Browse by Audience
Neuropathic pain in rodents can be driven by ectopic spontaneous activity (SA) generated by sensory neurons in dorsal root ganglia (DRG). The recent demonstration that SA in dissociated human DRG neurons is associated with reported neuropathic pain in patients enables detailed comparison of pain-linked electrophysiological alterations driving SA in human DRG neurons to alterations that distinguish SA in nociceptors from SA in low-threshold mechanoreceptors (LTMRs) in rodent neuropathy models. Analysis of recordings from dissociated somata of patient-derived DRG neurons showed that SA and corresponding pain in both sexes were significantly associated with the three functional electrophysiological alterations sufficient to generate SA in the absence of extrinsic depolarizing inputs. These include enhancement of depolarizing spontaneous fluctuations of membrane potential (DSFs), which were analyzed quantitatively for the first time in human DRG neurons. The functional alterations were indistinguishable from SA-driving alterations reported for nociceptors in rodent chronic pain models. Irregular, low-frequency DSFs in human DRG neurons closely resemble DSFs described in rodent nociceptors while differing substantially from the high-frequency sinusoidal oscillations described in rodent LTMRs. These findings suggest that conserved physiological mechanisms of SA in human nociceptor somata can drive neuropathic pain despite documented cellular differences between human and rodent DRG neurons. Perspective: Electrophysiological alterations in human sensory neurons associated with patient-reported neuropathic pain include all three of the functional alterations that logically can promote spontaneous activity. The similarity of distinctively altered spontaneous depolarizations in human DRG neurons and rodent nociceptors suggests that spontaneously active human nociceptors can persistently promote neuropathic pain in patients.
Learn More >The mechanisms underlying the transition from acute to chronic pain are unclear but may involve the persistence or strengthening of pain memories acquired in part through associative learning. Contextual cues, which comprise the environment in which events occur, were recently described as a critical regulator of pain memory; both male rodents and humans exhibit increased pain sensitivity in environments recently associated with a single painful experience. It is unknown, however, how repeated exposure to an acute painful unconditioned stimulus in a distinct context modifies pain sensitivity or the expectation of pain in that environment. To answer this question, we conditioned mice to associate distinct contexts with either repeated administration of a mild visceral pain stimulus (intraperitoneal injection of acetic acid) or vehicle injection over the course of three days. On the final day of experiments animals received either an acid injection or vehicle injection prior to being placed into both contexts. In this way, contextual control of pain sensitivity and pain expectation could be tested respectively. When re-exposed to the noxious stimulus in a familiar environment, both male and female mice exhibited context-dependent conditioned analgesia, a phenomenon mediated by endogenous opioid signaling. However, when expecting the presentation of a painful stimulus in a given context, males exhibited conditioned hypersensitivity whereas females exhibited endogenous opioid-mediated conditioned analgesia. These results are evidence that pain perception and engagement of endogenous opioid systems can be modified through their psychological association with environmental cues. Successful determination of the brain circuits involved in this sexually dimorphic anticipatory response may allow for the manipulation of pain memories, which may contribute to the development of chronic pain states.
Learn More >This second paper in a 3-part series on antiracism in pain research across the translational spectrum focuses on study design factors. Although objectivity is a cornerstone value of science, subjectivity is embedded in every step of the research process as investigators make choices about who they collaborate with, which research questions they ask, how they recruit participants, which research tools they use, and how they analyze and interpret data. We present theory and evidence from disciplines such as sociology, medical anthropology, statistics, and public health to discuss 4 common study design factors, including 1) the dominant biomedical narrative of pain that restricts funding and exploration of social indicators of pain, 2) low diversity and inclusion in pain research enrollment that restricts generalizability to racialized groups, 3) the use of "race" or "ethnicity" as a statistical variable and proxy for lived experiences (eg, racism, resilience), and 4) limited modeling in preclinical research for the impact of social factors on pain physiology. The information presented in this article is intended to start conversations across stakeholders in the pain field to explore how we can come together to adopt antiracism practices in our work at large to achieve equity for racialized groups. PERSPECTIVE: This is the second paper in a 3-part series on antiracism in pain research. This part identifies common study design factors that risk hindering progress toward pain care equity. We suggest reframes using an antiracism framework for these factors to encourage all pain investigators to collectively make strides toward equity.
Learn More >Racism is an established health determinant across the world. In this 3-part series, we argue that a disregard of how racism manifests in pain research practices perpetuates pain inequities and slows the progression of the field. Our goal in part-1 is to provide a historical and theoretical background of racism as a foundation for understanding how an antiracism pain research framework – which focuses on the impact of racism, rather than "race," on pain outcomes – can be incorporated across the continuum of pain research. We also describe cultural humility as a lifelong self-awareness process critical to ending generalizations and successfully applying antiracism research practices through the pain research continuum. In part-2 of the series, we describe research designs that perpetuate racism and provide reframes. Finally, in part-3, we emphasize the implications of an antiracism framework for research dissemination, community-engagement practices and diversity in research teams. Through this series, we invite the pain research community to share our commitment to the active process of antiracism, which involves both self-examination and re-evaluation of research practices shifting our collective work towards eliminating racialized injustices in our approach to pain research. PERSPECTIVE: We call on the pain community to dismantle racism in our research practices. As the first paper of the 3-part series, we introduce dimensions of racism and its effect on pain inequities. We also describe the imperative role of cultural humility in adopting antiracism pain research practices.
Learn More >This third paper in the "Confronting Racism in All Forms of Pain Research" series discusses adopting an antiracism framework across all pain research disciplines and highlights the significant benefits of doing so. We build upon the previous call to action and the proposed reframing of study designs articulated in the other papers in the series and seek to confront and eradicate racism through a shared commitment to change current research practices. Specifically, we emphasize the systematic disadvantage created by racialization (ie, the Eurocentric social and political process of ascribing racialized identities to a relationship, social practice, or group) and discuss how engaging communities in partnership can increase the participation of racialized groups in research studies and enrich the knowledge gained. Alongside this critical work, we indicate why diversifying the research environment (ie, research teams, labs, departments, and culture) enriches our scientific discovery and promotes recruitment and retention of participants from racialized groups. Finally, we recommend changes in reporting and dissemination practices so that we do not stigmatize or reproduce oppressive forms of power for racialized groups. Although this shift may be challenging in some cases, the increase in equity, generalizability, and credibility of the data produced will expand our knowledge and reflect the pain experiences of all communities more accurately. PERSPECTIVE: Perspective: In this third paper in our series, we advocate for a shared commitment toward an antiracism framework in pain research. We identify community partnerships, diversification of research environments, and changes to our dissemination practices as areas where oppressive forms of power can be reduced.
Learn More >Chronic non-cancer pain in children and adolescents can be impairing and results in substantial health care costs. Intensive Interdisciplinary Pain Treatment (IIPT), an inpatient or day hospital treatment delivered by a team of three or more health professionals, may be an effective intervention for these children and adolescents. Based on previous reviews and meta-analyses, we updated the findings regarding the description of available treatments and estimated the effectiveness of IIPT, overcoming methodological shortcomings of previous work by requesting and analyzing individual participant data. On June 26, 2021, we searched five literature databases (PubMed, PsycINFO, Web of Science, Cochrane Library, and PubPsych) for studies examining the effectiveness of IIPT. Included studies employed a pre-post design, assessed patients under the age of 22 years, and presented their results in English, German, French, or Spanish. We used standard methodological procedures expected by Cochrane to pool treatment effects and assess risk of bias. We identified 13 different treatment sites with similar treatment inclusion criteria and treatment components, but the descriptions of those treatments varied widely. Regarding treatment effectiveness, IIPT may result in large improvements in mean pain intensity (g=-1.28), disability (g=-1.91), and number of missed school days at 12-month follow-up (g=-0.99), as well as moderate improvements in anxiety (g=-0.77) and depression (g=-0.76). The certainty of the evidence, however, was graded very low to low. We recommend future researchers employ more scientific rigor to increase the certainty of the evidence for IIPT and to standardize treatment outcomes for children and adolescents with chronic pain.
Learn More >Adolescence is a sensitive period for both brain development and the emergence of chronic pain particularly in females. However, the brain mechanisms supporting pain perception during adolescence remain unclear. This study compares perceptual and brain responses to pain in female adolescents and adults to characterize pain processing in the developing brain. Thirty adolescent (ages 13-17 years) and 30 adult (ages 35-55 years) females underwent a functional magnetic resonance imaging scan involving acute pain. Participants received 12 ten-second noxious pressure stimuli that were applied to the left thumbnail at 2.5 and 4 kg/cm2, and rated pain intensity and unpleasantness on a visual analogue scale. We found a significant group-by-stimulus intensity interaction on pain ratings. Compared with adults, adolescents reported greater pain intensity and unpleasantness in response to 2.5 kg/cm2 but not 4 kg/cm2. Adolescents showed greater medial-lateral prefrontal cortex and supramarginal gyrus activation in response to 2.5 kg/cm2 and greater medial prefrontal cortex and rostral anterior cingulate responses to 4 kg/cm2. Adolescents showed greater pain-evoked responses in the neurologic pain signature and greater activation in the default mode and ventral attention networks. Also, the amygdala and associated regions played a stronger role in predicting pain intensity in adolescents, and activity in default mode and ventral attention regions more strongly mediated the relationship between stimulus intensity and pain ratings. This study provides first evidence of greater low-pain sensitivity and pain-evoked brain responses in female adolescents (vs adult women) in regions important for nociceptive, affective, and cognitive processing, which may be associated with differences in peripheral nociception.
