Nociceptive System Research Articles

Room‐Temperature‐Integrated Flexible Diffusive Oxide Memristors for Artificial Nociceptive Systems

AbstractNovel areas of human–computer interaction and intelligent robotics are rapidly boosted by flexible electronic devices, among which artificial nociceptors for pain perception are considered essential sensory devices. Recently, flexible diffusive memristors with volatile behavior are extensively studied to emulate biological synapses and neurons because of their rich threshold–switching dynamics, which are crucial for nociceptive functions. Herein, flexible diffusive memristors with an Ag/TaO1.8/TaO2.7/TaO1.8/Ag (ATTTA) structure are fabricated at room temperature, demonstrating a high switching ratio of 107, an ultra‐fast turn‐on speed of 40 ns, a long endurance up to 104 sweep cycles, low positive and negative threshold variation rates (6.7%/7.8%) for 50 devices, a good thermal stability at an 85 °C measurement temperature, and a high flexibility under an 8 mm bending radius. These high performances are attributed to the oxygen‐rich TaO2.7 layer, which can prevent the excessive migration of Ag atoms. Moreover, multiple biological nociceptor functions, including threshold firing, no adaptation, and sensitization, are successfully emulated in the flexible ATTTA diffusive memristor. Accordingly, the human–skin nociceptive system is successfully emulated by integrating ATTTA diffusive memristor array with force–sensing resistors (FSRs), which enables stereoscopic injury perception of inhomogeneous stimuli.

Structural changes in the nociceptive system induced by long-term conventional spinal cord stimulation in experimental painful diabetic polyneuropathy

BackgroundClinical studies suggest that long-term conventional spinal cord stimulation (LT-SCS) for painful diabetic peripheral neuropathy (PDPN) is initially effective but may decline in efficacy over time. Preclinical studies indicate that...

Repetitive daily oxytocin treatment reduces weight gain but not acute neonatal procedural pain.

While the incidence of neonatal intensive care unit (NICU) admission steadily increases, neonatology lacks evidence of a safe, effective, and preventive analgesic for treating procedural pain. Given its role in nociception and promoting healthy neurodevelopment, the endogenous neuropeptide oxytocin (OT) emerges as a promising candidate. This study investigates the use of daily repeated subcutaneous OT (1 mg/kg) treatment in an established model of neonatal repetitive procedural pain and assesses the effectivity of OT treatment on mechanical sensitivity and body weight. Contrary to our hypothesis repeated daily OT treatment did not prevent the development of mechanical hypersensitivity following needle pricks. Furthermore, treatment with OT diminished body weight gain in neonatal pups, a major side effect observed throughout the neonatal week. These results highlight the unique nature of the maturing nociceptive system that makes the identification and selection of analgesic options for the treatment of acute neonatal procedural pain a major challenge. In conclusion, our preclinical results do not support the use of repeated OT for acute pain relief in the NICU, and the side effects on body weight gain raise concerns about the use of OT in the NICU. Repeated daily OT treatment inhibits weight gain in neonatal rat pus. Repetitive daily OT administration does not prevent the development of mechanical hypersensitivity in a model of neonatal procedural pain. Future research must focus on the unique physiology of the developing nociceptive system to establish safe, effective and protective treatment of neonatal procedural pain.

Effect of limb position change on capsaicin-evoked pain: Evidence of interplays between the vascular and nociceptive systems?

This experiment aimed at confirming our incidental observation that, when capsaicin is applied on the volar forearm, raising the arm to a vertical position leads to a dramatic increase in capsaicin-evoked pain and to explore possible underlying mechanisms. Twenty healthy volunteers received a 2% capsaicin patch on one forearm and a vehicle patch on the other. Patches were kept in place for 60 min. The perception caused by the patch was assessed repeatedly before, during and after patch application, both with the arm in horizontal resting position and raised vertically. In addition, capsaicin-induced secondary hyperalgesia was assessed using mechanical pinprick stimuli. Half of the participants were seated upright while the other half were lying supine, to assess whether the effect of limb position on capsaicin-evoked pain was due to gravity. After a few minutes of patch application, raising the capsaicin-treated arm (but not the vehicle-treated arm) led to a strong increase of the pain experienced at the patch. This effect of raising the arm did not differ between participants in the supine and seated groups and is therefore likely related to the position of the arm relative to the ground rather than to the body. Mechanical secondary hyperalgesia and the arm raising effect were strongly decorrelated at the last time point after patch removal, indicating different underlying mechanisms. Our results indicate that capsaicin-evoked pain can be strongly modulated by limb posture and that this effect may be caused by an interplay between vascular and nociceptive systems. Capsaicin-evoked pain can be strongly modulated by limb posture and this effect may be caused by an interplay between vascular and nociceptive systems.

