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Rheumatic diseases, such as osteoarthritis and rheumatoid arthritis, affect over 750 million people worldwide and contribute to approximately 40% of chronic pain cases. Inflammation and tissue damage contribute to pain in rheumatic diseases, but pain often persists even when inflammation/damage is resolved. Mechanisms that cause this persistent pain are still unclear. Mitochondria are essential for a myriad of cellular processes and regulate neuronal functions. Mitochondrial dysfunction has been implicated in multiple neurological disorders, but its role in sensory processing and pain in rheumatic diseases is relatively unexplored. This review provides a comprehensive understanding of how mitochondrial dysfunction connects inflammation and damage-associated pathways to neuronal sensitization and persistent pain. To provide an overall framework on how mitochondria control pain, we explored recent evidence in inflammatory and neuropathic pain conditions. Mitochondria have intrinsic quality control mechanisms to prevent functional deficits and cellular damage. We will discuss the link between neuronal activity, mitochondrial dysfunction and chronic pain. Lastly, pharmacological strategies aimed at reestablishing mitochondrial functions or boosting mitochondrial dynamics as therapeutic interventions for chronic pain are discussed. The evidence presented in this review shows that mitochondria dysfunction may play a role in rheumatic pain. The dysfunction is not restricted to neuronal cells in the peripheral and central nervous system, but also includes blood cells and cells at the joint level that may affect pain pathways indirectly. Pre-clinical and clinical data suggest that modulation of mitochondrial functions can be used to attenuate or eliminate pain, which could be beneficial for multiple rheumatic diseases.
Learn More >Endometriosis is a disease defined by the presence of endometrial tissue in extrauterine locations. This chronic condition is frequently associated with pain and emotional disorders and has been related with altered immune function. However, the specific involvement of immune cells in pain and behavioral symptoms of endometriosis has not been yet elucidated. Here, we implement a mouse model of non-surgical endometriosis in which immunocompetent mice develop abdomino-pelvic hypersensitivity, cognitive deficits, anxiety and depressive-like behaviors. This behavioral phenotype correlates with expression of inflammatory markers in the brain, including the immune cell marker CD4. Depletion of CD4 + cells decreases the anxiety-like behavior of mice subjected to the endometriosis model, whereas abdomino-pelvic hypersensitivity, depressive-like behavior and cognitive deficits remain unaltered. The present data reveal the involvement of the immune response characterized by CD4 + white blood cells in the anxiety-like behavior induced by endometriosis in mice. This model, which recapitulates the symptoms of human endometriosis, may be a useful tool to study the immune mechanisms involved in pain and behavioral alterations associated to endometriosis.
Learn More >Chronic pain is a significant and costly problem all over the world that negatively impacts the quality of life of sufferers. There are clear discrepancies between the prevalence of chronic pain in society and the low priority assigned to educating future physicians about the complexities of pain. This condition also occurs in other undergraduate health science students, although research in this area has not been studied as much as in medical schools. Based on the International Association for the Study of Pain (IASP) Pain Curriculum Outline, a systematic search of the available literature, and the authors' own experiences, we highlight some relevant tips to educate health science trainees in the management of patients with chronic pain. These tips highlight current international recommendations for a comprehensive approach to this prevalent problem in society, which should be learnt during the university training of health professionals.
Learn More >Discrimination of cues predicting non-nociceptive/nociceptive stimuli is essential for predicting whether a non-painful or painful stimulus will be administered and for eliciting placebo/nocebo (pain reduction/pain enhancement) effects. Dysfunction of the neural system involved in placebo effects has been implicated in the pathology of chronic pain, while female sex is one of the important risk factors for development of chronic pain in young adults. The dorsolateral prefrontal cortex (dl-PFC) is suggested to be involved in placebo effects and is sensitive to sex and age. In this study, to examine the neural mechanisms by which sex and age alter placebo and nocebo effects, we analyzed cerebral hemodynamic activities in the dl-PFC in different sex and age groups during a differential conditioning task. During the training session, two different sounds were followed by low- and high-intensity electrical shocks. In the following recording session, electrical shocks, the intensity of which was mismatched to the sounds, were occasionally administered to elicit placebo and nocebo effects. In young female participants, both placebo effects and hemodynamic responses to the conditioned sounds in the right dl-PFC were significantly lower than those in elderly female participants, while there were no age differences in male participants. The hemodynamic responses to the sound paired with the safe stimulus in the right dl-PFC were significantly correlated with placebo effects, except in the young female group. These results suggest that blunted placebo effects in the young female participants are ascribed to blunted responses to the sound associated with the safe stimulus in the right dl-PFC, and that sex- and age-related factors may alter the responsiveness of the right dl-PFC to associative cues predicting a safe stimulus.
