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Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. Randomized, double-blind, placebo-, and positive- (moxifloxacin) controlled study evaluated single ascending doses of 15 µg, 30 µg, and 45 µg TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (C) within 1.5 h. Both extent of exposure (AUC) and C increased in proportion to dose. No QT prolongation was identified by concentration-QTc analysis and the upper bounds of the two-sided 90% confidence interval of predicted maximum baseline and placebo corrected QTcF (ΔΔQTcF) value did not exceed 10 ms for all tetrodotoxin doses, thereby meeting the criteria of a negative QT study. Safety assessments showed no clinically relevant changes with values similar between all groups and no subject withdrawing due to adverse events. Paresthesia, oral-paresthesia, headache, dizziness, nausea, and myalgia were the most common TEAEs (overall occurrence ≥5%) in the TTX treatment groups. TTX doses investigated in this study are safe, well-tolerated, and lack proarrhythmic proclivity.
Learn More >Temporomandibular disorder is a common musculoskeletal pain condition with development of chronic symptoms in 49% of patients. Although a number of biological factors have shown an association with chronic temporomandibular disorder in cross-sectional and case control studies, there are currently no biomarkers that can predict the development of chronic symptoms. The PREDICT study aims to undertake analytical validation of a novel peak alpha frequency (PAF) and corticomotor excitability (CME) biomarker signature using a human model of the transition to sustained myofascial temporomandibular pain (masseter intramuscular injection of nerve growth factor [NGF]). This article describes, a priori, the methods and analysis plan.
Learn More >An American Academy of Orthopaedic Surgeons guideline recommends tramadol for patients with knee osteoarthritis, and an American College of Rheumatology guideline conditionally recommends tramadol as first-line therapy for patients with knee osteoarthritis, along with nonsteroidal anti-inflammatory drugs.
Learn More >Inhibitory pain modulation has been reported to be deficient in adults across different types of chronic pain, including migraine. To determine if a similar phenomenon occurs in youth, we performed a quantitative sensory testing investigation in adolescents with migraine (N=19). These patients were compared to healthy adolescents with (Fam-His; N=20) or without (Healthy; N=29) a family history of migraine (e.g., first degree relative with migraine). Subjects were first familiarized with the stimuli and visual analog rating scales using graded noxious stimuli (0°C, 43-49°C range). These data were used to explore potential pain sensitivity differences between the groups. Pain inhibition was assessed by conditioned pain modulation (CPM), which used both suprathreshold heat pain (heat CPM) and pressure pain thresholds (pressure CPM) as the test stimuli before and during cold water immersion (8°C). In response to the graded heat stimuli Fam-His participants reported higher pain intensity ratings compared to migraine patients, who in turn, reported higher pain intensity ratings than the healthy controls [F=3.6, (df=2, 459), p=0.027]. For heat- and pressure- CPM, there was no significant group difference in the magnitude of CPM responses. Thus, adolescents with migraine and healthy adolescents have similar inhibitory pain modulation capability despite having marked differences in pain sensitivity. Although Fam-His participants are asymptomatic, they demonstrate alterations in pain processing which may serve as markers for prediction of migraine development.
Learn More >Little is still known about the underlying mechanisms that drive and maintain neuropathic pain (NeuP). Recently, lipids have been implicated as endogenous proalgesic ligands affecting onset and maintenance of pain; however, in the case of NeuP, the relationship is largely unexplored.
Learn More >Chronic pain conditions affect up to one third of the adult population in the United Kingdom. Sleep problems are prevalent and negatively impact quality of life. Lack of standardised tools for routine screening and assessment of sleep changes have been a barrier for sleep management. Novel sleep wearables offer an exciting and accessible way to measure sleep but have not been tested outside of the consumer-led landscape and are not commonly used in research and clinical settings.
Learn More >Chronic pain (CP) patients often display lower heart rate variability (HRV) and baroreceptor sensitivity (BRS), which are associated with increased evoked pain intensity and decreased pain tolerance.
Learn More >Depression, anxiety and somatization influence the recovery of people with musculoskeletal pain. A Delphi study was conducted to reach consensus on the most appropriate self-administered questionnaires to assess these psychosocial factors in people at risk of developing persistent musculoskeletal pain. A multidisciplinary panel of international experts was identified via PubReMiner. The experts (N=22) suggested 24 questionnaires in Round 1. In Round 2, experts rated the questionnaires on suitability, considering clinimetrics, content, feasibility, personal experiences and expertise. The highest ranked questionnaires were retained for Round 3, in which the experts made a final assessment of the suitability of the questionnaires. Sensitivity analyses were performed to assess the impact of (1) not all experts having participated in each round, and (2) experts having been involved in relevant questionnaire development. Consensus (i.e., ≥75% agreement) was reached for the following questionnaires. For depression: Patient Health Questionnaire-9, Beck Depression Inventory-II, Center for Epidemiological Studies-Depression Scale, and Depression Subscale of the Depression, Anxiety and Stress Scales. In the sensitivity analyses, consensus was also reached for the Depression Subscale of the Hospital Anxiety Depression Scale. For anxiety: Generalized Anxiety Disorder Scale-7, State and Trait Anxiety Inventory, and Pain Anxiety Symptoms Scale. For somatization: no recommendation could be made. Perspective This study generated a short-list of preferred questionnaires to assess depression, anxiety and somatization in people with musculoskeletal pain. Broad implementation of these questionnaires by clinicians and researchers will facilitate easier comparison and pooling of baseline and outcome data. Some of the recommended questionnaires still require validation in this population.
Learn More >Chronic pain is a frequent severe disease and often associated with anxiety, depression, insomnia, disability, and reduced quality of life. This maladaptive condition is further characterized by sensory loss, hyperalgesia, and allodynia. Blue light has been hypothesized to modulate sensory neurons and thereby influence nociception.
Learn More >A growing pediatric and adult literature highlights the role of injustice appraisals in adjustment to pain. However, interpersonal injustice dynamics have remained largely unexplored. The present study investigated the factor structure and criterion validity of parentally-adjusted versions of the Injustice Experience Questionnaire, assessing child-oriented (IEQ-Pc) and self-oriented appraisals (IEQ-Ps) in the context of child pain. Participants were triads of healthy children (N=407, M=12) and both their parents and dyads of children with chronic pain (N=319, M=14) and one parent. In both samples, children completed measures of functional disability and quality of life (physical, emotional, social, academic); parents completed the IEQ-Pc, IEQ-Ps, and a measure of parental catastrophizing about child pain. Across samples, a confirmatory oblique two-factor model (Severity/Irreparability-Blame/Unfairness) provided a better fit to the data compared to a one-factor model; nevertheless, the two-factor solution was considered suboptimal. A post-hoc exploratory factor analysis consistently revealed one factor. In terms of criterion validity, the IEQ-Pc and IEQ-Ps demonstrated differential associations depending on the child's pain vs. healthy status, independent of parental catastrophizing. Further, findings in the healthy sample indicated that fathers' self-oriented injustice appraisals related to lower child social function. In the clinical sample, parental child-oriented injustice appraisals related to greater child functional disability and lower physical, emotional, social, and academic function. Current findings support the unique role of parental injustice appraisals, assessed by the IEQ-Pc and IEQ-Ps, in understanding child pain, but also suggest these may only partially capture the phenomenology of parental injustice appraisals in the context of child pain. PERSPECTIVE: This manuscript presents an examination of the construct and criterion validity of two parentally adjusted versions of the Injustice Experience Questionnaire. These measures could be valuable tools for clinicians in examining how parents respond to their child's pain as it impacts both the child's life as well as the parents'.
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