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Chronic pain is common among persons living with HIV and changes in opioid prescribing practices may complicate HIV care management. Using medical record data from a retrospective cohort study conducted January 1, 2012 to June 30, 2019 for 300 publicly insured HIV-positive primary care patients prescribed opioids for chronic non-cancer pain in San Francisco, we examined associations between opioid dose changes and both time to disengagement from HIV care and experiencing virologic failure using logistic regression. Discontinuation of prescribed opioids was associated with increased odds of disengagement in care at 3, 6, and 9 months after discontinuation. There were no associations with virologic failure. Providers and policy makers must weigh impacts on HIV care when implementing necessary changes in opioid prescribing.
Learn More >SignificanceIn this study, we identify microRNA-32-5p (miR-32-5p) as a key functional noncoding RNA in trigeminal-mediated neuropathic pain. We report that injury-induced histone methylation attenuates the binding of glucocorticoid receptor to the promoter region of the gene and decreases the expression of miR-32-5p, in turn promoting the development of neuropathic pain through regulation of Cav3.2 channels. miRNA-mediated gene regulation has been proposed as a therapeutic approach in neuropathic pain. Our findings identify miR-32-5p replenishment as a therapeutic strategy for treating chronic neuropathic pain.
Learn More >Transcranial direct current stimulation (tDCS) has demonstrated clinical benefits such as analgesia, anti-inflammatory, and neuroprotective effects. However, the mechanisms of action of a single tDCS session are poorly characterized. The present study aimed to evaluate the effects of a single tDCS session on pain sensitivity, inflammatory parameters, and astrocyte activity in naive rats. In the first experiment, sixty-day-old male Wistar rats (n=95) were tested for mechanical pain threshold (von Frey test). Afterward, animals were submitted to a single bimodal tDCS (0.5mA, 20minutes) or sham-tDCS session. According to the group, animals were re-tested at different time intervals (30, 60, 120minutes, or 24hours) after the intervention, euthanized, and the cerebral cortex collected for biochemical analysis. A second experiment (n=16) was performed using a similar protocol to test the hypotheses that S100B levels in the cerebrospinal fluid (CSF) are altered by tDCS. Elisa assay quantified the levels of tumor necrosis factor-alfa (TNF-α), interleukin-10 (IL10), S100 calcium-binding protein B (S100B), and Glial fibrillary acidic protein (GFAP). Data were analyzed using ANOVA and independent t-test (P<0.05). Results showed that tDCS decreased pain sensitivity (30 and 60min), cerebral TNF-α and S100B levels (30min). CSF S100B levels increased 30minutes after intervention. There were no differences in IL10 and GFAP levels. TCDS showed analgesic, anti-inflammatory, and neuroprotective effects in naive animals. Therefore, this non-invasive and inexpensive therapy may potentially be a preemptive alternative to reduce pain, inflammation, and neurodegeneration in situations where patients will undergo medical procedures (e.g., surgery).
Learn More >Cognitive functional therapy (CFT) is a physiotherapy-led intervention which has evolved from an integration of foundational behavioral psychology and neuroscience within the physiotherapist practice directed at the multidimensional nature of chronic low back pain (CLBP). The current evidence about the comparative effectiveness of CFT for CLBP is still scarce. We aimed to investigate whether CFT is more effective than core training exercise and manual therapy (CORE-MT) in pain and disability in patients with CLBP. A total of 148 adults with CLBP were randomly assigned to receive five one-hour individualised sessions of either CFT (n = 74) or CORE-MT (n = 74) within a period of 8 weeks. Primary outcomes were pain intensity (numeric pain rating scale, 0-10) and disability (Oswestry Disability Index, 0-100) at 8 weeks. Patients were assessed pre-intervention, at 8 weeks, 6 and 12 months after the first treatment session. Altogether, 97.3% (n=72) of patients in each intervention group completed the 8 weeks of the trial. CFT was more effective than CORE-MT in disability at 8 weeks (MD= -4.75; 95% CI -8.38 to -1.11; p=0.011, effect size= 0.55), but not in pain intensity (MD= -0.04; 95% CI -0.79 to 0.71; p=0.916). Treatment with CFT reduced disability, but the difference was not clinically important compared with CORE-MT post-intervention (short term) in patients with CLBP. There was no difference in pain intensity between interventions, and the treatment effect was not maintained in the mid-term and long-term follow-ups.