Learn More >Immunogenicity of erenumab, a human anti-calcitonin gene-related peptide receptor monoclonal antibody developed for migraine prevention, has been evaluated throughout clinical development.
Learn More >Osteoarthritis (OA) is the most common degenerative joint disease and a major cause of age-related disability worldwide, mainly due to pain, the disease's main symptom. Although OA was initially classified as a non-inflammatory joint disease, recent attention has been drawn to the importance of synovitis and fibroblast-like synoviocytes (FLS) in the pathogenesis of OA. FLS can be divided into two major populations: thymus cell antigen 1 (THY1)- FLS are currently classified as quiescent cells and assumed to destroy bone and cartilage, whereas THY1+ FLS are invasively proliferative cells that drive synovitis. Both THY1- and THY1+ FLS share many characteristics with fibroblast-like progenitors – mesenchymal stromal cells (MSC). However, it remains unclear whether synovitis-induced metabolic changes exist in FLS from OA patients and whether metabolic differences may provide a mechanistic basis for the identification of approaches to precisely convert the pathologically proliferative synovitis-driven FLS phenotype into a healthy one. To identify novel pathological mechanisms of the perpetuation and manifestation of OA, we analyzed metabolic, proteomic, and functional characteristics of THY1+ FLS from patients with OA. Proteome data and pathway analysis revealed that an elevated expression of pyruvate dehydrogenase kinase (PDK) 3 was characteristic of proliferative THY1+ FLS from patients with OA. These FLS also had the highest podoplanin (PDPN) expression and localized to the sublining but also the lining layer in OA synovium in contrast to the synovium of ligament trauma patients. Inhibition of PDKs reprogrammed metabolism from glycolysis towards oxidative phosphorylation and reduced FLS proliferation and inflammatory cytokine secretion. This study provides new mechanistic insights into the importance of FLS metabolism in the pathogenesis of OA. Given the selective overexpression of PDK3 in OA synovium and its restricted distribution in synovial tissue from ligament trauma patients and MSC, PDKs may represent attractive selective metabolic targets for OA treatment. Moreover, targeting PDKs does not affect cells in a homeostatic, oxidative state. Our data provide an evidence-based rationale for the idea that inhibition of PDKs could restore the healthy THY1+ FLS phenotype. This approach may mitigate the progression of OA and thereby fundamentally change the clinical management of OA from the treatment of symptoms to addressing causes.
Learn More >Chronic pain development is a frequent outcome of severe stressor exposure, with or without tissue injury. Enduring stress-induced hyperalgesia (ESIH) is believed to play a central role, but the precise mechanisms mediating the development of chronic posttraumatic pain, and the time-dependency of these mechanisms, remain poorly understood. Clinical and pre-clinical data suggest that the inhibition of FK506-binding protein 51 (FKBP51), a key stress system regulator, might prevent ESIH. We evaluated whether peritraumatic inhibition of FKBP51 in an animal model of traumatic stress exposure, the single prolonged stress (SPS) model, reversed ESIH evaluated via daily mechanical von Frey testing. FKBP51 inhibition was achieved using SAFit2, a potent and specific small molecule inhibitor of FKBP51, administered to male and female Sprague-Dawley rats via intraperitoneal injection. To assess timing effects, FKBP51 was administered at different times relative to stress (SPS) exposure. SAFit2 administration immediately after SPS produced a complete reversal in ESIH lasting >7d. In contrast, SAFit2 administration 72h following SPS produced only temporary hyperalgesia reversal, and administration 120h following SPS had no effect. Similarly, animals undergoing SPS together with tissue injury (plantar incision) receiving SAFit2 immediately post-surgery developed acute hyperalgesia but recovered by 4d and did not develop ESIH. These data suggest that (1) FKBP51 plays an important, time-dependent role in ESIH pathogenesis, (2) time windows of opportunity may exist to prevent ESIH via FKBP51 inhibition after traumatic stress, with or without tissue injury, and (3) the use of inhibitors of specific pathways may provide new insights into chronic post-traumatic pain development.
Learn More >SignificanceFunctional plasticity of the nociceptive circuit is a remarkable feature and is of clinical relevance. As an example, nociceptors lower their threshold upon tissue injury, a process known as allodynia that would facilitate healing by guarding the injured areas. However, long-lasting hypersensitivity could lead to chronic pain, a debilitating disease not effectively treated. Therefore, it is crucial to dissect the mechanisms underlying basal nociception and nociceptive hypersensitivity. In both vertebrate and invertebrate species, conserved transient receptor potential (Trp) channels are the primary transducers of noxious stimuli. Here, we provide a precedent that in larvae, heat sensing in the nociception and hypersensitivity states is mediated by distinct heat-sensitive neurons and TrpA1 alternative isoforms.
Learn More >Systemic treatments for atopic dermatitis are being evaluated primarily in placebo-controlled trials; network meta-analysis can provide relative efficacy and safety estimates for treatments that have not been compared head to head.
Learn More >Transcutaneous electrical nerve stimulation (TENS) uses endogenous opioids to produce analgesia, and effectiveness can be reduced in opioid-tolerant individuals. We examined TENS effectiveness (primary aim), and differences in fibromyalgia symptoms (secondary aim), in women with fibromyalgia regularly taking opioid (RTO) medications compared with women not- regularly taking opioids (not-RTO). Women (RTO n=79; not-RTO not-n=222) with fibromyalgia with daily pain levels ≥4 were enrolled and categorized into RTO (taking opioids at least 5 of 7 days in last 30 days) or not-RTO groups. For the RTO group, participants were categorized into tramadol n=52 (65.8%) and other opioids n=27 (34.2%). Participants were phenotyped across multiple domains including demographics, fibromyalgia characteristics pain, fatigue, sleep, psychosocial factors, and activity. Participants were randomized to active TENS (n=101), placebo TENS (n=99), or no TENS (n=99) for 1-month with randomization stratified by opioid use. Active TENS was equally effective in movement-evoked pain in those in the RTO and not-RTO groups. Women with fibromyalgia in the RTO group were older (p=0.002), lower income (p=0.035), more likely to smoke (p=0.014), and more likely to report depression (p=0.013), hypertension (p=0.005) or osteoarthritis (p=0.027). The RTO group demonstrated greater bodily pain on SF-36 (p=0.005), lower quality of life on the physical health component of the SF-36 (p=0.040), and greater fatigue (MAF-ADL p=0.047; fatigue with sit to stand test (p=0.047) These differences were small of and unclear clinical significance. In summary, regular use of opioid analgesics does not interfere with effectiveness of TENS for movement-evoked pain. Clinical Trial Registration Number: NCT01888640 Perspective: Individuals treated with mixed frequency TENS at strong but comfortable intensity that were taking prescription opioid analgesics showed a significant reduction in movement-evoked pain and fatigue. These data support the use of TENS, using appropriate parameters of stimulation, as an intervention for individuals with fibromyalgia taking opioid analgesics.
Learn More >In our previous multicenter randomized controlled trial, we demonstrated the clinical effectiveness of peripheral nerve field stimulation (PNFS) as add-on therapy to spinal cord stimulation (SCS) for the treatment of chronic back pain in patients with failed back surgery syndrome. To our knowledge, no previous study has investigated the effect of PNFS as an add-on to SCS on the energy consumption of the implanted neurostimulators. Therefore, in this study, we compared the specific stimulation parameters and energy requirements of a previously unreported group of patients with only SCS with those of a group of patients with SCS and add-on PNFS. We also investigated differences that might explain the need for PNFS in the treatment of chronic low back pain.
Learn More >We aimed in this case series to identify shortcomings in assessment of long-term painful and psychosocial consequences of EI and to demonstrate the value of biopsychosocial assessment and the commonalities in outcomes.
Learn More >Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that is characterized by abdominal pain and an altered defecation pattern. It affects between 5 and 20% of the general population and can seriously impact quality of life. The pathophysiology of IBS is rather complex and multifactorial including, for example, altered signalling by the gut-brain axis, dysbiosis, abnormal visceral pain signalling and intestinal immune activation. The latter has gained particular interest in recent years, with growing insight into the bidirectional communication between the nervous system and the immune system. In this Review, we detail the current evidence suggesting that immune activation contributes to the pathology seen in patients with IBS and discuss the potential mechanisms involved. Moreover, we describe how immune mediators, particularly those released by mast cells, can directly activate or sensitize pain-transmitting nerves, leading to increased pain signalling and abdominal pain. Finally, we discuss the potential of interventions targeting immune activation as a new therapeutic strategy for patients suffering from IBS.