Complex therapy of musculoskeletal pain: the role of centrally acting muscle relaxants

Chronic pain is the main manifestation of musculoskeletal diseases (MSDs), leading to deterioration of quality of life and loss of ability to work. The importance of this problem is determined by the widespread prevalence of MSDs, osteoarthritis (OA), acute and chronic non-specific back pain (NBP), periarticular soft tissues lesions. Introduction of effective methods of treatment of musculoskeletal pain (MSP) into medical practice is one of the fundamental tasks of modern medicine.The pathogenesis of MSP includes mechanisms such as injury, inflammation, peripheral sensitization, biomechanical disorders, dysfunction of the nociceptive system and psychoemotional disorders. Painful muscle tension plays an important role in the development of MSP, especially in NBP. Given the complex pathogenesis of MSP, its treatment is based on the combined use of drugs with different mechanisms of action and nonpharmacological methods. Non-steroidal anti-inflammatory drugs (NSAIDs) have a central place in this context. However, they can cause serious adverse reactions (ARs), so when choosing NSAIDs, it is necessary to consider comorbid pathology and risk factors. One of the most acceptable NSAIDs with a pronounced analgesic effect and low incidence of ARs is aceclofenac, which is available in various dosage forms (tablets, sachets, topical cream for external use). This medication is characterized by proven efficacy and good tolerability.Centrally acting muscle relaxants (CM) play an important role in the treatment of MSP. They eliminate muscle spasm, enhance the effect of analgesics and reduce the need for NSAIDs. The effect of CM has been demonstrated in spasticity and NBP. However, the use of many drugs of this group can be associated with serious ARs, which limits their use.Tolperisone has the best combination of efficacy and favorable safety profile among CM. Its positive effect in the complex treatment of NBP has been confirmed in several well-organized, placebo-controlled trials. There are also studies demonstrating the efficacy of tolperisone in OA. An important advantage of this drug is virtually no sedative effect, and no negative impact on hemodynamics and on the ability to perform concentration-intensive work. Emergence of a new form of tolperisone – extended-release tablets (Mydocalm® Long 450 mg) – increases patient compliance with CM therapy and facilitates the physician's work.

Bioinspired Artificial Intelligent Nociceptive Alarm System Based on Fibrous Biomemristors.

With the advancement of modern medical and brain-computer interface devices, flexible artificial nociceptors with tactile perception hold significant scientific importance and exhibit great potential in the fields of wearable electronic devices and biomimetic robots. Here, a bioinspired artificial intelligent nociceptive alarm system integrating sensing monitoring and transmission functions is constructed using a silk fibroin (SF) fibrous memristor. This memristor demonstrates high stability, low operating power, and the capability to simulate synaptic plasticity. As a result, an artificial pressure nociceptor based on the SF fibrous memristor can detect both fast and chronic pain and provide a timely alarm in the event of a fall or prolonged immobility of the carrier. Further, an array of artificial pressure nociceptors not only monitors the pressure distribution across various parts of the carrier but also provides direct feedback on the extent of long-term pressure to the carrier. This work holds significant implications for medical support in biological carriers or targeted maintenance of electronic carriers.

Olokizumab effect on chronic pain in rheumatoid arthritis: Results of the PROLOGUE observational study.

Evaluate the efficacy and safety ® (olokizumab) in patients with rheumatoid arthritis (RA) in real-world clinical practice, with a targeted assessment of patient report outcomes (PRO) and central sensitization. An open-label observational non-interventional study was conducted, enrolling 183 patients with moderate and severe RA activity. All patients received OKZ 64 mg SC as injections every 4 weeks (Q4W) with methotrexate. The patients' follow-up period was 24 weeks or less. RA activity (DAS28-CRP), pain severity (NRS), patient global assessment (PGA, NRS), functional impairment (NRS), fatigue (FACIT-F), central sensitization (central sensitization inventory, CSI), and symptoms of neuropathic pain (PainDETECT) were evaluated. The study cohort was comprised of 144 patients. And 39 patients were lost to follow-up, refused OKZ treatment, or were not dosed with OKZ for administrative reasons. In 6 months, DAS28-CRP decreased to 3.3 ± 0.9 (p < .001) and statistically significant reductions in pain intensity, PGA, functional impairment, and fatigue were achieved. Pain intensity decreased as early as 2 days after the first OKZ administration (p < .05). The number of patients with CSI >40 in 24 weeks decreased from 71.0% to 21.0% (p < .001), with PainDETECT >18 - from 21.5% to 13.2%. NSAIDs use decreased from 70.8% to 33.8% (р < .001), steroids - from 54.2% to 32.6%. AEs were reported in 14.2% patients, serious events were observed in three patients. OKZ is effective in reducing RA activity and controlling chronic pain related to dysfunction of the nociceptive system.

