Increased Pain Perception Research Articles

Desenvolvimento de um dispositivo de fixação para aplicações de injeção com seringa em pacientes diabéticos

Hypodermic needles are widely used in both medicine and dentistry, which makes their study crucial. Understanding the pain perception caused by the insertion of these needles is particularly important for patients who fear or are phobic about seeing or feeling that they penetrate their skin. Our previous research focused on the impact of various needle characteristics on pain sensation during hypodermic injections and identified ways to reduce discomfort and injection-related phobia. We hypothesized that reducing the force required for needle penetration could minimize tissue trauma, and therefore, the pain experienced. That previous study investigated how factors such as cannula diameter, surface roughness, penetration depth, lubrication, and angle of the needle's bevel tip influence pain perception during injections, employing an artificial tissue model to gauge the effort needed for penetration. The findings indicated that needles with larger bevel angles required more penetration force, which correlated with increased pain perception among patients. In the presente study we further examined the wear and burr formation on repeatedly used needles using a profile projector and Scanning Electron Microscopy (SEM), which can hinder penetration and cause tissue damage. Additionally, we explored mechanical methods to prevent needles intended for subcutaneous injections from inadvertently penetrating muscle tissue. We developed a device to simplify the process of administering and self-administering injections, enhancing safety, comfort, and reducing the pain experienced by patients. This approach not only addresses the technical aspects of needle design but also considers the psychological impacts on patients, potentially improving therapeutic outcomes

Association Between Systemic Neuroinflammation, Pain Perception and Clinical Status in Fibromyalgia Patients: Cross-Sectional Study.

Fibromyalgia (FM) is characterized by chronic pain and a complex array of symptoms, with neuroinflammation implicated in its pathophysiology. This study aimed to explore the association between neuroinflammation, measured through interleukin levels (IL-1, IL-6, IL-8), and clinical outcomes in FM patients. Using a cross-sectional study design, blood levels of these interleukins were correlated with pain severity and disability, assessed via the Fibromyalgia Impact Questionnaire (FIQ) and pain measures. Results indicated that IL-6 and IL-8 may particularly serve as biomarkers for pain severity and disability in FM patients, showing significant associations with worse clinical outcomes. Elevated IL-8 levels, for instance, correlated strongly with increased pain perception and higher disability scores. These findings suggest that specific interleukins are not only elevated in FM but are actively involved in the modulation of pain and disability, underscoring the role of systemic neuroinflammation in the clinical severity of FM. This study contributes to a deeper understanding of the inflammatory mechanisms in FM and underscores the potential of targeting interleukins in therapeutic strategies.

Clinical implications of midazolam in preoperative anxiety and sedation: a review

Preoperative anxiety, a common reaction to the unfamiliar setting of medical procedures, affects 60-80% of patients and can lead to significant psychological and physiological stress. This stress can exacerbate hemodynamic instability during surgery, complicate anesthetic management, and contribute to adverse postoperative outcomes such as increased pain perception, longer recovery times, and extended hospital stays. Midazolam, a short-acting benzodiazepine, is frequently used to address these issues due to its rapid onset and effective anxiolytic and sedative properties. By acting on GABA-A receptors, midazolam provides relief from preoperative anxiety and facilitates smoother anesthesia induction. However, its use is not without risks, including potential respiratory depression, paradoxical reactions, and oversedation, which may be particularly concerning in vulnerable populations. These concerns have prompted exploration of non-pharmacological approaches, such as cognitive-behavioral therapy and mindfulness-based interventions, which can reduce anxiety without the side effects associated with pharmacological agents. This review aims to critically evaluate the clinical implications of midazolam use for preoperative anxiety and sedation, highlighting its efficacy, safety profile, and the growing interest in alternative non-pharmacological strategies.

Investigating the effects of artificial baroreflex stimulation on pain perception: A comparative study in no-pain and chronic low back pain individuals.

