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Pain during adolescence is common and is associated with future pain chronicity and mental health in adulthood. However, understanding of the neural underpinnings of chronic pain has largely come from studies in adults, with recent studies in adolescents suggesting potentially unique neural features during this vulnerable developmental period. In addition to alterations in the pain network, resting state functional magnetic resonance imaging studies in adults suggest alterations in the default mode network (DMN), involved in internally-driven, self-referential thought, may underlie chronic pain; however, these findings have yet to be examined in adolescents. The current study sought to investigate associations between pain frequency and intensity, and disruptions in DMN connectivity, in adolescents. Adolescents (ages 12-20) with varying levels of pain frequency and intensity, recruited from a pediatric pain clinic and the local community (n = 86; 60% female), underwent resting state functional magnetic resonance imaging. Using independent components analysis, the DMN was identified and correlated voxel-wise to assess associations between pain frequency and intensity and DMN connectivity. Findings revealed that adolescents with greater pain frequency demonstrated greater DMN to superior frontal gyrus connectivity, while adolescents with greater pain intensity demonstrated lesser DMN to cerebellum (lobule VIII) connectivity, during rest. These findings suggest that increasing levels of pain are associated with potential desegregation of the DMN and the prefrontal cortex, important for cognitive control, and with novel patterns of DMN to cerebellum connectivity. These findings may prove beneficial as neurobiological targets for future treatment efforts in adolescents.
Learn More >Knee pain from osteoarthritis is frequent in the adult population. Prior trials have had conflicting results concerning vitamin D's therapeutic effects on knee pain and few trials have investigated marine omega-3 fatty acids (n-3 FA).
Learn More >It is unclear whether a diagnosis of chronic pain is associated with an increase or decrease in the placebo response. The aim of this study was to use an experimental placebo conditioning paradigm to test if expectancy for pain relief impacts on acute pain perception in individuals with a chronic pain diagnosis of osteoarthritis (OA) or fibromyalgia (FM), compared to healthy individuals (HI). An inert cream was applied to the dominant forearm of participants (60 OA, 79 FM and 98 HI), randomly assigned to either a placebo or control group. In both groups an inactive cream was applied to the dominant forearm. The placebo group was told this may or may not be a local anaesthetic cream, while the control group was told the cream was inactive. Laser pain was delivered, and numerical pain intensity ratings collected before, during and after cream application, along with expectation of pain relief and anxiety. The procedure was repeated two weeks later to assess reproducibility. There was a significant reduction in pain in the placebo group, independent of clinical diagnosis. Diagnostic groups (OA,FM,HI) did not differ in their magnitude of placebo analgesia or expectancy of pain relief. The results were similar in the repeat session. The results demonstrate that individuals with chronic pain respond to experimental placebo analgesia in a similar and reproducible manner as healthy individuals, despite higher levels of psychological co-morbidity. This has implications for utilising placebo analgesia in the treatment of chronic pain.
Learn More >Next generation transcriptomics in combination with imaging-based approaches have emerged as powerful tools for the characterization of dorsal root ganglion (DRG) neuronal subpopulations. The mouse DRG has been well-characterized by many independently conducted studies with convergent findings, but few studies have directly compared expression of population markers between mouse and human. This is important because of our increasing reliance on the mouse as a preclinical model for translational studies. While calcitonin gene-related peptide (CGRP) and P2X purinergic ion channel type 3 receptor (P2X3R) have been used to define peptidergic and non-peptidergic nociceptor subpopulations, respectively, in mouse DRG, these populations may be different in other species. To directly test this, as well as a host of other markers, we used multiplex RNAscope in-situ hybridization to elucidate the distribution of a multitude of unique and classic neuronal mRNAs in peptidergic (CGRP expressing) and non-peptidergic (P2X3R expressing) nociceptor subpopulations in mouse and human DRG. We found a large overlapping CGRP and P2X3R neuronal subpopulation in human, lumbar DRG that was not present in mouse. We also found differential expression in a variety of mRNAs for TRP-channels, cholinergic receptors, potassium channels, sodium channels, other markers/targets. These data offer insights into the spatial and functional organization of neuronal cell subpopulations in the rodent and human DRG and support the idea that sensory system organizational principles are likely different between both species.