Scratch-collapse test in reflex cervical-elbow syndrome

The scratch-collapse test was proposed in 2008 to detect the level of compression of the ulnar and median nerves in tunnel lesions. Further study of this phenomenon has shown that weakness of the shoulder external rotators occurs in nerve lesions at other levels as well. The scratch-collapse test was studied in 155 patients (mean age 45 years) with unilateral reflex cervical-elbow syndrome, with complaints of different localization. The scratch-collapse test was positive in all patients on the affected side. The localization of the trigger zone depended on the patient’s complaints and was established experimentally. Short-term kneading of the trapezius muscle or voluntary contraction of the forearm muscles on the side of the lesion was used to prove the reflex nature of the cervico-elbow syndrome, resulting in complete recovery of triceps or extensor strength of the first and third finger. In the course of the study, suppression of the scratch-collapse test in reflex cervico-elbow syndrome with proprioceptive stimulation was found. In confirmed carpal tunnel and cubital tunnel syndromes, the phenomenon of suppression of the scratch-collapse test was also observed in response to proprioceptive stimulation. The scratch-collapse test and reflex cervical-elbow syndrome have a common mechanism of occurrence, which is based on the protective reaction of the body in the form of a nociceptive shortening reflex. The scratch-collapse test at skin irritation over the site of nerve injury can be considered as a subthreshold physiologic nociceptive reflex. Based on the theory of prognostic action of the nociceptive system, cervicolumbar reflex syndrome is a pathologic nociceptive reflex. Scratchcollapse test suppression phenomenon and recovery of muscle strength in reflexive cervical-elbow syndrome after shortterm kneading of the trapezius muscle are the result of activation of the antinociceptive system in response to proprioceptive stimulation. This suppression phenomenon can be used for the treatment of reflex cervical lockjaw syndrome.

Multiple mechanisms of action of an extremely painful venom.

Evolutionary arms races between predator and prey can lead to extremely specific and effective defense mechanisms. Such defenses include venoms that deter predators by targeting nociceptive (pain-sensing) pathways. Through co-evolution, venom toxins can become extremely efficient modulators of their molecular targets. The venom of velvet ants (Hymenoptera: Mutillidae) is notoriously painful. The intensity of a velvet ant sting has been described as "Explosive and long lasting, you sound insane as you scream. Hot oil from the deep fryer spilling over your entire hand." [1] The effectiveness of the velvet ant sting as a deterrent against potential predators has been shown across vertebrate orders, including mammals, amphibians, reptiles, and birds [2-4]. The venom's low toxicity suggests it has a targeted effect on nociceptive sensory mechanisms [5]. This leads to the hypothesis that velvet ant venom targets a conserved nociception mechanism, which we sought to uncover using Drosophila melanogaster as a model system. Drosophila larvae have peripheral sensory neurons that sense potentially damaging (noxious) stimuli such as high temperature, harsh mechanical touch, and noxious chemicals [6-9]. These polymodal nociceptors are called class IV multidendritic dendritic arborizing (cIV da) neurons, and they share many features with vertebrate nociceptors, including conserved sensory receptor channels [10,11]. We found that velvet ant venom strongly activated Drosophila nociceptors through heteromeric Pickpocket/Balboa (Ppk/Bba) ion channels. Furthermore, we found a single venom peptide (Do6a) that activated larval nociceptors at nanomolar concentrations through Ppk/Bba. Drosophila Ppk/Bba is homologous to mammalian Acid Sensing Ion Channels (ASICs) [12]. However, the Do6a peptide did not produce behavioral signs of nociception in mice, which was instead triggered by other non-specific, less potent, peptides within the venom. This suggests that Do6a is an insect-specific venom component that potently activates insect nociceptors. Consistent with this, we showed that the velvet ant's defensive sting produced aversive behavior in a predatory praying mantis. Together, our results indicate that velvet ant venom evolved to target nociceptive systems of both vertebrates and invertebrates, but through different molecular mechanisms.