The autonomic nervous system (ANS) and pain exhibit a reciprocal relationship, where acute pain triggers ANS responses, whereas resting ANS activity can influence pain perception. Nociceptive signalling can also be altered by 'top-down' processes occurring in the brain, brainstem and spinal cord, known as 'descending modulation'. By employing the conditioned pain modulation (CPM) paradigm, we previously revealed a connection between reduced low-frequency heart rate variability and CPM. Individuals with chronic pain often experience both ANS dysregulation and impaired CPM. Baroreceptors, which contribute to blood pressure and heart rate variability regulation, may play a significant role in this relationship, although their involvement in pain perception and their functioning in chronic pain have not been sufficiently explored. In the present study, we combined artificial 'baroreceptor stimulation' in both pressure pain and CPM paradigms, seeking to explore the role of baroreceptors in pain perception and descending modulation. In total, 22 individuals with chronic low back pain (CLBP) and 29 individuals with no-pain (NP) took part in the present study. We identified a differential modulation of baroreceptor stimulation on pressure pain between the groups of NP and CLBP participants. Specifically, NP participants perceived less pain in response to baroreflex activation, whereas CLBP participants exhibited increased pain sensitivity. CPM scores were associated with baseline measures of baroreflex sensitivity in both CLBP and NP participants. Our data support the importance of the baroreflex in chronic pain and a possible mechanism of dysregulation involving the interaction between the ANS and descending pain modulation. KEY POINTS: Baroreflex stimulation has different effects on pressure pain in participants with chronic pain compared to matched individuals with no-pain. Baroreceptor activation decreases pain in participants with no-pain but increases pain perception in participants with chronic pain. Baroreflex sensitivity is associated with conditioned pain modulation in both groups of chronic pain and no-pain participants. The reactivity of the baroreflex during autonomic stress demonstrated a positive correlation with Pain Trait scores in participants with chronic back pain.

Nocebo Effect on Pain Perception and Attention with Children With and Without Attention Deficit And/Or Hyperactivity Disorder.

Attention deficit disorder with or without hyperactivity (ADHD) has negative consequences for children. The effectiveness of medical interventions and educational outcomes are strongly influenced by expectations, which can be modulated by nocebo effects. The aims of this study were to compare the nocebo effect on pain perception and attention in children with and without ADHD as well as to characterize the associations of the nocebo effect with personal variables, such as anxiety, sleep, and pain catastrophizing. Data were collected from 30 children with and without ADHD. The nocebo effect was induced using an inactive pill, "increasing" pain perception and attention deficits. Experimental thermal pain was evoked using a thermode and recorded using a computerized visual analog scale. Attention abilities were measured with the Stop-Signal Task. We also used questionnaires to measure personal variables. When combining groups, the nocebo treatment led to comparable nocebo effects for pain (increased pain perception) and attention (increased time needed for inhibition). When comparing groups, the nocebo effect on pain perception was similar for children with and without ADHD. Inattention, learning problems, anxiety, and sleep problems were associated with the nocebo response for pain and attention. This exploratory study conducted in an experimental setting emphasizes the importance of managing children's expectations for pain perception and attention as well as the potentially deleterious impact of negative suggestions on elementary school children.

The effects of C-tactile stimulation on temporal summation of second pain: A study of the central and peripheral neural correlates

Affective touch is mediated by specialized receptors sensitive to gentle and slow touch called C-tactile afferents (CT). The activation of these receptors has shown promise in reducing subjective pain ratings, however, how this type of touch can affect central sensitization processes is poorly studied. This work aimed to investigate if affective touch is able to modulate pain sensitization and its electrophysiological correlates during Temporal Summation of Second Pain (TSSP), a phenomenon characterized by an increase in pain perception due to repeated noxious stimuli.Thirty-seven participants underwent a TSSP protocol involving three conditions: TSSP alone, TSSP during vibrotactile stimulation, and TSSP during CT stimulation (administered with a brush mounted in a robot arm). We measured subjective pain ratings, electroencephalographic (N2-P2 complex) and electrocardiographic activity during these conditions.Participants reported a significantly lower increase of pain during CT stimulation compared to vibrotactile stimulation, but not to TSSP alone. In addition, TSSP was reduced when administered in the ipsilateral arm compared to the other somatosensory stimulation. Subjective reports of attention towards painful stimuli, amplitude of the N2-P2 complex, and heart rate were also reduced during CT stimulation. Conclusion: Our results indicated that the activation of CT receptors may reduce sensitization compared to other types of somatosensory stimulation, which is possibly related to the reduction of the attention devoted to nociceptive stimulation. Our results suggest that activation of CT receptors may alleviate the occurrence of central pain sensitization.

Resting-State Functional Connectivity of the Cerebellum in Patients with Chronic Low Back Pain.

Chronic low back pain (cLBP) affects nociceptive responses in the cerebellum, which leads to increased pain perception and sensorimotor control dysfunction. This study aimed to investigate altered functional connectivity in the anterior and posterior lobes of the cerebellum during cLBP. Twenty patients with cLBP and 18 healthy participants underwent 3.0 T resting-state functional magnetic resonance imaging. The bilateral lobule V of the anterior cerebellum and Crus I of the posterior cerebellum were selected as the region of interest for identifying the corresponding networks. The left lobule V had a greater intrinsic connectivity with the left insular cortex, left orbitofrontal cortex, and bilateral medial prefrontal cortex in patients with cLBP. In contrast, the right lobule V and bilateral Crus I had a significantly decreased connectivity with the contralateral multimodal cerebral networks, including the default mode network, salience network, and emotional network. The cerebellum had mechanistic implications in pain-related changes, which are involved in motor control, cognition, and emotion processing. These findings provide a novel perspective on the role of functional subregions in cLBP, which add to the growing body of evidence that the cerebellum can be a potential target for noninvasive brain stimulation for chronic pain treatment.