Learn More >The onset of both chronic pain and insomnia is high during adolescence. Although a bidirectional relationship between pain and insomnia has support, how pain and sleep co-develop throughout adolescence remains unknown. Sleep-wake patterns, pre-sleep behavior and pre-sleep arousal may influence the co-development of pain and insomnia. Four waves of longitudinal self-report data were used (N = 2767, Age M = 13.65 years, SD = 0.65). Multidimensional growth mixture modeling was used to identify four subgroups of adolescents with different concurrent trajectories of pain and insomnia. The trajectories followed each other across time in all classes: one class of consistently low pain and insomnia (68.7%), one class with persistent high symptoms (4.9%), as well as one class of increasing (13.9%), and one of decreasing (12.5%), trajectories. Later sleep-wake patterns and more pre-sleep cognitive-emotional arousal predicted both increasing and decreasing trajectories of concurrent pain and insomnia. The current study showed that developmental trajectories of pain and insomnia follow each other within adolescents and across adolescence. Both sleep-phase focused interventions as well as psychological interventions that focus on pre-sleep cognitive-emotional arousal may prove beneficial for adolescents with comorbid pain and insomnia.
Learn More >To identify groups of people with rheumatoid arthritis (RA) with different disability trajectories over ten years, despite comparable levels of inflammation.
Learn More >To use daily data collected via a smartphone app for characterisation of patient-reported and "symptom-based" (using an a priori definition) flares in an adult idiopathic inflammatory myopathy (IIM) cohort.
Learn More >Increasing evidence suggests that migraine may be the result of an impaired brain glucose metabolism. Several studies have reported brain mitochondrial dysfunction, impaired brain glucose metabolism and gray matter volume reduction in specific brain areas of migraineurs. Furthermore, peripheral insulin resistance, a condition demonstrated in several studies, may extend to the brain, leading to brain insulin resistance. This condition has been proven to downregulate insulin receptors, both in astrocytes and neurons, triggering a reduction in glucose uptake and glycogen synthesis, mainly during high metabolic demand. This scoping review examines the clinical, epidemiologic and pathophysiologic data supporting the hypothesis that abnormalities in brain glucose metabolism may generate a mismatch between the brain's energy reserve and metabolic expenditure, triggering migraine attacks. Moreover, alteration in glucose homeostasis could generate a chronic brain energy deficit promoting migraine chronification. Lastly, insulin resistance may link migraine with its comorbidities, like obesity, depression, cognitive impairment and cerebrovascular diseases. Perspective: Although additional experimental studies are needed to support this novel "neuroenergetic" hypothesis, brain insulin resistance in migraineurs may unravel the pathophysiological mechanisms of the disease, explaining the migraine chronification and connecting migraine with comorbidities. Therefore, this hypothesis could elucidate novel potential approaches for migraine treatment.
Learn More >Assessing the impact of migraine preventive treatments on acute medication consumption is important in clinical evaluation. The number of acute medication intakes per each monthly migraine day (MMD) could provide insights on migraine burden and represent a new proxy of treatment effectiveness in clinical trials and real-life studies. We evaluated the effect of monoclonal antibodies acting on calcitonin gene-related peptide (CGRP) pathway on the consumption of migraine acute medication in real-life.
Learn More >Bladder pain syndrome/interstitial cystitis (BPS/IC) is a refractory disease accompanied by bladder-related pain and hyperactivity. Studies have shown that the translocator protein (TSPO) modulates neuroinflammation and central sensitisation associated with pain. Moreover, we previously demonstrated that brain-derived neurotrophic factor (BDNF) regulates neuroinflammation and mechanical allodynia in cyclophosphamide (CYP)-induced cystitis through activation of glial cells. Here, we aimed to explore whether activation of TSPO attenuates mechanical allodynia and bladder dysfunction by regulating BDNF induced neuroinflammation in a CYP-induced cystitis model.
Learn More >Poly(etheretherketone) (PEEK) implants suffer from poor osseointegration because of chronic inflammation. In this study, we hypothesized that adding NH and COOH groups to the surface of PEEK could modulate macrophage responses by altering protein adsorption and improve its osseointegration. NH and COOH-functionalized PEEK surfaces induced pro- and anti-inflammatory macrophage responses, respectively, and differences in protein adsorption patterns on these surfaces were related to the varied inflammatory responses. The macrophage responses to NH surfaces significantly reduced the osteogenic differentiation of mesenchymal stem cells (MSCs). MSCs cultured on NH surfaces differentiated less than those on COOH surfaces even though NH surfaces promoted the most mineralization in simulated body fluid solutions. After 14 days in rat tibia unicortical defects, the bone around NH surfaces had thinner trabeculae and higher specific bone surface than the bone around unmodified implants; surprisingly, the NH implants significantly increased bone-binding over the unmodified implants, while COOH implants only showed a trend for increasing bone-binding. Taken together, these results suggest that both mineral-binding and immune responses play a role in osseointegration, and PEEK implant integration may be improved with mixtures of these two functional groups to harness the ability to reduce inflammation and bind bone strongly.
Learn More >To evaluate the use of low-dose naltrexone (LDN) as a broad-spectrum analgesic. Retrospective cohort study from a single pain management practice using data from 2014 to 2020. Thirty-six patients using LDN for ≥2 months were matched to 42 controls. Pain scores were assessed at initial visit and at most recent/final documented visit using a 10-point scale. Cases reported significantly greater pain reduction (-37.8%) than controls (-4.3%; p < 0.001). Whole sample multivariate modeling predicts 33% pain reduction with LDN, with number needed to treat (for 50% pain reduction) of 3.2. Patients with neuropathic pain appeared to benefit even more than those with 'nociceptive'/inflammatory pain. LDN is effective in a variety of chronic pain states, likely mediated by TLR-4 antagonism.
Learn More >To examine postpartum opioid prescribing practices. Obstetricians were interviewed about opioids: choice of opioid, clinical factors considered when prescribing, thoughts/beliefs about prescribing, and typical counseling provided. Inductive thematic analyses were used to identify themes. A total of 38 interviews were analyzed. Several key points emerged. The choice of opioid, dosing and number of pills prescribed varied widely. The mode of delivery is the primary consideration for prescribing opioids. All providers would prescribe opioids to breastfeeding women. Some providers offered counseling on nonopioid treatment of pain. At two large tertiary centers in Pennsylvania, the 38 physicians interviewed wrote 38 unique opioid prescriptions. Patient counseling addressed short-term pain management, but not the chronic overuse of opioids.
Learn More >Casitas B-lineage lymphoma b (Cbl-b) is one of the E3 ubiquitin ligases that ubiquitinate Tropomyosin-related kinase A (TrkA), a key nerve growth factor receptor involved in the pathological pain. Here we found that Cbl-b was abundant in dorsal root ganglion (DRG) neurons of mice and co-localized with TrkA. Ubiquitination of TrkA by Cbl-b exerted a tonic negative control over the protein level of TrkA. Knockdown of Cbl-b caused TrkA accumulation in DRGs and evoked mechanical and heat hypersensitivity in intact mice. Our data showed that knee osteoarthritis induced by destabilization of the medial meniscus (DMM) led to the dissociation of Cbl-b with TrkA in DRG neurons, which impaired the ability of Cbl-b to ubiquitinate TrkA and served as an important mechanism to cause TrkA-dependent pain sensitization. Viral expression of constitutively active Cbl-b in DRGs of osteoarthritic mice effectively repressed TrkA protein level and more importantly, alleviated mechanical allodynia and heat hyperalgesia. Viral delivery of Cbl-b through intra-articular route generated a similar analgesic action. These data suggested that ubiquitination of TrkA by Cbl-b might represent an effective way to treat the osteoarthritic pain.
Learn More >Cranial autonomic symptoms (CASs) during migraine attacks are reported to be quite common regardless of ethnicity. In our previous study investigating 373 migraineurs, we found that 42.4% of them had CASs. The patients with CASs more frequently had cutaneous allodynia than did those without CASs, and we speculated that CASs were associated with central sensitization. The present study searched for substantial evidence on the relationship between CASs and central sensitization in migraine patients.
Learn More >Over 50% of adolescents with chronic pain report comorbid sleep disturbances (e.g., difficulties with falling asleep), which is associated with increased pain-related disability and poorer quality of life. However, limited longitudinal data are available to understand how sleep disturbance may impact response to psychological treatment. Our primary hypothesis was that baseline sleep disturbances would significantly modify how adolescents responded to an internet-delivered psychological intervention for chronic pain in terms of outcome trajectories. The sample included 85 adolescents, 12 to 17 years, with chronic pain recruited from a multidisciplinary pain clinic and headache clinic who received access to an internet-delivered psychological intervention for chronic pain. Baseline sleep assessment included actigraphy monitoring for 7 days and survey measures. Outcomes were assessed at baseline, 8 weeks, and 3 months including core pain-related outcomes, executive functioning, fatigue, positive and negative affect. Results demonstrated that greater baseline insomnia and poorer sleep quality was associated with worse outcome trajectories for pain-related disability, depression, anxiety, fatigue, negative affect, and executive functioning. Findings extend the limited studies that examine how sleep disturbance may modify effectiveness of psychological treatments for adolescent chronic pain and emphasize the importance of treating comorbid sleep disturbance. This trial was registered at clinicaltrials.gov (NCT04043962). Perspective: Our study suggests that sleep deficiency, in particular insomnia and poor sleep quality, may modify the effectiveness of psychological treatments for chronic pain, highlighting the urgent need to screen youth for sleep problems prior to initiating treatment, and to consider implementation of sleep-specific treatments such as cognitive-behavioral therapy for insomnia.
