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Reactive nitroxidative species, such as nitric oxide but particularly peroxynitrite, have been strongly implicated in pain mechanisms. Targeting peroxynitrite is anti-nociceptive in pain models, but little is known about its role in migraine mechanisms. Given the need to validate novel targets for migraine headache, our objective was to study the potential of reactive nitroxidative species, particularly peroxynitrite, as novel targets for drug discovery and their role in migraine mechanisms.
Learn More >Cluster headache is a severe primary headache disorder commonly featuring a strikingly distinct circadian attack pattern. Therefore, the circadian system has been suggested to play a crucial role in the pathophysiology of cluster headache. Cryptochromes are key components of the molecular clock generating circadian rhythms and have previously been shown to be associated with several psychiatric disorders, including seasonal affective disorder, bipolar disorder, and depression.
Learn More >To assess the effectiveness of a pain e-consult program (PEP), a multidisciplinary telementoring service based on the ECHO model to reduce opioid use, in the outpatient setting.
Learn More >Opioids relieve acute pain, but there is little evidence to support the stability of the benefit over long-term treatment of chronic noncancer pain. Previous systematic reviews consider only group level published data which did not provide adequate detail. Our goal was to use patient-level data to explore the stability of pain, opioid dose, and either physical function or pain interference in patients treated for 12 months with abuse deterrent formulations of oxycodone and hydrocodone. All available studies in the Food and Drug Administration Document Archiving, Reporting, and Regulatory Tracking System were included. Patient-level demographics, baseline data, exposure, and outcomes were harmonized. Individual patient slopes were calculated from a linear model of pain, physical function, and pain interference to determine response over time. Opioid dose was summarized by change between baseline and the final month of observation. Patients with stable or less pain, stable or lower opioid dose, and stable or better physical function (where available) met our prespecified criteria for maintaining long-term benefit from chronic opioids. Of the complete data set of 3192 patients, 1422 (44.5%) maintained their pain level and opioid dose. In a secondary analysis of 985 patients with a measured physical function, 338 (34.3%) maintained their physical function in addition to pain and opioid dose. Of 2040 patients with pain interference measured, 788 (38.6%) met criteria in addition. In a carefully controlled environment, about one-third of patients successfully titrated on opioids to treat chronic noncancer pain demonstrated continued benefit for up to 12 months.
Learn More >To determine if a clinical presentation indistinguishable from migraine can occur due to an underlying condition or pathology, that is, "symptomatic migraine."
Learn More >Previous reviews of mobile messaging for individuals with musculoskeletal pain have shown positive effects on pain and disability. However, the configuration of digital content, method of presentation and interaction, dose and frequency needed for optimal results remain unclear. Patient preferences concerning such systems are also unclear. Addressing these knowledge gaps, incorporating evidence from both experimental and observational studies, may be useful to understand the extent of the relevant literature, and to influence the design and outcomes of future messaging systems. We aim to map information that could be influential in the design of future mobile messaging systems for individuals with musculoskeletal pain conditions, and to summarise the findings of efficacy, effectiveness, and economics derived from both experimental and observational studies.
Learn More >Pressure pain thresholds (PPTs) are commonly assessed to quantify mechanical sensitivity in various conditions, including migraine. Digital and analogue algometers are used, but the concurrent validity between these algometers is unknown. Therefore, we assessed the concurrent validity between a digital and analogue algometer to determine PPTs in healthy participants and people with migraine.
Learn More >Delineating the Ligand-Receptor Interactions That Lead to Biased Signaling at the μ-Opioid Receptor.
Biased agonists, which selectively stimulate certain signaling pathways controlled by a G protein-coupled receptor (GPCR), hold great promise as drugs that maximize efficacy while minimizing dangerous side effects. Biased agonists of the μ-opioid receptor (μOR) are of particular interest as a means to achieve analgesia through G protein signaling without dose-limiting side effects such as respiratory depression and constipation. Rational structure-based design of biased agonists remains highly challenging, however, because the ligand-mediated interactions that are key to activation of each signaling pathway remain unclear. We identify several compounds for which the and enantiomers have distinct bias profiles at the μOR. These compounds serve as excellent comparative tools to study bias because the identical physicochemical properties of enantiomer pairs ensure that differences in bias profiles are due to differences in interactions with the μOR binding pocket. Atomic-level simulations of compounds at μOR indicate that and enantiomers adopt different poses that form distinct interactions with the binding pocket. A handful of specific interactions with highly conserved binding pocket residues appear to be responsible for substantial differences in arrestin recruitment between enantiomers. Our results offer guidance for rational design of biased agonists at μOR and possibly at related GPCRs.
Learn More >Body perceptual disturbances are an increasingly acknowledged set of symptoms and possible clinical markers of Complex Regional Pain Syndrome (CRPS), but the neurophysiological and neurocognitive changes that underlie them are still far from being clear. We adopted a multivariate and neurodynamical approach to the analysis of EEG modulations evoked by touch to highlight differences between patients and healthy controls, between affected and unaffected side of the body, and between "passive" (i.e. no task demands and equiprobable digit stimulation) and "active" tactile processing (i.e. where a digit discrimination task was administered and spatial probability manipulated). When correct identifications are considered, an early reduction in cortical decodability (28-56 ms) distinguishes CRPS patients from healthy volunteers. However, when error trials are included in the classifier's training, there is an unexpected increased decodability in the CRPS group compared to healthy volunteers (280-320 ms). These group differences in neural processing seemed to be driven by the affected rather than the unaffected side. We corroborated these findings with several exploratory analyses of neural representation dynamics and behavioural modelling, highlighting the need for single participant analyses. Although several limitations impacted the robustness and generalizability of these comparisons, the proposed analytical approach yielded promising insights (as well as possible biomarkers based on neural dynamics) into the relatively unexplored alterations of tactile decision-making and attentional control mechanisms in chronic CRPS.
Learn More >Normally, an obvious antagonism exists between pain and itch. In normal conditions, painful stimuli suppress itch sensation, whereas pain killers often generate itch. Although pain and itch are mediated by separate pathways under normal conditions, most chemicals are not highly specific to one sensation in chronic pathologic conditions. Notably, in patients with neuropathic pain, histamine primarily induces pain rather than itch, while in patients with atopic dermatitis, bradykinin triggers itch rather than pain. Accordingly, repetitive scratching even enhances itch sensation in chronic itch conditions. Physicians often prescribe pain relievers to patients with chronic itch, suggesting common mechanisms underlying chronic pain and itch, especially peripheral and central sensitization. Rather than separating itch and pain, studies should investigate chronic itch and pain including neuropathic and inflammatory conditions. Here, we reviewed chronic sensitization leading to chronic pain and itch at both peripheral and central levels. Studies investigating the connection between pain and itch facilitate the development of new therapeutics against both chronic dysesthesias based on the underlying pathophysiology.
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