Diffusive Memristor with CuS Nanoparticles Embedded in Polymeric Film as Artificial Nociceptor.

The threshold behavior and the ion diffusion dynamics in diffusive volatile memristors have a very uncanny resemblance to the transduction process of biological nociceptors. Hence, the diffusive memristors are considered the most suited for making artificial nociceptive systems. To facilitate their widespread adoption, it is imperative to develop polymeric or organic-inorganic hybrid material-based diffusive memristors that are economical, biocompatible, and easily processable. In this study, we present a cluster-type polymeric diffusive memristor where copper is used as the active top electrode. The switching medium comprises copper(II) sulfide (CuS) nanoparticles embedded in poly(ethylene oxide) (PEO). The devices show electrochemical metalization (ECM)-type and bidirectional diffusive volatile memory with high nonlinearity (104) and turn-on slope (5.6 mV/dec). They reliably remain diffusive volatile with up to 10 wt % CuS in PEO and for a wide range of compliance (10-6 to 10-2 A) without transitioning to the bipolar nonvolatile type. The low reduction potential of CuS and optimal segmental dynamics of PEO work synergistically to ensure stable and reproducible diffusive memory. The CuS nanoparticles act as bipolar electrodes, undergoing local oxidation and reduction under the influence of the bias. The switching of resistance states in the CuS-PEO memristors is attributed to the formation of cluster-type filaments between CuS nanoparticles within the PEO matrix supported by the participation of copper ions from the top Cu electrode. The observation of low filament temperature and the independence of on-state resistance with respect to the device area and temperature further corroborate the cluster-type filament in CuS-PEO memristors. Using a 5 wt % CuS-based device, an artificial nociceptor is realized, which successfully mimics most of the nociceptive plasticities such as threshold, relaxation, no adaptation, and sensitization.

Pain research in a petri dish? Advantages and limitations of neuro-glial primary cell cultures from structures of the nociceptive system

How can we learn more about pain without causing pain in humans or animals? This short review focuses on neuro-glial primary cell cultures as models to study neuro-immune interactions in the context of pain and discusses their advantages and limitations.The field of basic pain research places scientists in an ethical dilemma. We aim to understand underlying mechanisms of pain for an improved pain therapy for humans and animals. At the same time, this regularly includes the induction of pain in model animals. Within the field of psychoneuroimmunology, the examination of the complexity of neuro-immune interactions in health and disease as well as the bi-directional communication between the brain and the periphery make animal experiments an inevitable part of pain research. To address ethical and legal considerations as well as the growing societal awareness for animal welfare, scientists push for the identification and characterization of complementary methods to implement the 3R principle of Russel and Burch. As such, methods to replace animal studies, reduce the number of animals used, and refine experiments are tested. Neuro-glial primary cell cultures of structures of the nociceptive system, such as dorsal root ganglia (DRG) or the spinal dorsal horn (SDH) represent useful in vitro tools, when research comes to a cellular and molecular level. They allow for studying mechanisms of neuronal sensitization, glial cell activation, or the role of specific inflammatory mediators and intracellular signaling cascades involved in the development of inflammatory and neuropathic pain. Moreover, DRG/SDH-cultures provide the opportunity to test novel strategies for interventions, such as pharmaceuticals or cell-based therapies targeting neuroinflammatory processes. Thereby, in vitro models contribute to a better understanding of neuron-glia-immune communication in the context of pain and in the advancement of pain therapies. However, this can only be one piece in a large puzzle. Our knowledge about the complexity of pain will depend on studies in humans and animals applied in vitro and in vivo and will benefit from clear and open-minded interdisciplinary communication and transparency in public outreach.

Application of the grading system for "nociplastic pain" in chronic primary and chronic secondary pain conditions: a field study.