Learn More >The time criteria used in many studies of postherpetic neuralgia (PHN) are arbitrary and do not have supporting evidence. Therefore, this study sought to determine the definite time criterion for PHN by analyzing the skin temperature to estimate the time point when zoster-induced skin inflammatory reaction ends.
Learn More >Functional improvement is a critical outcome for individuals living with chronic pain. Graded exposure treatment has been associated with statistically significant improvements in functional outcomes for youth with chronic pain by targeting pain-related fear and avoidance.
Learn More >Throughout the somatosensory system, neuronal ensembles generate high-frequency signals in the range of several hundred Hertz in response to sensory input. High-frequency signals have been related to neuronal spiking, and could thus help clarify the functional architecture of sensory processing. Recording high-frequency signals from subcortical regions, however, has been limited to clinical pathology whose treatment allows for invasive recordings. Here, we demonstrate the feasibility to record 200-1200 Hz signals from the human spinal cord non-invasively, and in healthy individuals. Using standard electroencephalography equipment in a cervical electrode montage, we observed high-frequency signals between 200 and 1200 Hz in a time window between 8 and 16 ms after electric median nerve stimulation (n=15). These signals overlapped in latency, and, partly, in frequency, with signals obtained via invasive, epidural recordings from the spinal cord in a patient with neuropathic pain. Importantly, the observed high-frequency signals were dissociable from classic spinal evoked responses. A spatial filter that optimized the signal-to-noise ratio of high-frequency signals led to submaximal amplitudes of the evoked response, and vice versa, ruling out the possibility that high-frequency signals are merely a spectral representation of the evoked response. Furthermore, we observed spontaneous fluctuations in the amplitude of high-frequency signals over time, in the absence of any concurrent, systematic change to the evoked response. High-frequency, "spike-like" signals from the human spinal cord thus carry information that is complementary to the evoked response. The possibility to assess these signals non-invasively provides a novel window onto the neurophysiology of the human spinal cord, both in a context of top-down control over perception, as well as in pathology.
Learn More >Background In the mid-1990s, the development of combination antiretroviral therapy converted HIV infection into a chronic condition, with newly diagnosed patients now living longer than the general population. HIV affects both the central and peripheral nerve systems, resulting in a variety of clinical problems, including peripheral neuropathy, which is a common neurological consequence. Despite this, there is a scarcity of information on the extent of peripheral sensory neuropathy and its underlying factors in Ethiopia, necessitating this study.
Learn More >Interventions to reduce harms related to prescription opioids are needed in primary care settings.
Learn More >The aim of this study was to identify the manual therapy (MT) methods and techniques that have been evaluated for the treatment of cervicogenic headache (CH) and their effectiveness.
Learn More >Implanted and transcutaneous nerve stimulators have shown promise as novel non-pharmacologic treatment for episodic and chronic migraines. The purpose of this study was to summarize the reported efficacy of transcutaneous single nerve stimulators in management of migraine frequency and severity.
Learn More >The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health crisis that has had a range of impacts on people living with migraine.
Learn More >Cluster headache, a primary headache disorder, consists of short (15-180 minutes), frequent (up to eight a day), unilateral attacks of facial pain with associated ipsilateral autonomic features and restlessness. The attacks are suspected to be one of the most painful human experiences, and the disorder is associated with a high rate of suicidal ideation. Proper diagnosis is key, as some of the most effective treatments, such as high flow oxygen gas, are rarely used in other headache disorders. Yet diagnostic delay is typically years for this disorder, as it is often confused with migraine and trigeminal neuralgia, and secondary causes may be overlooked. This review covers the clinical, pathophysiologic, and therapeutic features of cluster headache. Recent updates in diagnosis include the redefinition of chronic cluster headache (remission periods lasting less than three months instead of the previous one month), and recent advances in management include new treatments for episodic cluster headache (galcanezumab and non-invasive vagus nerve stimulation).
Learn More >Chronic prurigo (CPG) is characterized by intensive itch and nerve-neuropeptide-mast cell interactions. The role of some neuropeptides such as cortistatin and its receptor MRGPRX2 in CPG is poorly investigated.
Learn More >To describe the design, development and pilot of a multicomponent intervention aimed at supporting withdrawal of opioids for people with chronic non-malignant pain for future evaluation in the Improving the Wellbeing of people with Opioid Treated CHronic pain (I-WOTCH) randomised controlled trial.
Learn More >Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are promising targets for neuropathic pain and other CNS disorders. Based on our previous lead compound SIH 3, we designed and synthesized a series of 4-methylsulfonylphenyl semicarbazones and evaluated for FAAH and MAGL inhibition properties. Most of the compounds showed potency towards both enzymes with leading FAAH selectivity. Compound (Z)-2-(2,6-dichlorobenzylidene)-N-(4-(methylsulfonyl)phenyl)hydrazine-1-carboxamide emerged as the lead inhibitor against both FAAH (IC = 11 nM) and MAGL (IC = 36 nM). The lead inhibitor inhibited FAAH by non-competitive mode, but showed a mixed-type inhibition against MAGL. Molecular docking study unveiled that the docked ligands bind favorably to the active sites of FAAH and MAGL. The lead inhibitor interacted with FAAH and MAGL via π-π stacking via phenyl ring and hydrogen bonding through sulfonyl oxygen atoms or amide NH. Moreover, the stability of docked complexes was rationalized by molecular simulation studies. PAMPA assay revealed that the lead compound is suitable for blood-brain penetration. The lead compound showed better cell viability in lipopolysaccharide-induced neurotoxicity assay in SH-SY5Y cell lines. Further, in-vivo experiments unveiled that dual inhibitor was safe up to 2000 mg/kg with no hepatotoxicity. The dual FAAH-MAGL inhibitor produced significant anti-nociceptive effect in the CCI model of neuropathic pain without altering locomotion activity. Lastly, the lead compound exhibited promising ex-vivo FAAH/MAGL inhibition activity at the dose of 10 mg/kg and 20 mg/kg. Thus, these findings suggest that the semicarbazone-based lead compound can be a potential template for the development of agents for neuropathic pain.
Learn More >Virtual reality (VR) is a burgeoning treatment option for chronic pain. Its use has been heterogenous in the literature. This scoping review assesses the current literature for the use of VR in the treatment of chronic low back pain (CLBP). The following themes were identified by the analysis: safety and feasibility of VR, quality of life associated with VR treatment for CLBP, efficacy of VR to treat CLBP, and efficacy of VR to treat functional changes associated with CLBP. Gaps were identified after analysis of the extant literature. Although the nascent research uncovered in this scoping review found good evidence for safety and tolerability of VR, more studies of safety, acceptance, and satisfaction are recommended including focused studies of spinal pain risks specific to use of VR. Overall, the methodological quality of studies reviewed in this scoping review was poor and outcomes were limited to short-term posttreatment outcomes.
Learn More >The outbreak of COVID-19 poses a serious threat to global health. Musculoskeletal (MSK) pain is the most frequent symptom in patients with COVID-19 besides fever and cough. There are limited studies addressing MSK symptoms in patients with COVID-19. This review aims to provide an overview of current studies related to MSK pain in patients with COVID-19, summarize the possible mechanisms of myalgia, and describe the current management options. In addition to acute respiratory manifestations, COVID-19 might also affect neurological systems which include skeletal manifestations and muscular injury. A possible mechanism of MSK pain and myalgia in COVID-19 may be related to the distribution of angiotensin-converting enzyme 2 (ACE-2) and the occurrence of cytokine storms. ACE-2 has been shown to be the receptor of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV2). Moreover, studies have shown that inflammatory cytokines could cause myalgia by inducing prostaglandin E2 (PGE2) production. In addition, it was also found that the plasma levels of IL2, IL7, IL10, IL-6, TNFα, and e lymphopenia were higher in patients with COVID-19. In general, the treatment of MSK pain in patients with COVID-19 falls into pharmacological and non-pharmacological interventions. Various treatments of each have its own merits. The role of vaccination is irreplaceable in the efforts to prevent COVID-19 and mitigates its subsequent symptoms.
Learn More >Mitochondrial reactive oxygen species (mROS) that are overproduced by mitochondrial dysfunction are linked to pathological conditions including sensory abnormalities. Here, we explored whether mROS overproduction induces itch through transient receptor potential canonical 3 (TRPC3), which is sensitive to ROS. Intradermal injection of antimycin A (AA), a selective inhibitor of mitochondrial electron transport chain complex III for mROS overproduction, produced robust scratching behavior in naïve mice, which was suppressed by MitoTEMPO, a mitochondria-selective ROS scavenger, and Pyr10, a TRPC3-specific blocker, but not by blockers of TRPA1 or TRPV1. AA activated subsets of trigeminal ganglion neurons and also induced inward currents, which were blocked by MitoTEMPO and Pyr10. Besides, dry skin-induced chronic scratching was relieved by MitoTEMPO and Pyr10, and also by resveratrol, an antioxidant. Taken together, our results suggest that mROS elicit itch through TRPC3, which may underlie chronic itch, representing a potential therapeutic target for chronic itch.
