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Anti-inflammatory corticosteroids are a common treatment for different conditions involving chronic pain and inflammation. Clinically used steroids target the glucocorticoid receptor (GR) for its anti-inflammatory effects. We previously reported that GR in sensory neurons may play central roles in some pain models and that GR immunoreactivity signal in dorsal root ganglia (DRG) decreased after local inflammation of the DRG (a model of low back pain). In the current study, we aimed to determine if similar changes in GR signal also exist in a skin inflammation model, the complete Freund's adjuvant (CFA) model (a model of peripheral inflammatory pain), in which the terminals of the sensory neurons rather than the somata are inflamed.
Learn More >Pain of a moderate or severe intensity affects over half of patients with advanced cancer and remains undertreated in at least one-third of these patients.
Learn More >Introduction There is limited evidence for effect of interventional treatment, and pragmatic studies are needed to assess these interventions within a clinical setting. The aim of this study was to describe patients referred to an interventional pain clinic and investigate responses after spinal intervention in general and for radiofrequency ablation (RFA) and transforaminal epidural corticosteroid administration (TECA), specifically. Methods This is a prospective, non-controlled study of patients with chronic spinal pain. The procedures were performed in accordance with the Spine Intervention Society recommendations. Outcome data after a median of 4.5 months are presented, and for those treated with RFA also after 6 and 12 months. Results Among 815 patients, 190 patients underwent diagnostic blocks only and 625 interventional treatment, of these 94 RFA and 246 TECA. Of the whole sample 70% reported pain reduction, for 49% ≥ 50%, while 9% were pain free (p < 0.001). Highest pain intensity decreased from 7.1 to 5.4 [95% Confidence Interval of the Difference (95%-CI): 1.4-1.9] (p < 0.001), while Euroqual – visual analogue scale for general health (EQ-VAS) improved from 48 to 58 (95%-CI: 7.6-11.9) (p < 0.001), and Euroqual-5 Dimensions-5 Levels Index for health related quality of life (EQ-5D-5L Index) from 0.489 to 0.628 (95%-CI: 0.123-0.157) (p < 0.001). The proportions, not taking analgesics, increased from 16% to 30%, and proportion taking strong opioids decreased from 14% to 9% (p < 0.001). We found no significant change in proportion receiving physiotherapy/other treatment nor occupational status. No complications were reported. Among patients treated with RFA, 77% reported pain reduction, for 56% ≥ 50%, while 9% were pain free (p < 0.001). Highest pain intensity decreased from 6.9 to 4.6 (95%-CI: 1.6-3.0) (p < 0.001), while EQ-VAS improved from 47 to 57 (95%-CI: 4.8-13.6 (p < 0.001), and EQ-5D-5L Index from 0.489 to 0.643 (95%-CI: 0.117-0.191) (p < 0.001). The proportion not taking analgesics, increased from 7% to 23% and proportion taking strong opioids decreased from 16% to 10%. Among patients who responded at 6- and 12-month follow up, the proportions reporting pain reduction, EQ-VAS, and EQ-5D-5L Index remained significantly improved from baseline, and the change in proportions taking analgesic and opioids achieved statistical significance. We found no significant change in proportion receiving physiotherapy/other treatment nor occupational status. Among patients treated with TECA, 58% reported pain reduction, for 36% ≥ 50%, while 5% were pain free (p < 0.001). Highest pain intensity decreased from 7.2 to 6.2 (95%-CI 0.5-1.4) (p < 0.001), while EQ-VAS improved from 46 to 52 (95%-CI: 2.0-3.6) (p < 0.001), and EQ-5D-5L Index from 0.456 to 0.571 (95%-CI: 0.077-0.138) (p < 0.001). The proportions, not taking analgesics, increased from 17% to 27% and proportion taking strong opioids decreased from 15% to 10%, but the changes did not reach statistical significance. We found no significant changes in the proportion who recieved physiotherapy/other treatment nor occupational status. Conclusion The study demonstrates substantial short-term responses after spinal intervention and long-lasting improvement for a subsample of the RFA treated patients. We observed larger proportions reporting pain reduction among those treated with cervical RFA. Implementation Quality assessment should be implemented in interventional pain clinics to improve treatment quality.
Learn More >Although there is evidence of suboptimal outcomes in older people with chronic pain, little emphasis has been placed on those in remote and rural settings.