Association between leisure-time physical activity and musculoskeletal pain before and during the COVID-19 pandemic in working adults.

The COVID-19 pandemic had major impacts on the physical lives of individuals, especially on home office workers. In this way, the practice of physical activity has been identified as an ally in the reduction and prevention of musculoskeletal pain. To investigate the association between leisure-time physical activity and musculoskeletal pain in adult workers before and during the COVID-19 pandemic. A cross-sectional study was conducted with 374 workers of both sexes (age = 46.5±10.5 years). Leisure-time physical activity, number of pain sites, and musculoskeletal pain status were investigated using a questionnaire designed for the study. Statistical analysis was performed using Multinomial Logistic Regression. The significance level adopted was 5%. A significant association was found between physical activity status and the number of pain sites (p = 0.002). In addition, an inverse association was found between physical activity before and during the quarantine and the number of pain sites (two pain sites - OR = 0.40; 95% CI = 0.2-0.7; three or more pain sites - OR = 0.24; 95% CI = 0.1-0.5). Physical activity interruption during quarantine increased pain perception by 2.86 times (OR = 2.86; 95% CI = 1.0-7.5). The findings showed that physical activity before and during the pandemic was a protective factor for body pain during the COVID-19 pandemic.

Evolution of anxiety management in prostate biopsy under local anesthesia: a narrative review

Introduction and methodsProstate biopsy (PB) is an essential step in the diagnosis and active surveillance of prostate cancer (PCa). Transperineal PB (TP-PB) is now the recommended approach and is mostly conducted under local anesthesia. However, this procedure can potentially cause anxiety for patients, given the oncological context and the fear of peri-procedural pain and complications. The objective of this narrative review is to summarize the currently available tools for the management of peri-interventional anxiety during TP-PB, with a particular emphasis on the potential role of virtual reality (VR) in this setting.ResultsIn TP-PB, preoperative anxiety can lead to increased pain perception, longer procedure time, and decreased patient satisfaction. Pharmacological and non-pharmacological approaches have been explored to reduce anxiety, such as premedication, deep sedation, education, relaxation techniques, hypnosis, and music therapy, albeit with mixed results. VR has recently emerged in the technological armamentarium for managing pain and anxiety, and the efficiency of this technology has been evaluated in various medical fields, including pediatrics, gastroenterology, urology, gynecology, and psychiatry.ConclusionDespite the paucity of available data, VR appears to be a safe and effective technique in reducing anxiety in many procedures, even in frail patients. No studies have evaluated the role of VR in TP-PB. Future research should thus explore the optimal way to implement VR technology and any potential benefits for TP-PB patients.

Chronic pain in the elderly: Exploring cellular and molecular mechanisms and therapeutic perspectives.

Chronic pain is a debilitating condition frequently observed in the elderly, involving numerous pathological mechanisms within the nervous system. Diminished local blood flow, nerve degeneration, variations in fiber composition, alterations in ion channels and receptors, accompanied by the sustained activation of immune cells and release of pro-inflammatory cytokines, lead to overactivation of the peripheral nervous system. In the central nervous system, chronic pain is strongly associated with the activation of glial cells, which results in central sensitization and increased pain perception. Moreover, age-related alterations in neural plasticity and disruptions in pain inhibitory pathways can exacerbate chronic pain in older adults. Finally, the environmental influences on the development of chronic pain in the elderly must be considered. An understanding of these mechanisms is essential for developing novel treatments for chronic pain, which can significantly improve the quality of life for this vulnerable population.

Age-dependent decrease in inhibitory drive on the excitatory superficial spinal dorsal horn neurons

The excitatory and inhibitory interneurons of superficial laminae I-II of the spinal dorsal horn (SDH) receive and process pain-related information from the primary afferents and transmit it to the brain via the projection neurons. Thus, the interaction between excitatory and inhibitory SDH interneurons is crucial in determining the output from the spinal cord network. Disruption of this interaction in pathological conditions leads to increased SDH output to the higher brain centers, which could underlie pathological pain. Here, we examined whether the changes in the intrinsic SDH connectivity also occur with age, possibly underlying age-related increase in pain sensitivity. Using Vgat;tdTomato transgenic mouse line, we compared the spontaneous inhibitory postsynaptic currents (sIPSCs) in inhibitory tdTomato+ and excitatory tdTomato− interneurons between adult (3–5 m.o.) and aged (12–13 m.o.) mice. We demonstrate that in adult mice, the amplitude and frequency of the sIPSCs on the excitatory interneurons were significantly higher than on inhibitory interneurons. These differences were annulled in aged mice. Further, we show that in aged mice, excitatory neurons receive less inhibition than in adult mice. This could lead to overall disinhibition of the SDH network, which might underlie increased pain perception among the aged population.

