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Multiple human and animal studies suggest that the up-regulation of inflammatory cytokines and other pain-related molecules in degenerated or injured intervertebral discs (IVDs) may cause discogenic low back pain (LBP). We previously reported that macrophages in injured IVD in mice produced inflammatory cytokines, but not other pain-related molecules. CD14 is a monocyte marker expressed mainly by macrophages. The aim of the current study was to evaluate the role of CD14-positive cells in inflammatory cytokine and pain-related molecule expression in human degenerated IVD. IVD samples were harvested from 14 patients, including 10 with lumbar spinal stenosis, 4 with adult spinal deformity, and 1 with lumbar disc herniation during spinal interbody fusion surgery. Harvested IVD-derived mononuclear cells were obtained and CD14-positive (+) and CD14-negative (-) cells were separated using CD14 antibody and streptavidin-labeled magnetic beads. Inflammatory cytokines mRNA in the CD14(+) and CD14(-) cells, including tumor necrosis factor alpha (TNFA), in,terleukin-1β (IL1B) and IL6, were determined using quantitative polymerase chain reaction(qPCR) and their expression levels were compared. To evaluate factors controlling the regulation of pain-related molecules mRNA expression, cultured CD14(-) and CD14(+) cells from IVDs were stimulated with recombinant human TNF-alpha and IL-1beta and levels of pain-related molecules, including calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) were determined using qPCR. Levels of TNFA, IL1B, IL6, and NGF in CD14(+) cells were significantly increased compared with those in CD14(-) cells (TNFA, p=0.006; IL1B, p=0.017; IL6, p=0.010; NGF, p=0.027). Following TNFA stimulation, NGF levels were significantly increased in CD14(-) and CD14(+) cells (CD14(-), p=0.003; CD14(+), p<0.001) and CGRP was significantly increased in CD14(-) IVD cells (p=0.040). Following IL1B stimulation, NGF levels were significantly increased in CD14(-) cells (p=0.004). CD14(+) cells had higher TNFA, IL1B, IL6, and NGF expressions than CD14(-) cells in human degenerated IVDs. Additionally, TNFA stimulation promoted the upregulation of NGF and CGRP in CD14(-) cells. These findings suggested that CD14(+) cells directly and indirectly contributed to inflammatory cytokine and pain-related molecule expression in human degenerated IVD. CD14(+) cells might be important in the pathological mechanism of chronic discogenic LBP in humans. This article is protected by copyright. All rights reserved.
Learn More >The development of painful diabetic neuropathy (PDN) is a common complication of chronic diabetes that can be associated with significant disability and healthcare costs. Prompt symptom identification and aggressive glycemic control is essential in controlling the development of neuropathic complications; however, adequate pain relief remains challenging and there are considerable unmet needs in this patient population. Although guidelines have been established regarding the pharmacological management of PDN, pain control is inadequate or refractory in a high proportion of patients. Pharmacotherapy with anticonvulsants (pregabalin, gabapentin) and antidepressants (duloxetine) are common first-line agents. The use of oral opioids is associated with considerable morbidity and mortality and can also lead to opioid-induced hyperalgesia. Their use is therefore discouraged. There is an emerging role for neuromodulation treatment modalities including intrathecal drug delivery, spinal cord stimulation, and dorsal root ganglion stimulation. Furthermore, consideration of holistic alternative therapies such as yoga and acupuncture may augment a multidisciplinary treatment approach. This aim of this review is to focus on the current management strategies for the treatment of PDN, with a discussion of treatment rationale and practical considerations for their implementation.
Learn More >Despite the clinical effectiveness of Spinal Cord Stimulation (SCS), potential structural brain modifications have not been explored. Our aim was to identify structural volumetric changes during subsensory SCS, in patients with Failed Back Surgery Syndrome (FBSS).