Learn More >Osteoarthritis (OA), although extensively researched, still lacks an effective and safe treatment. The only current treatment option available for advanced OA is joint replacement surgery. This surgery may pose the risks of persistent pain, surgical complications and limited implant lifespan. Transforming growth factor (TGF)‑β has a crucial role in multiple cellular processes such as cell proliferation. Any deterioration in TGF‑β signaling pathways can have an immense impact on OA. Owing to the crucial role of TGF‑β in cartilage homeostasis, targeting it could be an alternative therapeutic approach. Additionally, stem cell‑based therapy has recently emerged as an effective treatment strategy that could replace surgery. A number of recent findings suggest that the tissue regeneration effect of stem cells is attributed to the paracrine secretion of anti‑inflammatory and chondroprotective mediators or trophic factors, particularly nanosized extracellular vesicles (i.e., exosomes). Literature searches were performed in the MEDLINE, EMBASE, Cochrane Library and PubMed electronic database for relevant articles published before September 2021. Multiple investigators have confirmed TGF‑β3 as a promising candidate which has the chondrogenic potential to repair articular cartilage degeneration. Combining TGF‑β3 with bone morphogenetic proteins‑6, which has synergistic effect on chondrogenesis, with an efficient platform such as exosomes, which themselves possess a chondroprotective function, offers an innovative and more efficient approach to treat injured cartilage. In addition, multiple findings stating the role of exosomes in chondroprotection has also verified a similar fact showing exosomes may be a more favorable choice than the source itself. In the present review, the importance of TGF‑β family in OA and the possibility of therapeutic treatment using stem cell‑derived exosomes are described.
Learn More >Gout is a common hyperuricemic metabolic condition, leading to recurrent inflammatory arthritis and some of the most severe pain experienced by humans. As detailed in a recent Global Burden of Disease analysis of 195 countries and territories between 1990 and 2017, the incidence, prevalence, and disability burden of gout have risen worldwide for decades, and the condition now affects > 10 million US adults (4%)..
Learn More >Botulinum toxin type A (BTX-A) is a recently developed treatment for the management of peripheral neuropathic pain. The objective of this study was to provide a synthesis of the evidence concerning the efficacy and safety of subcutaneous botulinum toxin type A injections.
Learn More >During and after general anaesthesia, opioids are commonly used for pain treatment. Since preclinical studies underlined the potential immunosuppressive activity of these drugs, it was postulated that their perioperative administration could influence cancer outcomes after surgery. Nevertheless, clinical data have been extrapolated mainly from retrospective analyses. Consequently, the precise link between perioperative opioid use and cancer recurrence/metastasis or cancer-related mortality/morbidity is still an unsolved issue.
Learn More >Despite the rising number of older adults with medical encounters for opioid misuse, dependence, and poisoning, little is known about patterns of prescription opioid dose and their association with risk for opioid-related adverse events (ORAEs) in older patients. The study aims to compare trajectories of prescribed opioid doses in 6 months preceding an incident ORAE for cases and a matched control group of older patients with chronic noncancer pain (CNCP).
Learn More >The posterior-superior insula (PSI) has been shown to be a safe and potentially effective target for neuromodulation in peripheral neuropathic pain (PNP) in humans and animal models. However, it remains unknown whether there is a measurable responder profile to PSI stimulation. Two factors were hypothesized to influence the response of repetitive transcranial magnetic stimulation (rTMS) of the PSI: differences in rTMS target (discrete subregions of the PSI) or PNP phenotype.
Learn More >Migraine is a common primary headache disorder. Transcutaneous auricular vagus nerve stimulation (taVNS) has been verified to be effective in patients with migraine without aura (MWoA). However, there are large interindividual differences in patients' responses to taVNS. This study aimed to explore whether pretreatment fractional amplitude of low frequency fluctuation (fALFF) features could predict clinical outcomes in MWoA patients after 4-week taVNS. Sixty MWoA patients and sixty well-matched healthy controls (HCs) were recruited, and migraineurs received 4-week taVNS treatment. Resting-state functional magnetic resonance imaging (rs-fMRI) data were collected, and the significant differences of fALFF were detected between MWoA patients and HCs using two-sample -test. A mask of these significant regions was generated and used for subsequent analysis. The abnormal fALFF in the mask was used to predict taVNS efficacy for MWoA using a support vector regression (SVR) model combining with feature select of weight based on the LIBSVM toolbox. We found that (1) compared with HCs, MWoA patients exhibited increased fALFF in the left thalamus, left inferior parietal gyrus (IPG), bilateral precentral gyrus (PreCG), right postcentral gyrus (PoCG), and bilateral supplementary motor areas (SMAs), but decreased in the bilateral precuneus and left superior frontal gyrus (SFG)/medial prefrontal cortex (mPFC); (2) after 4-week taVNS treatment, the fALFF values significantly decreased in these brain regions based on the pretreatment comparison. Importantly, the decreased fALFF in the bilateral precuneus was positively associated with the reduction in the attack times ( = 0.357, = 0.005, Bonferroni correction, 0.05/5), whereas the reduced fALFF in the right PoCG was negatively associated with reduced visual analog scale (VAS) scores ( = -0.267, = 0.039, uncorrected); (3) the SVR model exhibited a good performance for prediction ( = 0.411, < 0.001),which suggests that these extracted fALFF features could be used as reliable biomarkers to predict the treatment response of taVNS for MWoA patients. This study demonstrated that the baseline fALFF features have good potential for predicting individualized treatment response of taVNS in MWoA patients, and those weight brain areas are mainly involved in the thalamocortical (TC) circuits, default mode network (DMN), and descending pain modulation system (DPMS). This will contribute to well understanding the mechanism of taVNS in treating MWoA patients and may help to screen ideal patients who respond well to taVNS treatment.
Learn More >Machine learning (ML) has been largely applied for predicting migraine classification. However, the prediction of efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) in migraine is still in the early stages. This study aims to evaluate whether the combination of machine learning and amygdala-related functional features could help predict the efficacy of NSAIDs in patients with migraine without aura (MwoA). A total of 70 MwoA patients were enrolled for the study, including patients with an effective response to NSAIDs (M-eNSAIDs, = 35) and MwoA patients with ineffective response to NSAIDs (M-ieNSAIDs, = 35). Furthermore, 33 healthy controls (HCs) were matched for age, sex, and education level. The study participants were subjected to resting-state functional magnetic resonance imaging (fMRI) scanning. Disrupted functional connectivity (FC) patterns from amygdala-based FC analysis and clinical characteristics were considered features that could promote classification through multivariable logistic regression (MLR) and support vector machine (SVM) for predicting the efficacy of NSAIDs. Further, receiver operating characteristic (ROC) curves were drawn to evaluate the predictive ability of the models. The M-eNSAIDs group exhibited enhanced FC with ipsilateral calcarine sulcus (CAL), superior parietal gyrus (SPG), paracentral lobule (PCL), and contralateral superior frontal gyrus (SFG) in the left amygdala. However, the M-eNSAIDs group showed decreased FC with ipsilateral caudate nucleus (CAU), compared to the M-ieNSAIDs group. Moreover, the M-eNSAIDs group showed higher FC with left pre-central gyrus (PreCG) and post-central gyrus (PoCG) compared to HCs. In contrast, the M-ieNSAIDs group showed lower FC with the left anterior cingulate cortex (ACC) and right SFG. Furthermore, the MwoA patients showed increased FC with the left middle frontal gyrus (MFG) in the right amygdala compared to HCs. The disrupted left amygdala-related FC patterns exhibited significant correlations with migraine characteristics in the M-ieNSAIDs group. The MLR and SVM models discriminated clinical efficacy of NSAIDs with an area under the curve (AUC) of 0.891 and 0.896, sensitivity of 0.971 and 0.833, and specificity of 0.629 and 0.875, respectively. These findings suggest that the efficacy of NSAIDs in migraine could be predicted using ML algorithm. Furthermore, this study highlights the role of amygdala-related neural function in revealing underlying migraine-related neuroimaging mechanisms.
Learn More >Transcranial magnetic stimulation (TMS) is an FDA approved treatment for major depression, migraine, obsessive compulsive disorder, and smoking addiction. TMS has gained popular media support, but media coverage and commercial reporting of TMS services may be contributing to the landscape of ethical issues.
Learn More >It's been reported that the tumor necrosis factor alpha inducible protein 3 () gene played an important role in the pathogenesis of autoimmune and chronic inflammation diseases. Moreover, in degenerative diseases of the lumbar spine the nuclear factor-κB (NF-κB) pathway is significantly activated. This study aimed to explore the role of the tumor necrosis protein-induced zinc finger protein A20 (A20) protein in degenerative diseases of the lumbar spine on the NF-κBp65 pathway.
Learn More >Migraine affects more than one billion individuals each year across the world, and is one of the most common neurologic disorders, with a high prevalence and morbidity, especially among young adults and females. Migraine is associated with a wide range of comorbidities, which range from stress and sleep disturbances to suicide. The complex and largely unclear mechanisms of migraine development have resulted in the proposal of various social and biological risk factors, such as hormonal imbalances, genetic and epigenetic influences, as well as cardiovascular, neurological, and autoimmune diseases. This review presents a comprehensive review of the most up-to-date literature on the epidemiology, and risk factors, as well as highlighting the gaps in our knowledge.