Learn More >Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) have been implicated in the trafficking of postsynaptic glutamate receptors, including N-methyl-D-aspartate (NMDA)-subtype glutamate receptors (NMDARs) that are critical for nociceptive plasticity and behavioral sensitization. However, the components of SNAREs complex involved in spinal nociceptive processing remain largely unknown. Here we found that SNAP25, syntaxin4, VAMP2 and Munc18-1 were localized at postsynaptic sites and formed the complex in the superficial lamina of spinal cord dorsal horn of rats. The complex formation between these SNAREs components were accelerated after intraplantar injection of complete Freund's adjuvant (CFA), pharmacological removal of GABAergic inhibition or activation of NMDAR in intact rats. The increased SNAP25/syntaxin4/VAMP2/Munc18-1 interaction facilitated the surface delivery and synaptic accumulation of NMDAR during inflammatory pain. Disruption of the molecular interaction between SNAP25 with its SNARE partners by using a blocking peptide derived from the C-terminus of SNAP25 effectively repressed the surface and synaptic accumulation of GluN2B-containing NMDARs in CFA-injected rats. This peptide also alleviated inflammatory mechanical allodynia and thermal hypersensitivity. These data suggested that SNAREs complex assembly in spinal cord dorsal horn was involved in the inflammatory pain hypersensitivity through promoting NMDAR synaptic trafficking.
Learn More >Pain is the vital sense preventing tissue damage by harmful noxious stimuli. The capsaicin receptor TRPV1 is activated by noxious temperatures, however, acute heat pain is only marginally affected in mice after TRPV1 knockout but completely eliminated in mice lacking TRPV1 positive fibers. Exploring contribution of candidate signal transduction mechanisms to heat pain in humans needs translational models.
Learn More >Chronic pruritus is a frequent global condition. The pathophysiology, underlying aetiology, clinical manifestation, associated burden and response to therapy of chronic pruritus varies from patient to patient, making clinical research and management of this condition challenging. There are still several unmet needs, such as the need to standardize translational research protocols, diagnostic and therapeutic procedures and to enhance the knowledge of the humanistic and economic burden associated with chronic pruritus. Basic and clinical research is of the utmost importance to target these matters. Clinical research has the potential to identify new relevant mechanisms in affected patients, which may lead to identification of novel therapy targets. This article discusses in depth current shortcomings in the daily care of patients with chronic pruritus and the challenges clinical researchers and physicians treating chronic pruritus face in addressing these matters.
Learn More >Understanding molecular alterations associated with peripheral inflammation is a critical factor in selectively controlling acute and persistent pain. The present report employs in situ hybridization of the two opioid precursor mRNAs coupled with quantitative measurements of two peptides derived from the prodynorphin and proenkephalin precursor proteins: dynorphin A 1-8 and [Met]-enkephalin-Arg-Gly-Leu (MERGL). In dorsal spinal cord ipsilateral to the inflammation, dynorphin A 1-8 was elevated after inflammation, and persisted as long as the inflammation was sustained. Qualitative identification by HPLC and gel permeation chromatography revealed the major immunoreactive species in control and inflamed extracts to be dynorphin A 1-8. In situ hybridization in spinal cord after administration of the inflammatory agent, carrageenan, showed increased expression of prodynorphin (Pdyn) mRNA somatotopically in medial superficial dorsal horn neurons. The fold increase in preproenkephalin mRNA (Penk) was comparatively lower, although the basal expression is substantially higher than Pdyn. While Pdyn is not expressed in the dorsal root ganglion (DRG) in basal conditions, it can be induced by nerve injury, but not by inflammation alone. A bioinformatic meta-analysis of multiple nerve injury datasets confirmed Pdyn upregulation in DRG across different nerve injury models. These data support the idea that activation of endogenous opioids, notably dynorphin, is a dynamic indicator of persistent pain states in spinal cord and of nerve injury in DRG. [218/200] PERSPECTIVE: This is a systematic, quantitative assessment of dynorphin and enkephalin peptides and mRNA in dorsal spinal cord and dorsal root ganglia neurons in response to peripheral inflammation and axotomy. These studies form the foundational framework for understanding how endogenous spinal opioid peptides are involved in nociceptive circuit modulation. (48/50).
Learn More >Increasing numbers survive cancers in childhood and adolescence. Long-term survivors of cancers in adulthood have increased prevalence of pain and consumption of analgesics. It is not established whether long-term survivors of cancers in childhood and adolescence also have an increased use of analgesics. However, based on increased use of antidepressants and anxiolytics in long-term survivors of cancers in childhood and adolescence, we hypothesized that this group also had increased use of analgesics. Based on data from the two nationwide registers the Cancer Registry of Norway and the Norwegian Prescription Database a cohort of 5585 (52% males) long-term survivors of cancers in childhood, adolescence and early adult life was established. Age and gender adjusted comparisons were made to the general population. The age adjusted one-year periodic prevalence of receiving prescriptions of opioids, benzodiazepines and benzodiazepine-related hypnotics in the study population was increased by 20-50% and the one-year periodic prevalence of receiving prescriptions of gabapentinoids was approximately increased two-fold compared to the general population. For paracetamol and NSAIDs no difference was found. For those survivors, who were persistent or high-dose users of opioids, co-medication with high doses of benzodiazepines and/or benzodiazepine-related hypnotics was far more common than among persistent and high-dose opioid users in the general population. The high prevalence of gabapentinoids may indicate increased prevalence of neuropathic pain in this group. The high degree of co-medication with benzodiazepines and/or benzodiazepine-related hypnotics in survivors on persistent and high-dose opioids might be an indication of problematic opioid use or addiction.
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