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This systematic review and meta-analysis aimed to evaluate the evidence pertaining to attentional bias for painful and non-painful somatosensory stimuli in individuals with chronic pain. Eligible studies were identified via searches of Medline, PsycINFO, CINAHL, Web of Science, Scopus, and Cochrane Library databases. Search terms were words and phrases organised into three concept blocks: pain condition, cognitive process and stimuli/paradigm. The search identified 29 eligible studies (reporting 32 eligible experiments), of which quantitative meta-analysis was possible for 16 studies (19 experiments). The meta-analysis found that chronic pain patients, excluding somatoform pain patients, showed significantly greater attentional bias to stimuli in the somatosensory modality than healthy controls (k = 9, g = 0.34). Additionally, meta-analysis of studies that used a temporal order judgement task found that patients with unilateral chronic pain showed a spatial attentional bias away from somatosensory stimuli (k = 7, effect estimate = 22.43 milliseconds) and visual stimuli (k = 2, effect estimate = 13.75 milliseconds) on or near the painful body side. Most studies of attentional bias to the somatosensory modality recruited samples of patients with fibromyalgia whereas most studies of spatial attentional bias assessed patients with complex regional pain syndrome. The extent to which these results generalise to other pain conditions is therefore unclear. We recommend future research test spatial and modality attentional biases across chronic pain conditions and examine the psychometric properties of attentional bias measurement paradigms for use with chronic pain populations. PROSPERO registration number CRD42019124510.
Learn More >Visceral pain can be disabling for patients and challenging to treat in the clinic. Spinal cord stimulation is a NICE approved treatment for chronic neuropathic pain, presenting potential advantages over conventional therapies for managing chronic visceral pain. A retrospective study revealed that a specific type of spinal cord stimulation, BurstDR (Abbott, TX, USA), was effective at improving pain and quality of life in patients with chronic visceral pain. Baseline pain scores significantly correlated with change at follow-up, suggesting it may be possible to identify potential responders from the outset. BurstDR was safe: rates of revision, explantation and complications were low. Clinical trials exploring the long-term effects of BurstDR including a control arm are needed. Findings could have the potential to inform best practice and improve outcomes for individuals with chronic visceral pain.
Learn More >Objectives Chronic postoperative pain is prevalent after robot-assisted laparoscopic hysterectomy for endometrial cancer. Preoperative Quantitative Sensory Testing (QST) has been utilized to identify patients at risk of developing chronic postoperative pain after a range of surgical procedures. The aim of this prospective, observational study was to (1) determine the prevalence of chronic postoperative pain, (2) assess selected preoperative risk factors for chronic postoperative pain, and (3) evaluate if preoperative QST profiling could predict the development of chronic postoperative pain following robot-assisted laparoscopic hysterectomy for endometrial cancer. Methods One-hundred and sixty consecutive patients were included and handheld pressure algometry, cuff pressure algometry, temporal summation of pain, conditioned pain modulation, and heat pain thresholds were assessed prior to surgery. Patients were asked to fill out a questionnaire concerning pain in the pre- and post-operative time period six months after surgery. Chronic postoperative pain was defined as persistent, moderate to severe pain (mean visual analogue scale (VAS)≥3) on a daily basis six months after surgery. Results The prevalence of chronic postoperative pain after robot-assisted laparoscopic hysterectomy for endometrial cancer was of 13.6% (95% CI 8.4-20.4%). Patients that would develop chronic postoperative pain had a lower BMI (p=0.032), a higher prevalence of preoperative pelvic pain (p<0.001), preoperative heat pain hyperalgesia (p=0.043) and a higher level of acute postoperative pain (p<0.001) when compared to patients that would not develop chronic postoperative pain. A logistic regression model demonstrated that the presence of preoperative pelvic pain was a significant, independent predictive risk factor for development of chronic postoperative pain (OR=6.62, 95% CI 2.26-19.44), whereas none of the QST parameters could predict postoperative pain. Conclusions Preoperative QST assessment could not predict the development of chronic postoperative pain despite preoperative heat pain hyperalgesia in patients that would develop chronic postoperative pain.
Learn More >Retrospective longitudinal cohort.
Learn More >Small fiber pathology is increasingly recognized as a potential contributor to neuropathic pain in different clinical syndromes, however, the underlying mechanisms leading to nociceptor sensitization and degeneration are unclear. With the diversity in clinical pain phenotypes and etiology of small fiber pathology, individual mechanisms are assumed, but are not yet fully understood. The thinly-myelinated Aδ- and unmyelinated C-nerve fibers are mainly affected and clinically require special small fiber test methods to capture functional, morphological, and electrophysiological alterations. Several methods have been established and implemented in clinical practice in the last years. In parallel, experimental and in vitro test systems have been developed allowing important insights into the molecular mechanisms underlying nociceptor sensitization and degeneration as main hallmarks of small fiber pathology. In our narrative review we focus on these methods and current knowledge, and provide a synopsis of the achievements made so far in this exciting field.