Learn More >Both metabotropic (CBRs) and ionotropic cannabinoid receptors (ICRs) have implications in a range of neurological disorders. The metabotropic canonical CBRs CB1 and CB2 are highly implicated in these pathological events. However, selective targeting at CB2 versus CB1 offers optimized pharmacology due to the absence of psychoactive outcomes. The ICR transient receptor potential vanilloid type 1 (TRPV1) has also been reported to play a role in CNS disorders. Thus, activation of both targets, CB2 and TRPV1, offers a promising polypharmacological strategy for the treatment of neurological events including analgesia and neuroprotection. This brief research report aims to identify chemotypes with a potential dual CB2/TRPV1 profile. For this purpose, we have rationalized key structural features for activation and performed virtual screening at both targets using curated chemical libraries.
Learn More >Despite mounting evidence for the powerful influence of smell and taste substances in experimental pain, our knowledge of their effects in the clinical context is scarce, especially for patients with chronic oral burning pain. To fill this gap, we investigated the effect of olfactory and gustatory stimuli on pain perception in patients with chronic oral burning pain, a disabling condition that is difficult to manage and treat.
Learn More >Neuropathic pain is a chronic pain condition seen in patients with diabetic neuropathy, cancer chemotherapy-induced neuropathy, idiopathic neuropathy as well as other diseases affecting the nervous system. Only a small percentage of people with neuropathic pain benefit from current medications. The complexity of the disease, poor identification/lack of diagnostic and prognostic markers limit current strategies for the management of neuropathic pain. Multiple genes and pathways involved in human diseases can be regulated by microRNA (miRNA) which are small non-coding RNA. Several miRNAs are found to be dysregulated in neuropathic pain. These miRNAs regulate expression of various genes associated with neuroinflammation and pain, thus, regulating neuropathic pain. Some of these key players include adenylate cyclase ( toll-like receptor 8 suppressor of cytokine signaling 3 signal transducer and activator of transcription 3 and RAS p21 protein activator 1 . With advancements in high-throughput technology and better computational power available for research in present-day pharmacology, biomarker discovery has entered a very exciting phase. We dissect the architecture of miRNA biological networks encompassing both human and rodent microRNAs involved in the development of neuropathic pain. We delineate various microRNAs, and their targets, that may likely serve as potential biomarkers for diagnosis, prognosis, and therapeutic intervention in neuropathic pain. miRNAs mediate their effects in neuropathic pain by signal transduction through IRAK/TRAF6, TLR4/NF-κB, TXIP/NLRP3 inflammasome, MAP Kinase, TGFβ and TLR5 signaling pathways. Taken together, the elucidation of the landscape of signature miRNA regulatory networks in neuropathic pain will facilitate the discovery of novel miRNA/target biomarkers for more effective management of neuropathic pain.
Learn More >There is currently an emphasis on the biopsychosocial concept of pain in pain therapy programs. However, the complexity of chronic pain, in particular its importance for those affected by it, can only be insufficiently captured with this concept. This is due to the fact that, to date, one core aspect of the phenomenon chronic pain has only rarely been taken into account: its existential character. Chronic pain can threaten the self-image and the individual's understanding of the world, their wishes and goals in life, and ultimately the entire integrity of those affected. Statements by chronic pain sufferers show that such pain always represents an existential experience and affects the person as a whole. Two aspects make this very clear: the existential despair of the pain on the one hand, as well as questions of meaning and reorientation on the other. Current treatment concepts, however, do not adequately consider the existential character of such challenges. Chronic pain should therefore always be perceived and treated from a holistic perspective. In this context, the aspects of recognizing its uniqueness, helping to express the pain and giving space to the experience are to be given special consideration in order to support chronic pain patients in dealing with their pain.
Learn More >The human ATP- and UTP-activated P2Y receptor (P2YR) is a G protein-coupled receptor involved in several pathophysiological conditions including acute and chronic inflammation, cancer, and pain. Despite its potential as a novel drug target, only few P2YR antagonists have been developed so far, all of which suffer from severe drawbacks. These include (i) high polarity due to one or several negative charges resulting in low oral bioavailability, (ii) metabolic instability and generally poor pharmacokinetic properties, and/or (iii) lack of selectivity, which limits their utility for and studies aimed at target validation. In search of new druglike scaffolds for P2YR antagonists, we employed a structure-based virtual high-throughput screening approach utilizing the complex of a P2YR homology model with one of the most potent and selective orthosteric antagonists described so far, AR-C118925 (). After virtual screening of 3.2 million molecules, 58 compounds were purchased and pharmacologically evaluated. Several novel antagonist scaffolds were discovered, and their binding modes at the human P2YR were analyzed by molecular docking studies. The investigated antagonists likely share a similar binding mode with which includes accommodation of bulky, lipophilic groups in the putative orthosteric binding site of the P2YR. The discovered scaffolds and the elucidated structure-activity relationships provide a basis for the development of future drug candidates for the P2YR which have great potential as novel drugs.
Learn More >This paper discusses the growing problem of persisting pain after successful treatment of breast cancer and presents recommendations for improving pain-related outcomes for this group. We discuss the dominant treatment approach for persisting pain post-breast cancer treatment and draw contrasts with contemporary treatment approaches to persistent pain in non-cancer-related populations. We discuss modern application of the biopsychosocial model of pain and the notion of variable sensitivity within the pain system, moment by moment and over time. We present the implications of increasing sensitivity over time for treatment selection and implementation. By drawing on transformative changes in treatment approaches to persistent non-cancer-related pain, we describe the potentially powerful role that an intervention called pain science education, which is now recommended in clinical guidelines for musculoskeletal pain, may play in improving pain and disability outcomes after successful breast cancer treatment. Finally, we present several research recommendations that centre around adaptation of the content and delivery models of contemporary pain science education, to the post-breast cancer context.
Learn More >Painful diabetic neuropathy is one of the most common complications of diabetes in humans. The current treatments are not completely effective, and the main mechanisms implicated in the development of diabetic neuropathy are not completely elucidated. Thus, in male db/db mice, a murine model of type 2 diabetes, we investigated the effects of treatment with a heme oxygenase 1 (HO-1) inducer, cobalt protoporphyrin IX (CoPP), on the 1) hyperglycemia and mechanical allodynia associated with type 2 diabetes and 2) molecular changes induced by diabetic neuropathy in the central nervous system (CNS). Thus, we evaluated the effects of CoPP on the protein levels of 4-HNE (oxidative stress), Nrf2, superoxide dismutase 1 (SOD1), NAD(P)H quinone oxidoreductase 1 (NQO1), HO-1, glutathione S-transferase Mu 1 (GSTM1) (antioxidant enzymes), phosphatidylinositol 3-kinase/protein kinase B (nociceptive pathway), CD11b/c (microglial activation), and BAX (apoptosis) in the amygdala and spinal cord of db/db mice. Our results showed the antihyperglycemic and antiallodynic effects of CoPP treatment as well as the potent antioxidant, antinociceptive, anti-inflammatory, and antiapoptotic properties of this HO-1 inducer in the CNS of type 2 diabetic mice. Treatment with CoPP also prevented the downregulation of several antioxidant proteins (Nrf2, SOD-1, and NQO1) and/or enhanced the protein levels of HO-1 and GSTM1 in the spinal cord and/or amygdala of db/db mice. These effects might be implicated in the antiallodynic actions of CoPP. Our findings revealed the modulatory effects of CoPP in the CNS of db/db mice and provide new prospects for novel type 2 diabetes-associated neuropathy therapies.
Learn More >To use data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) to estimate mortality and disability trends for the population aged ≥70 and evaluate patterns in causes of death, disability, and risk factors.
Learn More >Ulcerative colitis (UC) is an inflammatory disease with chronic relapsing symptoms. This study investigated the effects of polysaccharides (LBP) and capsaicin (CAP) in dextran sulfate sodium (DSS)-induced UC rats. Rats were divided into normal, DSS-induced UC, and UC treated with 100 mg LBP/kg bw, 12 mg CAP/kg bw, or 50 mg LBP/kg bw and 6 mg CAP/kg bw. Rats were fed LBP or CAP orally by gavage for 4 weeks, and UC model was established by feeding 5% DSS in drinking water for 6 days during week 3. Oral CAP and mixture significantly reduced disease activity index. Oral LBP significantly decreased serum malondialdehyde, interleukin (IL)-6, colonic tumor necrosis factor (TNF)-α levels, and protein expression of transient receptor potential cation channel V1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1), but increased serum catalase activity. Oral CAP significantly suppressed serum IL-6, colonic TRPV1 and TRPA1 protein expression, but elevated IL-10 levels, serum superoxide dismutase and catalase activities. The mixture of LBP and CAP significantly reduced serum IL-6, colonic TNF-α and TRPA1 protein. In conclusion, administration of LBP and/or CAP attenuate DSS-induced UC symptoms through inhibiting oxidative stress, proinflammatory cytokines, and protein expression of TRPV1 and TRPA1.