The concept "nociplastic pain" has been developed for patients with features of nociceptive system sensitization that are not explained as nociceptive or neuropathic. Here, we tested how well the recently published grading system differentiates between chronic primary and secondary pain conditions. We recruited patients with fibromyalgia (FMS, n = 41), complex regional pain syndrome (CRPS, n = 11), osteoarthritis (OA, n = 21), or peripheral nerve injury (PNI, n = 8). We used clinical history, pain drawings, quantitative sensory testing (QST), and questionnaires to classify their pains as possibly or probably "nociplastic." All patients with chronic primary pain exhibited widespread/regional pain not explainable by either nociceptive or neuropathic mechanisms. Widespread pain occurred in 12 patients with OA but was identified as nociceptive in 11 of 12. Regional pain occurred in 4 patients with PNI but was identified as neuropathic in 3 of 4. At this step, the grading system had 100% sensitivity and 93% specificity. Clinical evidence for pain hypersensitivity by QST, and history of hypersensitivity and mental comorbidities did not differentiate between chronic primary pain (QST: 36/52 = 69%, history: 43/52 = 83%) and secondary pain conditions (QST: 20/29 = 69%, history: 24/29 83%). Based on these data, specificity remained excellent (93%), but sensitivity dropped substantially (60%) due to lacking evidence for pain hypersensitivity in many patients with FMS. This low sensitivity suggests that the published grading system is not suitable for screening purposes. We suggest structural and content modifications to improve sensitivity, including placement of patient history before clinical examination and addition of a high tender point count as evidence for widespread pain hypersensitivity.

Transsynaptic BMP Signaling Regulates Fine-Scale Topography between Adjacent Sensory Neurons.

Sensory axons projecting to the central nervous system are organized into topographic maps that represent the locations of sensory stimuli. In some sensory systems, even adjacent sensory axons are arranged topographically, forming "fine-scale" topographic maps. Although several broad molecular gradients are known to instruct coarse topography, we know little about the molecular signaling that regulates fine-scale topography at the level of two adjacent axons. Here, we provide evidence that transsynaptic bone morphogenetic protein (BMP) signaling mediates local interneuronal communication to regulate fine-scale topography in the nociceptive system of Drosophila larvae. We first show that the topographic separation of the axon terminals of adjacent nociceptors requires their common postsynaptic target, the A08n neurons. This phenotype is recapitulated by knockdown of the BMP ligand, Decapentaplegic (Dpp), in these neurons. In addition, removing the Type 2 BMP receptors or their effector (Mad transcription factor) in single nociceptors impairs the fine-scale topography, suggesting the contribution of BMP signaling originated from A08n. This signaling is likely mediated by phospho-Mad in the presynaptic terminals of nociceptors to ensure local interneuronal communication. Finally, reducing Dpp levels in A08n reduces the nociceptor-A08n synaptic contacts. Our data support that transsynaptic BMP signaling establishes the fine-scale topography by facilitating the formation of topographically correct synapses. Local BMP signaling for synapse formation may be a developmental strategy that independently regulates neighboring axon terminals for fine-scale topography.

Pain and heart rate variability in neonates receiving dexmedetomidine.

Neonates in a NICU experience pain. Based on the cardiovascular and nociceptive systems link, a Newborn Infant Parasympathetic Evaluation (NIPE) monitor was designed to assess pain. The use of α2-agonists as analgesic-sedative drugs has increased in neonates. Given their effect on the autonomic system, we hypothesized that their use may alter NIPE's measurement capacity. Data were prospectively collected. The included patients were evaluated using combined pain assessment systems. Sixteen newborns requiring sedoanalgesia underwent a total of 84 pain assessments. A good correlation was found between the NIPE-index and the COMFORT-neo and the crSO2 (cerebral regional oxygen saturation). No correlation was found in premature infants. By sedation group, the correlation remained in those receiving α2-agonist. NIPE is a reliable tool for pain assessment. Further studies in premature infants are needed. The use of α2-agonist does not alter the measuring capacity of NIPE. The correlation between NIPE-index and crSO2 was also demonstrated.

Innervation of nociceptor neurons in the spleen promotes germinal center responses and humoral immunity

Peripheral sensory neurons widely innervate various tissues to continuously monitor and respond to environmental stimuli. Whether peripheral sensory neurons innervate the spleen and modulate splenic immune response remains poorly defined. Here, we demonstrate that nociceptive sensory nerve fibers extensively innervate the spleen along blood vessels and reach B cell zones. The spleen-innervating nociceptors predominantly originate from left T8-T13 dorsal root ganglia (DRGs), promoting the splenic germinal center (GC) response and humoral immunity. Nociceptors can be activated by antigen-induced accumulation of splenic prostaglandin E2 (PGE2) and then release calcitonin gene-related peptide (CGRP), which further promotes the splenic GC response at the early stage. Mechanistically, CGRP directly acts on B cells through its receptor CALCRL-RAMP1 via the cyclic AMP (cAMP) signaling pathway. Activating nociceptors by ingesting capsaicin enhances the splenic GC response and anti-influenza immunity. Collectively, our study establishes a specific DRG-spleen sensory neural connection that promotes humoral immunity, suggesting a promising approach for improving host defense by targeting the nociceptive nervous system.

