevant randomized controlled trials (RCTs) published through to October 2018. Two reviewers performed a network meta-analysis of efficacy and toxicity on the basis of odds ratios (ORs). Ten randomized controlled trials involving 8,174 patients were included in our analysis. Olcegepant (OR: 4.09; CI: 1.81, 9.25), ubrogepant (OR: 2.11; CI: 1.10, 4.05), and BI 44370 (OR: 3.36; CI: 2.24, 5.04) were more effective in ensuring pain relief 2 h after treatment than was placebo treatment. BI 44370 was associated with an increased risk of adverse events when compared with placebo treatment (OR: 1.57; CI: 1.32, 1.88). Surface under the cumulative ranking curve analysis revealed that olcegepant was most effective and ubrogepant was associated with the lowest risk of adverse events among the six treatment options. Olcegepant was more effective, and ubrogepant had lower toxicity than the remaining treatments. CGRP antagonists are promising for the acute treatment of migraine, especially among patients who are unable to take triptans.
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