Learn More >Pain-related disability is a multi-faceted construct that refers to the impact of pain on an individual's capacity to fulfill their self-defined and social roles. This research examined the relationship between clinical, psychological and pain sensitivity factors and pain-related disability among adults with chronic temporomandibular disorder (TMD). We analyzed data from a cross-sectional community-based sample of 1088 men and women with chronic TMD. We first constructed and tested a measure of pain-related disability (i.e., pain impact) including a variable assessing presenteeism, created measurement models of jaw limitation, psychological unease (negative affect, somatic symptoms, catastrophizing), and experimental pain sensitivity (e.g., pressure pain threshold, thermal tolerance and mechanical pressure pain threshold). Subsequently, latent variables were combined in a structural equation model. Participants (n=1088) were 18-44 years old (mean 29.2, SD+7.8) whose chronic TMD had persisted, on average, for 6.9 years (SD+6.4). A model of pain related disability, jaw limitation, and psychological unease was created and refined with exploratory model revisions to account for correlation among variables. Estimation of the final model indicated excellent fit with the data (RMSEA=0.048, RMSEA 90% confidence interval (CI) 0.043, 0.053, CFI=0.956, SRMR=0.040). Jaw functional limitation and psychological unease was strongly related to pain-related disability. Experimental pain sensitivity was removed from our model due to weak direct effect and the burden of performing experimental pain sensitivity testing in a clinical setting. The final model explained 78% of the variance in pain-related disability.
Learn More >Emotional pain (i.e., pain affect in response to psychological experiences such as rejection or loss) may be a component of chronic pain syndromes given high co-occurrence with depression and neurobiological overlaps in pain affect resulting from physical and emotional experiences. In the current set of studies, we examined the relationship between emotional and physical pain using both nomothetic (i.e., group-level) and idiographic (i.e., individual-level) approaches.
Learn More >Vitamin D deficiency is associated with chronic pain syndromes and higher opioid use among cancer patients, but its association with opioid use among opioid-naïve subjects following a major surgical procedure with acute pain has not been explored.
Learn More >Despite broad clinical implications, the mechanisms linking inflammation and pain remain incompletely understood. Using human experimental endotoxemia as a translational model of systemic inflammation, we aimed to elucidate putative vulnerability factors of inflammation-induced musculoskeletal hyperalgesia. We pooled data from three published randomized controlled trials, resulting in a sample of N=98 healthy volunteers who received either low-dose endotoxin (lipopolysaccharide) or vehicle (saline) intravenously. As measure of musculoskeletal pain sensitivity, pressure pain thresholds (PPTs) were assessed at baseline and 3h post injection with a handheld algometer for the low back (erector spinae muscle), calf (gastrocnemius muscle), and shoulder region (deltoid muscle). Implementing multiple regression models, we tested the contribution of putative vulnerability factors on musculoskeletal hyperalgesia during systemic inflammation, including acute changes in pro-inflammatory cytokines, state anxiety and mood, as well as pre-existing symptoms of anxiety and depression. Endotoxin application led to significant increases in plasma cytokines, state anxiety, and negative mood, and significantly decreased PPTs for all muscle groups. Regression models revealed that greater M. erector spinae PPT changes were predicted by higher HADS-anxiety scores. Higher TNF-α concentration emerged as predictor for M. gastrocnemius PPT changes, and more pronounced TNF-α increase and higher HADS-anxiety were predictive for M. deltoideus PPTs. HADS scores emerged as predictor for a mean PPT score (computed across all body sites). Together, our results indicate that musculoskeletal hyperalgesia during systemic inflammation is related to pro-inflammatory cytokines, specifically TNF-α. Importantly, subclinical anxiety symptoms (even though in a low and normal range in this cohort of healthy volunteers) may contribute to inflammation-induced hyperalgesia, making individuals more vulnerable to the detrimental effects of systemic inflammation.
Learn More >Opioid-induced respiratory depression (OIRD) is a potentially fatal complication associated with conventional opioids. Currently, there is a paucity of validated endpoints available to measure respiratory safety. Oliceridine, an investigational intravenous (IV) opioid, is a G-protein selective μ-agonist with limited activity on β-arrestin2, a signaling pathway associated with adverse events including OIRD. In controlled phase III trials, oliceridine 0.35 mg and 0.5 mg demand doses demonstrated comparable analgesia to morphine 1 mg with favorable improvements in respiratory safety. In this exploratory analysis, we report dosing interruption (DI) and average cumulative duration of DI (CDDI) for both oliceridine and morphine.
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