Interleukin 17 as a central component of the pathogenesis of pain associated with immunoinflammatory process: A new “target” of pharmacotherapy

Modern pathogenetic therapy of inflammatory rheumatic diseases (IRD) is aimed not only at reducing disease activity (although achieving remission and low disease activity remains the main goal of treatment), but also at eliminating as quickly and completely as possible the main symptoms that cause a decrease in the quality of life of patients. Particular importance is attached to effective control of chronic pain – the main and most distressing manifestation of IRD. To solve this problem, the pathogenesis of chronic pain in IRD continues to be actively studied, aimed at finding new ”targets” of pharmacotherapy. Thus, the role of central sensitization (CS) and comorbid fibromyalgia in the formation of clinical manifestations of IRD is now clearly proven. Signs of CS, depending on the instrument of its detection, are determined in 20–40% of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA).Interleukin (IL) 17 plays a fundamental role in the development of chronic pain in IIRD. This cytokine takes a leading position in the development of the ”cytokine cascade”, inducing the synthesis of various cytokines and chemokines, as well as chemotaxis and activation of neutrophils and T cells. Induction of synthesis of inflammatory mediators (including prostaglandin E2) determines the role of IL-17 in activation of nociceptors and their sensitization. IL-17 also takes an active part in neuroimmune interactions by activating glia cells and affecting receptors present on the membrane of neurons of the posterior horns of the spinal cord. This defines the role of IL-17 as one of the inductors of CS development. Pharmacologic blockade of IL-17 is a known pathway to suppress the activity of IIRPs such as PsA and AxSpA. However, this mechanism also allows for significant effects on chronic pain. In particular, the IL-17 inhibitor ixekizumab has shown high analgesic potential in a series of studies in PsA and AxSpA (SPIRIT-P1 and SPIRIT-P2, COAST V and COAST W). It is important to note that this drug demonstrated a very rapid analgesic effect: pain intensity was significantly reduced already 7 days after the first injection. These data suggest a specific effect of ixekizumab on the nociceptive system, independent of the anti-inflammatory effect. This fact allows us to consider ixekizumab as a drug of choice for the treatment of patients with PsA and AxSpA who experience severe pain and have signs of CS and fibromyalgia.

Paradigms matter: why persistent pain is different and how dentists can help.

Dental professionals often expect, and are used to treating, pain that has a clear, organic and likely pathological cause. Patients visiting the dentist are also likely to share this expectation. However, in addition to potential organic contributions to the experience of pain, the nociceptive system (pain signalling system) also plays an important role. Alongside organic contributions, it is important to also consider that persistent pain is different to acute pain and requires different explanations and different management. Dental professionals need to be equipped to understand and explain persistent pain and to incorporate this understanding into their ongoing patient management so that patients can be educated in why the two are different and therefore require different approaches.

Evaluation of the efficacy of complex analgesic therapy, including a combination of B vitamins, in patients with combination of osteoarthritis and chronic non-specific low back pain (results of an open-label pilot clinical trial)

The vitamin B1, B6 and B12 complex (VBC) is frequently used to treat acute and chronic low back pain.Objective: to investigate the effect of a combination of a non-steroidal anti-inflammatory drug (NSAID) and a VBC on the main manifestations of nociceptive system dysfunction in patients with combination of osteoarthritis (OA) and chronic non-specific low back pain (NSLBP).Material and methods. The study group consisted of 99 patients (82% women, mean age 63.6±17.2 years) with OA of various localization andNSLBP who had moderate to severe pain (≥4 on a numerical rating scale, NRS 0–10). All patients received etoricoxib 60 mg/day (up to 14 days) and a course of intramuscular (IM) injections of VBC (a drug for parenteral administration containing solutions of thiamine 100 mg, pyridoxine 100 mg, cyanocobalamin 1.0 mg and lidocaine 20 mg) 2.0 ml №10. Treatment outcome was assessed after 14 days.Results and discussion. During treatment, the vast majority of patients showed a significant improvement: the median severity of pain on movement (NRS) decreased from 6.3 [5.0; 8.0] to 3.7 [3.0; 5.0], p=0.0001; functional impairment – from 3.8 [2.0; 6.0] to 2.2 [1.0; 3.0], p=0.001; fatigue – from 5.6 [4.0; 8.0] to 3.5 [0.0; 2.0], p=0.0001. 71.6% of patients rated the treatment results as good or excellent. Six patients had adverse reactions: 2 – local pain at the site of the intramuscular injections, 1 – arterial hypertension, 3 – epigastric pain. No serious adverse events were recorded.Conclusion. The combined use of NSAIDs and VBC can provide significant improvement in patients with a combination of OA and NSLBP.