Learn More >The purpose of our work was to determine the role of non-opioid peptides derived from opioid prohormones in sensory hypersensitivity characteristics of neuropathic pain and to propose a pharmacological approach to restore the balance of these endogenous opioid systems. Non-opioid peptides may have a pronociceptive effect and therefore contribute to less effective opioid analgesia in neuropathic pain. In our study, we used unilateral chronic constriction injury (CCI) of the sciatic nerve as a neuropathic pain model in rats. We demonstrated the pronociceptive effects of proopiomelanocortin (POMC)- and proenkephalin (PENK)-derived non-opioid peptides assessed by von Frey and cold plate tests, 7-14 days after injury. The concentration of PENK-derived pronociceptive peptides was increased more robustly than that of Met-enkephalin in the ipsilateral lumbar spinal cord of CCI-exposed rats, as shown by mass spectrometry, and the pronociceptive effect of one of these peptides was blocked by an antagonist of the melanocortin 4 (MC4) receptor. The above results confirm our hypothesis regarding the possibility of creating an analgesic drug for neuropathic pain based on enhancing opioid activity and blocking the pronociceptive effect of non-opioid peptides. We designed and synthesized bifunctional hybrids composed of opioid (OP) receptor agonist and MC4 receptor antagonist (OP-linker-MC4). Moreover, we demonstrated that they have potent and long-lasting antinociceptive effects after a single administration and a delayed development of tolerance compared to morphine after repeated intrathecal administration to rats subjected to CCI. We conclude that the bifunctional hybrids OP-linker-MC4 we propose are important prototypes of drugs for use in neuropathic pain.
Learn More >Activation of the trigeminal system causes the release of various neuropeptides, cytokines, and other immune mediators. Calcitonin gene-related peptide (CGRP), which is a potent algogenic mediator, is expressed in the peripheral sensory neurons of trigeminal ganglion (TG). It affects the inflammatory responses and pain sensitivity by modulating the activity of glial cells. The primary aim of this study was to use array analysis to investigate the effect of CGRP on the glial cells of TG in regulating nuclear factor kappa B (NF-κB) signaling genes and to further check if CGRP in the TG can affect neuron-glia activation in the spinal trigeminal nucleus caudalis. The glial cells of TG were stimulated with CGRP or Minocycline (Min) + CGRP. The effect on various genes involved in NF-κB signaling pathway was analyzed compared to no treatment control condition using a PCR array analysis. CGRP, Min + CGRP or saline was directly injected inside the TG and the effect on gene expression of , and and protein expression of cleaved Caspase3 (cleav Casp3) in the TG, and c-Fos and glial fibrillary acidic protein (GFAP) in the spinal section containing trigeminal nucleus caudalis was analyzed. Results showed that CGRP stimulation resulted in the modulation of several genes involved in the interleukin 1 signaling pathway and some genes of the tumor necrosis factor pathway. Minocycline pre-treatment resulted in the modulation of several genes in the glial cells, including anti-inflammatory genes, and neuronal activation markers. A mild increase in cleav Casp3 expression in TG and c-Fos and GFAP in the spinal trigeminal nucleus of CGRP injected animals was observed. These data provide evidence that glial cells can participate in neuroimmune interaction due to CGRP in the TG via NF-κB signaling pathway.
Learn More >Interactions between central glial cells and neurons in the pain circuitry are critical contributors to the pathogenesis of chronic pain. In the central nervous system (CNS), two major glial cell types predominate: astrocytes and microglia. Injuries or pathological conditions which evoke pain are concurrently associated with the presence of a reactive microglia or astrocyte state, which is characterized by a variety of changes in the morphological, molecular, and functional properties of these cells. In this review, we highlight the changes that reactive microglia and astrocytes undergo following painful injuries and insults and discuss the critical and interactive role these two cell types play in the initiation and maintenance of chronic pain. Additionally, we focus on several crucial mechanisms by which microglia and astrocytes contribute to chronic pain and provide commentary on the therapeutic promise of targeting these pathways. In particular, we discuss how the inflammasome in activated microglia drives maturation and release of key pro-inflammatory cytokines, which drive pain through neuronal- and glial regulations. Moreover, we highlight several potentially-druggable hemichannels and proteases produced by reactive microglia and astrocytes in pain states and discuss how these pathways regulate distinct phases during pain pathogenesis. We also review two emerging areas in chronic pain research: 1) sexually dimorphic glial cell signaling and 2) the role of oligodendrocytes. Finally, we highlight important considerations for potential pain therapeutics targeting glial cell mediators as well as questions that remain in our conceptual understanding of glial cell activation in pain states.
Learn More >Classification of headache disorders is dependent on a subjective self-report from patients and its interpretation by physicians. We aimed to apply objective data-driven machine learning approaches to analyze patient-reported symptoms and test the feasibility of the automated classification of headache disorders. The self-report data of 2162 patients were analyzed. Headache disorders were merged into five major entities. The patients were divided into training (n = 1286) and test (n = 876) cohorts. We trained a stacked classifier model with four layers of XGBoost classifiers. The first layer classified between migraine and others, the second layer classified between tension-type headache (TTH) and others, and the third layer classified between trigeminal autonomic cephalalgia (TAC) and others, and the fourth layer classified between epicranial and thunderclap headaches. Each layer selected different features from the self-reports by using least absolute shrinkage and selection operator. In the test cohort, our stacked classifier obtained accuracy of 81%, sensitivity of 88%, 69%, 65%, 53%, and 51%, and specificity of 95%, 55%, 46%, 48%, and 51% for migraine, TTH, TAC, epicranial headache, and thunderclap headaches, respectively. We showed that a machine-learning based approach is applicable in analyzing patient-reported questionnaires. Our result could serve as a baseline for future studies in headache research.
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