Learn More >Multitarget-directed ligands are a promising class of drugs for discovering innovative new therapies for difficult to treat diseases. In this study, we designed dual inhibitors targeting the human fatty acid amide hydrolase (FAAH) enzyme and human soluble epoxide hydrolase (sEH) enzyme. Targeting both of these enzymes concurrently with single target inhibitors synergistically reduces inflammatory and neuropathic pain; thus, dual FAAH/sEH inhibitors are likely to be powerful analgesics. Here, we identified the piperidinyl-sulfonamide moiety as a common pharmacophore and optimized several inhibitors to have excellent inhibition profiles on both targeted enzymes simultaneously. In addition, several inhibitors show good predicted pharmacokinetic properties. These results suggest that this series of inhibitors has the potential to be further developed as new lead candidates and therapeutics in pain management.
Learn More >Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a frequent and devastating side effect of cancer therapy. No preventive strategies are currently available. We investigated the use of resveratrol (RESV) in the prevention of CIPNP and evaluated key components of the antioxidant defense system and neuroinflammatory factors as possible mediators contributing to RESV actions. Male rats were injected with oxaliplatin (OXA) and received daily oral RESV. Paw mechanical and thermal allodynia, oxidative stress, antioxidant, pro-inflammatory and neuronal injury/activation markers were evaluated in the sciatic nerve (SN), lumbar dorsal root ganglia (DRG) and spinal cord (SC). OXA-injected animals developed mechanical and thermal allodynia, while those receiving OXA+RESV showed patterns of response similar to control animals. Higher TBARS levels and lower GSH/GSSG ratios were observed in the SN of animals receiving OXA. The mRNA levels of the transcription factor NFκB and the pro-inflammatory cytokine TNFα were found to be upregulated both in lumbar DRG and SC. In addition, the antioxidant enzymes NQO-1 and HO-1 and the neuronal injury marker ATF3 showed increased levels of expression in lumbar DRG. In the dorsal SC the neuronal activation marker c-fos and the transcription factor Nrf2, main regulator of antioxidant defenses, were found to be upregulated. RESV early and sustained administration prevented NFκB, TNFα, ATF3 and c-fos upregulation, while increasing the expression of Nrf2, NQO-1, HO-1 and the redox-sensitive deacetylase SIRT1. RESV treatment was also able to restore TBARS levels and GSH/GSSG ratio. Thus, RESV administration resulted in the upregulation of antioxidant mediators, suppression of pro-inflammatory parameters and prevention of OXA-induced mechanical and thermal allodynia.
Learn More >The opioid crisis has reached epidemic proportions, yet risk of persistent opioid use following curative intent surgery for cancer and factors influencing this risk are not well understood.
Learn More >The pathophysiology of pain in neuropathy is complex and may be linked to sensory phenotypes. Quantitative sensory testing, a standardized method to evaluate sensory profiles in response to defined stimuli, assesses functional integrity of small and large nerve fiber afferents and central somatosensory pathways. It has revealed detailed insights into mechanisms of neuropathy, yet, it remains unclear if pain directly affects sensory profiles. The main objective of this study was to investigate sensory profiles in patients with various neuropathic conditions, including polyneuropathy, mononeuropathy, and lesions to the central nervous system, in relation to self-reported presence or absence of pain and pain sensitivity using the Pain Sensitivity Questionnaire.A total of 443 patients (332 painful and 111 painless) and 112 healthy participants were investigated. Overall, loss of sensation was equally prevalent in patients with and without spontaneous pain. Pain thresholds were equally lowered in both patient groups, demonstrating that hyperalgesia and allodynia is just as present in patients not reporting any pain. Remarkably, this was similar for dynamic mechanical allodynia. Hypoalgesia was more pronounced in painful polyneuropathy whereas hyperalgesia was more frequent in painful mononeuropathy (compared to painless conditions). Self-reported pain sensitivity was significantly higher in painful than in painless neuropathic conditions.Our results reveal the presence of hyperalgesia and allodynia in patients with central and peripheral lesions of the somatosensory system not reporting spontaneous pain. This shows that symptoms and signs of hypersensitivity may not necessarily coincide, and that painful and painless neuropathic conditions may mechanistically blend into one another.