Learn More >Toothache (TA) is a common and severe pain, but its effects on the brain are somewhat unclear. In this study, functional magnetic resonance imaging (fMRI) was used to compare regional homogeneity (ReHo) between TA patients and a normal control group and to explore the brain activity changes during TA, establishing the theoretical basis for the mechanism of neuropathic pain. In total, 20 TA patients and 20 healthy controls (HCs) were recruited and underwent assessment of pain, and then resting-state fMRI (rs-fMRI). The ReHo method was used to analyze the original whole-brain images. Pearson's correlation analysis was used to assess the relationship between mean ReHo values in each brain region and clinical symptoms, and the receiver operating characteristic (ROC) curve was used to conduct correlation analysis on the brain regions studied. The ReHo values of the right lingual gyrus (RLG), right superior occipital gyrus (RSOG), left middle occipital gyrus (LMOG) and right postcentral gyrus (RPG) in the TA group were significantly higher than in HCs. The mean ReHo values in the RLG were positively correlated with the anxiety score (AS) ( = 0.723, < 0.001), depression score (DS) ( = 0.850, < 0.001) and visual analogue score (VAS) ( = 0.837, < 0.001). The mean ReHo values of RSOG were also positively correlated with AS ( = 0.687, = 0.001), DS ( = 0.661, = 0.002) and VAS ( = 0.712, < 0.001). The areas under the ROC curve of specific brain area ReHo values were as follows: RLG, 0.975; RSOG, 0.959; LMOG, 0.975; RPG, 1.000. Various degrees of brain activity changes reflected by ReHo values in different areas of the brain indicate the impact of TA on brain function. These findings may reveal related neural mechanisms underlying TA.
Learn More >Low back pain (LBP) is a multifactorial and the most prevalent musculoskeletal disorder, whose economic burden is of global concern. Evidence suggests that the burden of LBP in increasing and will continue rising with the greatest burden occurring in low-and-middle-income-countries (LMICs). This study sought to determine the economic burden of LBP in KwaZulu-Natal, South Africa from the providers perspective.
Learn More >Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently administered drugs, mainly for their anti-pyretic, but also for pain-relieving and anti-inflammatory effects in children. NSAIDs are composed of structurally divergent subgroups of drugs with similar pharmacological and adverse effects. Aspirin originates from salicin and was the first synthesized analgesic. As a prototype of NSAIDs; aspirin-induced hypersensitivity reactions were first reported, but subsequently, other phenotypes of hypersensitivity reactions were also described with aspirin and other NSAIDs. There are certain challenging aspects of NSAID-hypersensitivity in the pediatric population that need to be further investigated. These include the effect of age on drug metabolism and the natural history of the various phenotypes of NSAID-hypersensitivity, the effect of certain co-factors (infections, exercise) on NSAID-hypersensitivity, and diagnostic clinical and laboratory biomarkers clarifying the endotypes. In recent years, a non-negligible number of case series, studies and expert panel reports have been published in this field with some novel features and diagnostic modalities in the pediatric population. With the current review; the clinical phenotypes and diagnostic and management modalities of suspected NSAID-induced hypersensitivity reactions in childhood and adolescence were explained and updated by examining past and current publications.
Learn More >Cutaneous immune-related adverse events (irAEs) are the most common irAEs caused by immune-checkpoint inhibitors (ICI). Psoriasiform eruptions, both and flares, may occur. Evidence is lacking on inverse psoriasis subtype.
Learn More >This mini-review covers recent works on the study of pleasant touch in patients with chronic pain (CP) and its potential use as a treatment. While experiments have demonstrated that pleasant touch, through the activation of CT-afferents and the brain regions involved in its affective value, might reduce the unpleasantness and intensity of induced pain, the interaction between pleasant touch and CP remains under-examined. Some experiments show that CP might disrupt the positive aspects of receiving pleasant touch, while in other studies the perception of pleasantness is preserved. Moreover, only a few attempts have been made to test whether touch can have a modulatory effect on CP, but these results also remain inconclusive. Indeed, while one recent study demonstrated that CT-touch can diminish CP after a short stimulation, another study suggested that pleasant touch might not be sufficient. Future studies should further investigate the psychological and neural interplay between pleasant touch and CP. In the conclusion of this mini-review, we propose a new tool we have recently developed using immersive virtual reality (IVR).
Learn More >To systematically evaluate prevalence and clinical characteristics of adverse effects of antidepressants and OTC drugs interactions in a retrospective chart review. Dataset of 1,145 registered adverse events were evaluated. Reports were selected for further analysis if pharmacoepidemiological avaluation indicated the presence of high probability of a causal relationship between antidepressants and OTC interaction and the occurrence of side effect. Following variables were extracted from the records: sex, age, medical comorbidities, antidepressant and other concomitant medications, clinical consequences ant the possible interaction mechanisms. 368 showed causal relationship with the simultaneous use of antidepressant with another drug. 15 adverse events (4%) were related to the use of OTC medicine, particularly omeprazole, diphenhydramine, Japanese ginkgo biloba, ibuprofen, diclofenac and sildenafil. All of the analysed side effects were categorized as the result of pharmacokinetic interactions. Here we report identified OTC drugs with corresponding antidepressants and clinical manifestations of DDI. Omeprazole: agomelatine (nausea, abnormal dreams), fluoxetine (extrapyramidal symptoms, paresthesias), sertraline (vertigo, yawning), escitalopram (oral vesiculation). Diphenhydramine: sertraline (diaphoresis, insomnia, vertigo), paroxetine (pruritus, headache), duloxetine (oropharyngeal pain). Japanese ginkgo biloba: citalopram (bradycardia), trazodone (vertigo, taste pervesion), mianserine (restless legs syndrome). Diclofenac: escitalopram (oral vesiculation), and fluoxetine (restless legs syndrome). Ibuprofen: agomelatine (anxiety and nausea), sertraline and omeprazole (QTc prolongation). Sildenafil: fluoxetine (genital oedema) and sertraline (myocardial infarction). The use of OTC drugs by the patients should be monitored. Pharmacokinetic interactions between nonprescribed medicines and antidepressants may increase concentration and severity of side effects of latter ones.
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