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Chronic low back pain (CLBP) is a leading cause of disability and is associated with neurodegenerative changes in brain structure. These changes lead to impairments in cognitive function and are consistent with those seen in aging, suggesting an accelerated aging pattern. In this study we assessed this using machine-learning estimated brain age (BA) as a holistic metric of morphometric changes associated with aging. Structural imaging data from 31 non-depressed CLBP patients and 32 healthy controls from the Pain and Interoception Imaging Network were included. Using our previously developed algorithm, we estimated BA per individual based on grey matter density. We then conducted multivariable linear modeling for effects of group, chronological age, and their interaction on BA. We also performed two voxel-wise analyses comparing grey matter density between CLBP and control individuals and the association between gray matter density and BA. There was an interaction between CLBP and greater chronological age on BA such that the discrepancy in BA between healthy and CLBP individuals was greater for older individuals. In CLBP individuals, BA was not associated with sex, current level of pain, duration of CLBP, or mild to moderate depressive symptoms. CLBP individuals had lower cerebellar grey matter density compared to healthy individuals. Brain age was associated with lower gray matter density in numerous brain regions. CLBP was associated with greater BA, which was more profound in later life. BA as a holistic metric was sensitive to differences in gray matter density in numerous regions which eluded direct comparison between groups.
Learn More >Many epigenetic regulators are involved in pain-associated spinal plasticity. Coactivator-associated arginine methyltransferase 1 (CARM1), an epigenetic regulator of histone arginine methylation, is a highly interesting target in neuroplasticity. However, its potential contribution to spinal plasticity-associated neuropathic pain development remains poorly explored. Here, we report that nerve injury decreased the expression of spinal CARM1 and induced allodynia. Moreover, decreasing spinal CARM1 expression by Fbxo3-mediated CARM1 ubiquitination promoted H3R17me2 decrement at the K channel promoter, thereby causing K channel epigenetic silencing and the development of neuropathic pain. Remarkably, in naïve rats, decreasing spinal CARM1 using CARM1 siRNA or a CARM1 inhibitor resulted in similar epigenetic signaling and allodynia. Furthermore, intrathecal administration of BC-1215 (a novel Fbxo3 inhibitor) prevented CARM1 ubiquitination to block K channel gene silencing and ameliorate allodynia after nerve injury. Collectively, the results reveal that this newly identified spinal Fbxo3-CARM1-K channel gene functional axis promotes neuropathic pain. These findings provide essential insights that will aid in the development of more efficient and specific therapies against neuropathic pain.
Learn More >Patients frequently report chronic postsurgical pain (CPSP) after breast cancer surgery (BCS). The paravertebral block (PVB) is an effective technique to reduce acute postoperative pain after BCS, but its efficacy in preventing CPSP is unclear. This meta-analysis evaluates the efficacy of PVB in preventing CPSP after BCS. We searched Medline, Embase, CENTRAL, Database of Abstracts of Reviews of Effects, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform for studies comparing PVB with control for CPSP prevention after BCS, from inception to April 2020. The primary outcome was CPSP at 6 months, and the secondary outcomes were CPSP at 3 and 12 months, chronic postsurgical neuropathic pain (CPSNP) at 6 months, and PVB-related complications. Data were pooled and analyzed with a random-effects model, and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to evaluate the certainty of evidence. A total of 12 studies were included in the study; data for the 6-month time point from 7 studies (2161 patients) were analyzed, and no difference was found between PVB and control in terms of efficacy in preventing CPSP after BCS (risk ratio (RR) 0.82 (95% CI 0.62 to 1.08)), with a moderate quality of evidence according to the GRADE system. Similar results were obtained at 3 and 12 months (RR 0.78 (95% CI 0.57 to 1.06), RR 0.45 (95% CI 0.14 to 1.41), respectively). Data for the 12-month time point from seven studies (2087 patients) were analyzed and showed that PVB protected against CPSNP, with low quality of evidence (RR 0.51 (95% CI 0.31 to 0.85)). In conclusion, CPSP was not found significantly prevented by PVB after BCS despite the limits in the included studies; nevertheless, PVB could prevent CPSNP by impacting the transition from acute to chronic pain.
Learn More >A novel missense mutation in the CACNA1A gene that encodes the pore forming α subunit of the Ca2.1 voltage-gated calcium channel was identified in a patient with trigeminal neuralgia. This mutation leads to a substitution of proline 2455 by histidine (P2455H) in the distal C-terminus region of the channel. Due to the well characterized role of this channel in neurotransmitter release, our aim was to characterize the biophysical properties of the P2455H variant in heterologously expressed Ca2.1 channels. Whole-cell patch clamp recordings of wild type and mutant Ca2.1 channels expressed in tsA-201 cells reveal that the mutation mediates a depolarizing shift in the voltage-dependence of activation and inactivation. Moreover, the P2455H mutant strongly reduced calcium-dependent inactivation of the channel that is consistent with an overall gain of function. Hence, the P2455H Ca2.1 missense mutation alters the gating properties of the channel, suggesting that associated changes in Ca2.1-dependent synaptic communication in the trigeminal system may contribute to the development of trigeminal neuralgia.
Learn More >Thirty-three US states and Washington, D.C., have enacted medical cannabis laws allowing patients with chronic non-cancer pain to use cannabis, when recommended by a physician, to manage their condition. However, clinical guidelines do not recommend cannabis for treatment of chronic non-cancer pain due to limited and mixed evidence of effectiveness. How state medical cannabis laws affect delivery of evidence-based treatment for chronic non-cancer pain is unclear. These laws could lead to substitution of cannabis in place of clinical guideline-discordant opioid prescribing, reducing risk of opioid use disorder and overdose. Conversely, state medical cannabis laws could lead to substitution of cannabis in place of guideline-concordant treatments such as topical analgesics or physical therapy. This protocol describes a mixed-methods study examining the implementation and effects of state medical cannabis laws on treatment of chronic non-cancer pain. A key contribution of the study is the examination of how variation in state medical cannabis laws' policy implementation rules affects receipt of chronic non-cancer pain treatments.
Learn More >Monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway have been shown to be effective in migraine prevention. Eptinezumab, erenumab, fremanezumab, and galcanezumb have shown efficacy in clinical trials along with favorable safety and tolerability profiles. Although erenumab is a human mAb and the others have been humanized to varying degrees, they all have the capacity to provoke immune reactions. The present review article aims to discuss the current relationship between mAbs targeting the CGRP pathway (CGRP mAbs) and immunogenicity and their potential clinical implications.
Learn More >The moment-to-moment variability of resting-state brain activity has been suggested to play an active role in chronic pain. Here, we investigated the regional blood-oxygen-level-dependent signal variability (BOLD) and inter-regional dynamic functional connectivity (dFC) in the interictal phase of migraine and its relationship with the attack severity.
Learn More >Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, including the fully humanized monoclonal antibody (IgG2Δa) fremanezumab, have demonstrated safety and efficacy for migraine prevention. Clinical trials include responders and nonresponders; efficacy outcomes describe mean values across both groups and thus provide little insight into the clinical benefit in responders. Clinicians and their patients want to understand the extent of clinical improvement in patients who respond. This post hoc analysis of fremanezumab treatment attempts to answer this question: what is the benefit in subjects who responded to treatment during the two, phase 3 HALO clinical trials?
Learn More >Chronic pruritus (CP) is a subjective symptom and it is necessary to assess its intensity with validated patient-reported outcome tools in order to allow determination of the treatment course.
Learn More >Among opioid-treated chronic pain patients, response inhibition deficits in emotional contexts may contribute to opioid misuse.
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