Learn More >The concept of "invalidation" refers to the patient's perception that the social environment does not recognize their medical condition. This study explores and describes invalidation experiences among Swedish patients with chronic widespread pain with regard to sociodemographic and pain characteristics, impact of pain, self-reported health, and symptoms of anxiety and depressive. Methods: A cross-sectional design using questionnaires, including sociodemographic and pain variables, the Illness Invalidation Inventory (Likert scale items regarding 5 sources), the Hospital Anxiety and Depression Scale, and the Short-Form General Health Survey. Descriptive and univariate analyses were applied. Results: Of the 152 respondents, 91% were women. Swedish patients with chronic widespread pain experienced invalidation to a large extent from all sources. The highest scores for invalidation were reported from contacts with social services (68%), and the lowest from spouses (30%). Being younger (p < 0.006), having periodic pain (p = 0.011), and having had more frequent visits to a doctor in the previous year (p = 0.007) were characteristics associated with higher invalidation scores. Experiences of invalidation were associated with worse self-reported mental health scores (r = -0.29 to -0.46). Conclusion: Since patients with chronic widespread pain frequently experience invalidation from the social environment, this further challenge in daily life must be taken into consideration in pain management within multimodal pain rehabilitation.
Learn More >Pregabalin is widely used as a treatment for multiple neurological disorders; however, it has been reported to have the potential for misuse. Due to a lack of safety studies in pregnancy, pregabalin is considered the last treatment option for various neurological diseases, such as neuropathic pain. Therefore, pregabalin abuse in pregnant women, even at therapeutic doses, may impair fetal development. We used primary mouse embryonic neurons to investigate whether exposure to pregabalin can impair the morphogenesis and differentiation of ventral midbrain neurons. This study focused on ventral midbrain dopaminergic neurons, as they are responsible for cognition, movement, and behavior. The results showed that pregabalin exposure during early brain development induced upregulation of the dopaminergic progenitor genes and and the mature dopaminergic gene . Interestingly, pregabalin had different effects on the morphogenesis of non-dopaminergic ventral midbrain neurons. Importantly, our findings illustrated that a therapeutic dose of pregabalin (10 μM) did not affect the viability of neurons. However, it caused a decrease in ATP release in ventral midbrain neurons. We demonstrated that exposure to pregabalin during early brain development could interfere with the neurogenesis and morphogenesis of ventral midbrain dopaminergic neurons. These findings are crucial for clinical consideration of the use of pregabalin during pregnancy.
Learn More >For this systematic review, a search of the relevant literature was conducted in the EMBASE and PubMed databases. We used the following terms: 'rheumatoid arthritis' in conjunction with 'fatty acid'. The following inclusion criteria had to be satisfied for the studies to be included in the analysis: an RCT/observational/cohort study published in English. A total of seventy-one studies were analysed. The presented systematic review of the available data indicates that increased consumption of omega-3 fatty acids (FAs) may have a beneficial effect on human health by decreasing pain and disease activity in patients with RA. The beneficial effect of unsaturated FA on the clinical parameters of RA was demonstrated in all 71 studies analysed. The content of omega-3 FAs in the diet and the consumption of fish, which are their main source, may contribute to a reduced incidence of RA. FAs are an essential component in the synthesis of eicosanoids that exhibit anti-inflammatory properties. Due to the documented positive influence of unsaturated FAs on treatment outcomes, the use of a diet rich in long-chain unsaturated FAs should be the standard of care, along with pharmacotherapy, in the treatment of RA patients. An important element in the control of the treatment process should be the routine assessment of the quality of life of RA patients.
Learn More >Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. We focused on solute carrier family 17 member 9 (SLC17A9)/vesicular nucleotide transporter (VNUT) and purinergic receptor P2Y12 (P2RY12), both of which have been associated with neuropathic pain and pain transduction signaling in the trigeminal ganglion in rodents. We sought to corroborate these associations in humans. We investigated gene polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 150 patients with orofacial pain, including PTP, and 500 healthy subjects. We found that the rs735055 polymorphism of the gene and rs3732759 polymorphism of the gene were associated with the development of PTP. Carriers of the minor allele of rs735055 and individuals who were homozygous for the major allele of rs3732759 had a higher rate of PTP. Carriers of the minor allele of rs735055 reportedly had high mRNA expression in the spinal cord, which may increase the storage and release of adenosine triphosphate. Individuals who were homozygous for the major allele of rs3732759 may have higher P2RY12 expression that is more active in microglia. Therefore, these carriers may be more susceptible to PTP. These results suggest that specific genetic polymorphisms of the and genes are involved in PTP. This is the first report on genes that are associated with PTP in humans.
Learn More >Dexketoprofen is an enantiomer of ketoprofen (S+) that belongs to nonsteroidal anti-inflammatory drugs and has analgesic, anti-inflammatory, and antipyretic properties. Dexketoprofen has a stronger effect than ketoprofen, which makes it a readily used preparation. The review aims to find in recent original publications data about dexketoprofen and its comparison with other painkilling medications. The systematic literature review was conducted in November 2021 (2018 onwards). We selected 12 articles from PubMed, Google Scholar, Medline Complete databases. In the last 4 years, there have been many publications that shed a new light on dexketoprofen. The article is a comparative analysis of dexketoprofen's action vs other nonsteroidal anti-inflammatory drugs and the combination of dexketoprofen with tramadol vs paracetamol with tramadol. The findings of the review confirm that dexketoprofen is a very good pain reliever more potent than paracetamol. Dexketoprofen produces similar effects to lidocaine and dexmedetomidine. Complex preparations containing dexketoprofen and tramadol are very effective painkilling tandem and are more effective than tramadol and paracetamol therapy in the treatment of acute pain.
Learn More >Neuropathic pain is an unbearable condition caused by nervous system damage. As distinct acute pain, neuropathic pain is chronic, and it severely influences quality of life. N,N-Dimethyl-d-erythro-sphingosine (DMS), a neuropathic pain inducer, is metabolited de novo from sphingosine. In a recent study, metabolomics showed an increased concentration level of DMS in the spinal cord in mice with neuropathic pain. Nerve growth factor (NGF) is one of the peripheral nervous system targeted pain factors that interact with tropomyosin receptor kinase A (trkA). On the basis of this information, we were interested in the possibility that DMS may induce neuropathic pain-like behavior through an increase of NGF activity. In this study, we showed that DMS can enhance the binding of NGF to trkA, followed by neurite outgrowth of epidermal nerve fibers and phosphorylation of trkA. In addition, a stereoisomer, N,N-dimethyl-l-erythro-sphingosine, did not any show such biological activities. The results suggest that DMS can enhance the binding of NGF to trkA and that its stereochemistry is an essential factor for exhibiting its activity.
Learn More >Chronic pain is a major health challenge to those affected. Blended care with psychomotor physiotherapy (PMP) combined with eHealth self-management might be beneficial.
Learn More >To assess efficacy of an enhanced recovery after surgery (ERAS) protocol and determine its effect on racial/ethnic disparities in post-cesarean pain management.
Learn More >To assess painful diabetic neuropathy (PDN) as a cause for refractory ear pain in type 2 diabetics.
Learn More >This review article aims to describe the perioperative clinical implications of opioid use or opioid use disorder (OUD) and to provide recommendations related to analgesia, anesthesia, and postoperative care for patients with this 'new medical disease'.
Learn More >The purpose of this study is to determine whether pharmacogenetic testing could be used to effectively customize postoperative pain medicine following total joint replacement.
Learn More >Pain neuroscience education (PNE) programs have become popular among clinicians and are widely promoted through social and mainstream media.
Learn More >Comprehensive headache care involves numerous specialties and components that have not been well documented or standardized. This study aimed to elicit best practices and characterize important elements of care to be provided in multidisciplinary headache centers.
Learn More >Chronic pelvic pain (CPP) causes important negative effects on quality of life. Endometriosis is the most common cause of CPP in females, and diagnostic delay is over six years internationally. Data remain scarce for CPP impact or diagnostic delay in Aotearoa New Zealand. This study used an online survey to explore the impact of CPP on various life domains for those aged over 18. Additionally, for those with an endometriosis diagnosis, diagnostic delay and factors affecting this over time were explored. There were 800 respondent (620 with self-reported endometriosis). CPP symptoms, irrespective of final diagnosis, started prior to age 20 and negatively impacted multiple life domains including employment, education, and relationships. Mean diagnostic delay for those with endometriosis was 8.7 years, including 2.9 years between symptom onset and first presentation and 5.8 years between first presentation and diagnosis. Five doctors on average were seen prior to diagnosis. However, there was a reduction in the interval between first presentation and diagnosis over time, from 8.4 years for those presenting before 2005, to two years for those presenting after 2012. While diagnostic delay is decreasing, CPP, irrespective of aetiology, continues to have a significant negative impact on the lives of those affected.
Learn More >To develop a clinical practice guideline to support the management of chronic pain, including low back, osteoarthritic, and neuropathic pain in primary care.
