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Chronic pain is a complex biopsychosocial phenomenon. Lifestyle, behavioral, socioeconomic, and psychosocial factors such as depression and perceived injustice are often associated with the development of chronic pain and vice versa. We sought to examine the interaction of these factors with opioid intake.
Learn More >The main aim of this study was to assess the efficacy of exercise and manual therapy interventions in patients with primary headache through systematic review.
Learn More >Pain-related fear (PRF) can be a significant factor contributing to the development and maintenance of pain-related disability in individuals with persistent pain. One treatment approach to target PRF and related avoidance-behavior is exposure in vivo (EXP). EXP has a long history in the field of anxiety, a field that is constantly evolving. This Perspective outlines recent theoretical advancements and how they apply to EXP for PRF, including suggestions for how to optimize inhibitory learning during EXP; reviews mechanistic work from neuroimaging supporting the targeting of PRF in people with chronic pain; and focuses on clinical applications of EXP for PRF, as EXP is moving into new directions regarding who is receiving EXP (eg, EXP in chronic secondary pain) and how treatment is provided (EXP in primary care with a crucial role for physical therapists). Considerations are provided regarding challenges, remaining questions, and promising future perspectives.
Learn More >Migraine is the second most disabling disorder across all age groups worldwide. Since 2018, two classes of drugs that inhibit the actions of calcitonin gene-related peptide (CGRP), which is implicated in migraine pathophysiology, have become available: gepants (CGRP receptor antagonists) and monoclonal antibodies directed against CGRP or its receptor. Despite phase 3 clinical trials and some real world evidence, knowledge of the pharmacology and related clinical effects of these drugs is low, and trial data are not necessarily generalisable to all populations. Additionally, several pharmacodynamic processes affected by both gepants and monoclonal antibodies to CGRP and its receptor are not fully understood. Sex, body-mass index, age, ethnic background, and other characteristics, which are subject to considerable variation, might affect the pharmacokinetics of these therapies, especially gepants. If studies confirm this possibility, these characteristics could assist clinicians in choosing the optimal treatment for patients with migraine. The choice between a gepant or monoclonal antibody should be made carefully, taking into consideration a patient's comorbidities and preferences. As more becomes known about CGRP-targeted therapies, management based on the characteristics of patients could have a more prominent role in the treatment of migraine.
Learn More >Capable of reflecting the location and intensity of external harmful stimuli, a nociceptor network is of great importance for receiving pain-perception information. However, the hardware-based implementation of a nociceptor network through the use of a transistor array remains a great challenge in the area of brain-inspired neuromorphic applications. Herein, a simple ionotronic junctionless oxide transistor array with pain-perception abilities is successfully realized due to a coplanar-gate proton-coupling effect in sodium alginate biopolymer electrolyte. Several important pain-perception characteristics of nociceptors are emulated, such as a pain threshold, the memory of prior injury, and sensitization behavior due to pathway alterations. In particular, a good graded pain-perception network system has been successfully established through coplanar capacitance and resistance. More importantly, clear polarity reversal of Lorentz-type spatiotemporal pain-perception emulation can be finally realized in our projection-dependent nociceptor network. This work may provide new avenues for bionic medical machines and humanoid robots based on these intriguing pain-perception abilities.
Learn More >Bone cancer pain (BCP) seriously affects the quality of life, however, due to its complex mechanism the clinical treatment was unsatisfactory. Recent studies have showed several Rac-specific guanine nucleotide exchange factor (GEF) that affect development and structure of neuronal processes play a vital role in the regulation of chronic pain. P-Rex2 is one of GEFs that regulate spine density, and the present study was performed to examine the effect of P-Rex2 on the development of BCP. Tumor cells implantation induced the mechanical hyperalgesia, which was accompanied by an increase in spinal protein P-Rex2, phosphorylated Rac1 (p-Rac1) and phosphorylated GluR1 (p-GluR1), and number of spines. Intrathecal injection a P-Rex2-targeting RNAi lentivirus relieved BCP and reduced the expression of P-Rex2, p-Rac1, p-GluR1and number of spines in the BCP mice. Meanwhile, P-Rex2 knockdown reversed BCP-enhanced AMPA receptor (AMPAR)-induced current in dorsal horn neurons. In summary, this study suggested that P-Rex2 regulated GluR1-containing AMPAR trafficking and spine morphology via Rac1/pGluR1 pathway is a fundamental pathogenesis of BCP. Our findings provide a better understanding of the function of P-Rex2 as a possible therapeutic target for relieving BCP.
Learn More >Neuropathic pain after brachial plexus injury (NPBPI) is a highly disabling clinical condition and is increasingly prevalent due to increased motorcycle accidents. Currently, no randomized controlled trials have evaluated the effectiveness of non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS) in patients suffering from NPBPI. In this study, we directly compare the efficacy of 10-Hz rTMS and anodal 2 mA tDCS techniques applied over the motor cortex (5 daily consecutive sessions) in 20 patients with NPBPI, allocated into 2 parallel groups (active or sham). The order of the sessions was randomised for each of these treatment groups according to a crossover design and separated by a 30-day interval. Scores for "continuous" and "paroxysmal" pain (primary outcome) were tabulated after the last stimulation day and 30 days after. Secondary outcomes included the improvement in multidimensional aspects of pain, anxiety state and quality of life from a qualitative and quantitative approach. Active rTMS and tDCS were both superior to sham in reducing continuous (p < 0.001) and paroxysmal (p = 0.002; p = 0.02) pain as well as in multidimensional aspects of pain (p = 0.001; p = 0.002) and anxiety state (p = < 0.001; p = 0.005). Our results suggest rTMS and tDCS are able to treat NPBPI with little distinction in pain and anxiety state, which may promote the use of tDCS in brachial plexus injury pain management, as it constitutes an easier and more available technique.Clinical Trial Registration: http://www.ensaiosclinicos.gov.br/, RBR-5xnjbc – Sep 3, 2018.
Learn More >Tumor metastasis to bone is often accompanied by a severe pain syndrome (cancer-induced bone pain, CIBP) that is frequently unresponsive to analgesics, which markedly reduces patient quality of life and cancer treatment tolerance in patients. Prolonged pain can induce hypersensitivity via spinal plasticity, and several recent studies have implicated the involvement of vascular endothelial growth factor-A (VEGF-A) signaling in this process. Here, we speculated that CIBP is associated VEGF-A/VEGFR2 signaling could in the spinal cord. A mouse model of CIBP was established by intramedullary injection of Lewis lung carcinoma (LLC) cells in the mouse femur. Pain sensitization and potential amelioration via VEGF-A/VEGFR2 blockade were measured using paw withdrawal threshold to mechanical stimulation and paw withdrawal latency to thermal. Spinal VEGF-A/VEGFR2 signaling was blocked by intrathecal injection of the VEGF-A antibody or the specific VEGFR2 inhibitor ZM323881. Changes in the expression levels of VEGF-A, VEGFR2, and other pain-related signaling factors were measured using western blotting and immunofluorescence staining. Mice after LLC injection demonstrated mechanical allodynia and thermal hyperalgesia, both of which were suppressed via anti-VEGF-A antibody or ZM323881. Conversely, the intrathecal injection of exogenous VEGF-A was sufficient to cause pain hypersensitivity in naïve mice via the VEGFR2-mediated activation of protein kinase C. Moreover, the spinal blockade of VEGF-A or VEGFR2 also suppressed N-methyl-D-aspartate receptor (NMDAR) activation and downstream Ca2+-dependent signaling. Thus, spinal VEGF-A/VEGFR2/NMDAR signaling pathways may be critical mediators of CIBP.
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