Learn More >Complex regional pain syndrome (CRPS) is an inadequate local response after a limb trauma, which leads to severe pain and autonomic and trophic changes of the affected limb. Autoantibodies directed against human β2 adrenergic and muscarinic M2-receptors (hβ2AR and hM2R) have been described in CRPS-patients previously.We analyzed sera from CRPS-patients for autoantibodies against hß2AR, hM2R and endothelial cells, and investigated the functional effects of purified IgG, derived from 13 CRPS patients, on endothelial cells. Eleven healthy controls, seven radial fracture patients without CRPS, and 10 patients with peripheral arterial vascular disease served as controls.CRPS-IgG, but not control IgG, bound to the surface of endothelial cells (P < 0.001) and to hβ2AR and hM2R (P < 0.05), the latter being reversed by adding β2AR and M2R antagonists. CRPS-IgG led to an increased cytotoxicity and a reduced proliferation rate of endothelial cells, and by adding specific antagonists, the effect was neutralized. Regarding second messenger pathways, CRPS-IgG induced ERK-1/2-, P38-, and STAT1-phosphorylation, while AKT-phosphorylation was decreased at the protein level. In addition, increased expression of adhesion molecules (ICAM-1, VCAM-1) on the mRNA-level was induced by CRPS-IgG, thus inducing a pro-inflammatory condition of the endothelial cells.Our results show that patients with CRPS not only develop autoantibodies against hβ2AR and hM2R, but these antibodies interfere with endothelial cells, inducing functional effects on these in vitro, and thus might contribute to the pathophysiology of CRPS.
Learn More >The transient receptor potential ion channel TRPM3 is highly prevalent on nociceptive dorsal root ganglion (DRG) neurons, but its functions in neuronal plasticity of chronic pain remain obscure. In an animal model of nonspecific low back pain (LBP), latent spinal sensitization known as nociceptive priming is induced by nerve growth factor (NGF) injection. Here we address the TRPM3-associated molecular basis of NGF-induced latent spinal sensitization at presynaptic level by studying TRPM3-mediated calcium transients in DRG neurons. By investigating TRPM3-expressing HEK cells, we further show the dynamic mitochondrial activity downstream of TRPM3 activation. NGF enhances TRPM3 function, attenuates TRPM3 tachyphylaxis, and slows intracellular calcium clearance; TRPM3 activation triggers more mitochondrial calcium loading than depolarization does, causing a steady-state mitochondrial calcium elevation and a delayed recovery of cytosolic calcium; mitochondrial calcium buffering accounts for approximately 40% of calcium influx subsequent to TRPM3 activation. TRPM3 activation provokes an outbreak of pulsatile superoxide production (mitoflash) that comes in the form of a surge in frequency being tunable. We suggest that mitoflash pulsations downstream of TRPM3 activation might be an early signaling event initiating pain sensitization. Tuning of mitoflash activity would be a novel bottom-up therapeutic strategy for chronic pain conditions such as LBP and beyond.
Learn More >The dominant view in the field of pain is that peripheral neuropathic pain is driven by microglia in the somatosensory processing region of the spinal dorsal horn. Here, to the contrary, we discovered a form of neuropathic pain that is independent of microglia. Mice in which the nucleus pulposus (NP) of the intervertebral disc was apposed to the sciatic nerve developed a constellation of neuropathic pain behaviours: hypersensitivity to mechanical, cold and heat stimuli. However, NP application caused no activation of spinal microglia nor was pain hypersensitivity reversed by microglial inhibition. Rather, NP-induced pain hypersensitivity was dependent upon cells within the NP which recruited macrophages to the adjacent nerve. Eliminating macrophages systemically or locally prevented NP-induced pain hypersensitivity. Pain hypersensitivity was also prevented by genetically disrupting the neurotrophin BDNF selectively in macrophages. Moreover, the behavioural phenotypes as well as the molecular mechanisms of NP-induced pain hypersensitivity were not different between males and females. Our findings reveal a previously unappreciated mechanism for by which a discrete peripheral nerve lesion may produce pain hypersensitivity, which may help to explain the limited success of microglial inhibitors on neuropathic pain in human clinical trials.
Learn More >To review interventions to reduce long term opioid treatment in people with chronic non-cancer pain, considering efficacy on dose reduction and discontinuation, pain, function, quality of life, withdrawal symptoms, substance use, and adverse events.
Learn More >Very positive effects have been described in the application of pain neuroscience education (PNE) to chronic pain and migraine. However, there are few data on the applicability of this therapeutic approach in actual clinical practice in a primary care (PC) setting. The aim of this study was to explore the efficacy in fibromyalgia (FM) of an intervention based on PNE and exercise compared to treatment as usual (TAU).
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