Dorsal Root Ganglion Stimulation Relieves Chronic Neuropathic Pain Along With a Decrease in Cortical γ Power

BackgroundStimulation of dorsal root ganglion (DRG) is an ideal neuromodulative intervention, providing pain relief in localized chronic pain conditions because γ-band oscillations reflect the intensity of ongoing chronic pain in patients affected. ObjectiveWe aimed to observe the role of cortical γ-band power associated with the relief of chronic neuropathic pain through DRG stimulation (DRGS). Materials and MethodsWe examined nine patients (two women, mean age 56.8 years; range, 36–77 years) diagnosed with chronic neuropathic pain who underwent DRGS therapy. We used the numeric rating scale (NRS) on the painful limb and simultaneously recorded the electroencephalography to assess the broadband γ power. Assessments were conducted on the first day and on the seventh day after implantation of the DRGS system and then compared and correlated with the results of the NRS. ResultsThe NRS scores showed a significant decrease from the first day to the seventh day (p = 0.007). The resting-state γ power revealed a significant decrease (p = 0.021) between 30 and 45 Hz, recorded through the central electrode contralateral to the painful limb from the first day (mean [M] = 0.46, SD = 0.25) to the seventh day (M = 0.31, SD = 0.12) after DRGS. There was no significant change in the resting-state γ-band power recorded through the central electrode ipsilateral to the painful limb. However, we found a positive correlation in the γ-band power (rs = 0.628, p = 0.005) with the NRS rating. ConclusionsA lateralized decrease in broadband γ power may be considered further evidence supporting a reduction in the hyperexcitability of the nociceptive system in response to DRGS therapy. In the future, γ-band power could serve as a biomarker for assessing the efficacy of DRGS during the seven-day test phase preceding the implantation of the DRGS system.

Investigation of directional discrimination in the nociceptive system using temperature-controlled laser stimuli.

Cutaneous laser stimulation has commonly been employed to investigate the thermal properties of the nociceptive system. The aim of this study was to investigate how a temperature-controlled laser system improves the assessment of directional discrimination in the nociceptive system. In total, twenty healthy volunteers participated in this study. To determine the directional discrimination threshold (stimulation length 50% correct, expressed in mm), thermal stimuli were delivered using a diode laser and the laser beam was perpendicularly displaced across the skin to give a linear stimulation in four different directions (distal, proximal, lateral and medial) and displacement lengths (3 for lateral-medial and 5 for distal-proximal). Two temperature control modes were used in the stimulation system, open-loop and closed-loop control. The subjects had to report the perceived stimulus direction, the degree of certainty regarding the perceived direction and the intensity of the perceived stimulus (0-10 numerical rating scale, 3: pain threshold). During closed-loop control, the orientation of stimuli was discriminated significantly more accurately than during open-loop control. During closed-loop control, the directional discrimination threshold was 31.9 and 26.1 mm for distal-proximal and lateral-medial directed stimuli, respectively. A numerical rating scale was significantly higher for the lateral/medial directions. Moreover, the variability of the discrimination threshold is reduced in the closed-loop control system. The findings show that discrimination ability is better in the lateral-medial directions compared to the distal-proximal directions. This study indicates that using a system enabling closed-loop temperature control, allows more robust probing of the temporo-spatial mechanisms in the nociceptive system. This study shows that a newly developed temperature-controlled laser stimulation system enhances the possibilities to investigate the nociceptive temporo-spatial integration, as shown by a less variable directional discrimination threshold. The results also show that different orthogonal directions are discriminated differently. This new method allows a better investigation of the combined temporal and spatial mechanisms in the nociceptive system.