Learn More >This brief review provides a summary of existing research on virtual reality (VR) applications to pain. We distinguish three categories of studies – VR applications to clinical acute pain, chronic pain, and acute experimental pain, which are currently equally represented in the literature. The review highlights specific advancements in VR pain research as well as areas in need of more development in scrutiny. In particular, we note the pressing need for theoretical scaffolding to facilitate replicable, theoretically-driven methodology, communication, and advancements across the field. To that end, we provide a preliminary heuristic model of VR application to pain experience. The model distinguishes three categories of factors inherent in VR application to pain: VR Configuration Factors, User Experiential Factors, and Pain Targets and Outcomes. VR Configuration Factors comprise technical input devices, system processes, and output devices, which present a virtual world to the user and enable User Experiential Factors of presence, interactivity, immersion, and embodiment. These interdependent experiential factors serve as potential mediators and moderators for subsequent changes in cognitive, emotional, social, behavioral, and physiological outcomes that serve as Targets of pain-related therapy. Given that rapid technological progress can both facilitate and frustrate research progress within the field, systematic, theoretically-informed inquiry into factors comprising and driving the effects of VR pain applications, combined with more rigorous theoretically-informed methodology, is a critical challenge.
Learn More >Chronic neuropathic pain is frequently accompanied by memory impairment, yet the underlying mechanisms remain unclear. Here we showed that mice displayed memory impairment starting at 14 days and lasting for at least 21 days after chronic constriction injury (CCI) of unilateral sciatic nerve in mice. Systemic administration of the pan histone deacetylase (HDAC) inhibitor sodium butyrate attenuated this memory impairment. More specifically, we found that hippocampus HDAC3 was involved in this process because the levels of its mRNA and protein increased significantly in the hippocampus at 14 and 21 days after CCI, but not sham surgery. Systemic administration of the selective HDAC3 antagonist RGPF966 attenuated CCI-induced memory impairment, improved hippocampal long-term potentiation impairment and rescued reductions of dendritic spine density and synaptic plasticity-associated protein in the hippocampus. Additionally, HDAC3 overexpression in the hippocampus led to memory impairment without affecting basal nociceptive responses in naive mice. Our findings suggest that HDAC3 contributes to memory impairment after CCI by impairing synaptic plasticity in hippocampus. HDAC3 might serve as a potential molecular target for therapeutic treatment of memory impairment under neuropathic pain conditions.
Learn More >The STarT Back approach comprises subgrouping low back pain (LBP) patients according to risk of persistent LBP-related disability, with appropriate matched treatments. In a twelve-month clinical trial and implementation study, this stratified care approach was clinically and cost-effective compared to usual, non-stratified care. Despite the chronic nature of LBP and associated economic burden, model-based economic evaluations in LBP are rare and have shortcomings. This study therefore produces a de-novo decision model of this stratified care approach for LBP management to estimate the long-term cost-effectiveness and address methodological concerns in LBP modelling.A cost-utility analysis from the NHS perspective compared stratified care with usual care in patients consulting in primary care with non-specific LBP. A Markov state-transition model was constructed where patient prognosis over ten years was dependent upon physical function achieved at twelve months. Data from the clinical trial and implementation study provided short term model parameters, with extrapolation using two cohort studies of usual care in LBP.Base-case results indicate this model of stratified care is cost-effective, delivering 0.14 additional quality-adjusted life years (QALYs) at a cost-saving of £135.19 per patient over a time horizon of ten-years. Sensitivity analyses indicate the approach is likely to be cost-effective in all scenarios, and cost-saving in most.It is likely this stratified care model will help reduce unnecessary healthcare usage whilst improving patient quality of life. Whilst decision analytic modelling is employed in many conditions, its use has been underexplored in LBP and this paper also addresses associated methodological challenges.
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