Learn More >Background Mutations in gene encoding the Na,K-ATPase α isoform are associated with familial hemiplegic migraine type 2. Migraine with aura is a known risk factor for heart disease. The Na,K-ATPase is important for cardiac function, but its role for heart disease remains unknown. We hypothesized that is a susceptibility gene for heart disease and aimed to assess the underlying disease mechanism. Methods and Results Mice heterozygous for the familial hemiplegic migraine type 2-associated G301R mutation in the gene (α mice) and matching wild-type controls were compared. Reduced expression of the Na,K-ATPase α isoform and increased expression of the α isoform were observed in hearts from α mice (Western blot). Left ventricular dilation and reduced ejection fraction were shown in hearts from 8-month-old α mice (cardiac magnetic resonance imaging), and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3-month-old α mice were similar to wild-type mice. Amplified Na,K-ATPase-dependent Src kinase/Ras/Erk1/2 (p44/42 mitogen-activated protein kinase) signaling was observed in hearts from 8-month-old α mice, and this was associated with mitochondrial uncoupling (respirometry), increased oxidative stress (malondialdehyde measurements), and a heart failure-associated metabolic shift (hyperpolarized magnetic resonance). Mitochondrial membrane potential (5,5´,6,6´-tetrachloro-1,1´,3,3´-tetraethylbenzimidazolocarbocyanine iodide dye assay) and mitochondrial ultrastructure (transmission electron microscopy) were similar between the groups. Proteomics of heart tissue further suggested amplified Src/Ras/Erk1/2 signaling and increased oxidative stress and provided the molecular basis for systolic dysfunction in 8-month-old α mice. Conclusions Our findings suggest that mutation leads to disturbed cardiac metabolism and reduced cardiac function mediated via Na,K-ATPase-dependent reactive oxygen species signaling through the Src/Ras/Erk1/2 pathway.
Learn More >The use of medical ozone in the treatment of chronic pain is progressively expanding in Spain and today it is used both in public and private medical centers. However, there is a great lack of knowledge about this technology not only in primary care but also in medical specialties. Although its biochemical bases are well determined and there are various systematic reviews and meta-analyses in the literature that justify its use in pain medicine, some professionals still are prejudiced against it. The evidence level of using medical ozone according SIGN (Scotish Intercollegiate Guideline Network) criteria is similar or superior to most of the techniques used in a Pain Unit. In this paper, we have done a review on ozone therapy in pain medicine, compiling the evidence published about it.
Learn More >Ketamine is an intravenous anesthetic with analgesic effects that has a rapid onset and short duration of action. Many studies have been conducted on the use of ketamine; however, the quantity and quality of such studies have not been reported. Therefore, we aimed to conduct a bibliometric analysis of research on ketamine from 2001 to 2020.
Learn More >Certain constituents in migraine food triggers and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit sulfotransferases (SULTs) that detoxify drugs/chemicals and play role in the metabolism of neurotransmitters. We aimed to dissect SULT1A1 modulation of CSD susceptibility and behavior in an in vivo experimental model using hesperidin, a SULT1A1 inhibitor found in citrus fruits (known migraine triggers) and mefenamic acid (SULT1A1 inhibitor), an NSAID to simulate medication overuse.
Learn More >Morphine and its substitutes are frequently used in the clinical treatment of acute severe pain and advanced cancer patients. Long-term irregular use of morphine will lead to severe dependence. However, the genes behind the analgesic and addictive effects of morphine still need to be revealed.
Learn More >Our understanding of brain fog, or dyscognition, among youth with juvenile fibromyalgia syndrome is limited. We aimed to determine the prevalence of subjective (self-reported) and objective dyscognition, as well as factors associated with subjective dyscognition in juvenile fibromyalgia syndrome.
Learn More >One of the factors contributing to transformation of migraine are sleep disorders, which can act as a trigger and/or perpetuating factor in these patients. This study's primary objective was to identify predictive factors related to sleep quality in patients with chronic migraine (CM); the secondary objective was to identify any differences in psychological variables and disability between patients with CM with better or poorer sleep quality.
Learn More >There is concern that state laws to curb opioid prescribing may adversely affect patients with chronic noncancer pain, but the laws' effects are unclear because of challenges in disentangling multiple laws implemented around the same time.
Learn More >Recent scientific evidence suggests a link between migraine and brain energy metabolism. In fact, migraine is frequently observed in mitochondrial disorders. We studied 46 patients affected by mitochondrial disorders, through a headache-focused semi-structured interview, to evaluate the prevalence of migraine among patients affected by mitochondrial disorders, the possible correlations between migraine and neuromuscular genotype or phenotype, comorbidities, lactate acid levels and brain magnetic resonance spectroscopy. We explored migraine-related disability, analgesic and prophylactic treatments. Diagnoses were achieved according to International Classification of Headache Disorders, 3rd edition. Lifetime prevalence of migraine was 61% (28/46), with high values in both sexes (68% in females, 52% in males) and higher than the values found in both the general population and previous literature. A maternal inheritance pattern was reported in 57% of cases. MIDAS and HIT6 scores revealed a mild migraine-related disability. The high prevalence of migraine across different neuromuscular phenotypes and genotypes suggests that migraine itself may be a common clinical manifestation of brain energy dysfunction. Our results provide new relevant indications in favour of migraine as the result of brain energy unbalance.
Learn More >Chronic pain is a global public health issue with increasing prevalence. Chronic pain causes sleep disorder, reactive anxiety, and depression, impairs the quality of life; it burdens the individual and society as a whole. The aim of this study was to examine non-medical factors related to the outcome of the treatment of chronic non-malignant pain.
Learn More >To explore the associations between habitual self-reported physical activity, pain sensitivity and patient-reported outcomes (including pain intensity) in patients with chronic pain. Design: Cross-sectional, experimental study. Subjects: Patients (n = 78), age range 18-65 years, with different chronic pain conditions (> 3 months) were compared with age- and gender-matched healthy controls (n = 98). Methods: Multivariate correlations between self-reported physical activity, pressure pain thresholds, and patient-reported outcome measures were assessed. Results: Lower perceived health status (p < 0.001, Cohen's d = 2.34), higher levels of depression (p < 0.001, Cohen's d = 1.77), and lower pressure pain tolerance threshold (p < 0.001, Cohen's d = 1.66) were the most prominent variables discriminating patients from controls. In patients, bivariate and multivariate analyses showed that higher pressure pain tolerance was associated with male gender, lower pain intensity and fewer painful regions, higher self-efficacy and more self-reported physical activity, but not with lower levels of anxiety and depression. Conclusion: Pressure pain tolerance thresholds, as well as degree of depression and perceived health status discriminated between patients and controls, and there was an association between pain tolerance and level of self-reported physical activity in patients. This study highlights the importance of further research into how increased physical activity may improve pain sensitivity in patients with chronic pain.
Learn More >The epidemiology of psoriasis has not been widely assessed in Polish population so far. This study aimed to investigate psoriasis epidemiological situation by evaluating disease course and severity, management, comorbidities, environmental factors, and knowledge about this disorder among psoriatic patients in Poland. A cross-sectional cohort population-based study enrolled 1080 psoriatic patients and 1200 controls. The mean age of psoriasis onset was 27.6 years; 78.24% had type I psoriasis. Positive family history of psoriasis was reported in 44.81% of patients, whereas itch was reported in vast majority of patients (83.33%). Based on PASI score moderate psoriasis was the most common in studied group (mean 12.63 ± 9.33, range 0-67.2). The DLQI score (12.01 ± 7.41, range 0-30.0) indicated a very large effect of psoriasis on the quality of life. Hypertension was the most prevalent comorbidity (33.80%), followed by obesity (16.85%) and dyslipidemia (11.85%). Stress was the foremost cause of disease exacerbation (66.20%); however, infections (44.07%) and seasonal changes (45.09%) had also an impact on the course of psoriasis. Psoriatic patients were more often smokers (37.59%) vs. general population (27.50%; < 0.0001). In conclusion, epidemiological studies help clinicians in better disease and patient understanding, which may translate into better management and patient compliance.
Learn More >Fabry disease is an X-linked lysosomal disease in which defects in the alpha-galactosidase A enzyme activity lead to the ubiquitous accumulation of glycosphingolipids. Whereas the classic disease is characterized by neuropathic pain, progressive renal failure, white matter lesions, cerebral stroke, and hypertrophic cardiomyopathy (HCM), the non-classic phenotype, also known as cardiac variant, is almost exclusively characterized by HCM. Circulating sphingosine-1-phosphate (S1P) has controversially been associated with the Fabry cardiomyopathy. We measured serum S1P levels in 41 patients of the FFABRY cohort. S1P levels were higher in patients with a non-classic phenotype compared to those with a classic phenotype (200.3 [189.6-227.9] vs. 169.4 ng/mL [121.1-203.3], = 0.02). In a multivariate logistic regression model, elevated S1P concentration remained statistically associated with the non-classic phenotype (OR = 1.03; < 0.02), and elevated lysoGb3 concentration with the classic phenotype (OR = 0.95; < 0.03). S1P levels were correlated with interventricular septum thickness (r = 0.46; = 0.02). In a logistic regression model including S1P serum levels, phenotype, and age, age remained the only variable significantly associated with the risk of HCM (OR = 1.25; = 0.001). S1P alone was not associated with cardiac hypertrophy but with the cardiac variant. The significantly higher S1P levels in patients with the cardiac variant compared to those with classic Fabry suggest the involvement of distinct pathophysiological pathways in the two phenotypes. S1P dosage could allow the personalization of patient management.
Learn More >