HIF-1α/MMP-9 promotes spinal cord central sensitization in rats with bone cancer pain

Bone cancer pain (BCP) is one of the most prevalent and serious symptoms of patients with cancer. Currently, the medical interventions used for the treatment of BCP do not act with optimal safety and efficacy. In this study, we appraised whether the hypoxia-inducible factor 1α (HIF-1α)/metalloproteinase-9 (MMP9) axis activates the PI3K/AKT pathway, resulting in elevated spinal cord central sensitization and aggravated BCP. BCP rats were established by tibial injection of Walker 256 cells, followed by different interventions in rats using HIF-1ɑ inhibitor LW6 or antibody treatments. After treatment with LW6 or antibody against HIF-1α, central sensitization in the spinal cord tissues of rats was inhibited, and pain perception in rats was reduced. Moreover, the activation of glial cells in the spinal cord tissues was ameliorated. The expression of MMP9 was remarkably suppressed in spinal cord tissues after inhibition of HIF-1ɑ activity, and the activity of the PI3K/AKT signaling pathway was inhibited. Further activation of MMP9 expression suppressed the alleviating effect of HIF-1ɑ inhibitor LW6 or antibody on pain perception in rats inoculated with tumors. Taken together, our studies suggest a HIF-1α/MMP9-mediated activation of PI3K/AKT in the spinal cord tissues, resulting in increased pain perception in a rat model with BCP.

Acute Responses to High-Intensity Back Squats with Bilateral Blood Flow Restriction.

This study examined the acute effects of high-intensity resistance exercise with blood flow restriction (BFR) on performance and fatigue, metabolic stress, and markers of inflammation (interleukin-6 (IL-6)), muscle damage (myoglobin), angiogenesis (vascular endothelial growth factor (VEGF)). Thirteen resistance-trained participants (four female, 24.8 ± 4.7 years) performed four sets of barbell back-squats (75% 1RM) to failure under two conditions: blood flow restriction (BFR, bilateral 80% occlusion pressure) and control (CTRL). Completed repetitions and pre-post-exercise changes in maximal voluntary isometric contractions, countermovement jump, barbell mean propulsive velocity, and surface electromyography were recorded. Pre-post blood lactate (BLa) and venous blood samples for analysis of IL-6, myoglobin, and VEGF were collected. Ratings of perceived exertion (RPE) and pain were recorded for each set. Fewer repetitions were performed during BFR (25.5 ± 9.6 reps) compared to CTRL (43.4 ± 14.2 reps, p < 0.001), with greater repetitions performed during sets 1, 2, and 4 (p < 0.05) in CTRL. Although RPE between conditions was similar across all sets (p > 0.05), pain was greater in BFR across all sets (p < 0.05). Post-exercise fatigue was comparable between conditions. BLa was significantly greater in CTRL compared to BFR at two minutes (p = 0.001) but not four minutes post-exercise (p = 0.063). IL-6 was significantly elevated following BFR (p = 0.011). Comparable increases in myoglobin (p > 0.05) and no changes in VEGF were observed (p > 0.05). BFR increases the rate of muscular fatigue during high-intensity resistance exercise and acutely enhances IL-6 response, with significantly less total work performed, but increases pain perception, limiting implementation.

Society of Anesthesia and Sleep Medicine Position Paper on Patient Sleep During Hospitalization.

This article addresses the issue of patient sleep during hospitalization, which the Society of Anesthesia and Sleep Medicine believes merits wider consideration by health authorities than it has received to date. Adequate sleep is fundamental to health and well-being, and insufficiencies in its duration, quality, or timing have adverse effects that are acutely evident. These include cardiovascular dysfunction, impaired ventilatory function, cognitive impairment, increased pain perception, psychomotor disturbance (including increased fall risk), psychological disturbance (including anxiety and depression), metabolic dysfunction (including increased insulin resistance and catabolic propensity), and immune dysfunction and proinflammatory effects (increasing infection risk and pain generation). All these changes negatively impact health status and are counterproductive to recovery from illness and operation. Hospitalization challenges sleep in a variety of ways. These challenges include environmental factors such as noise, bright light, and overnight awakenings for observations, interventions, and transfers; physiological factors such as pain, dyspnea, bowel or urinary dysfunction, or discomfort from therapeutic devices; psychological factors such as stress and anxiety; care-related factors including medications or medication withdrawal; and preexisting sleep disorders that may not be recognized or adequately managed. Many of these challenges appear readily addressable. The key to doing so is to give sleep greater priority, with attention directed at ensuring that patients' sleep needs are recognized and met, both within the hospital and beyond. Requirements include staff education, creation of protocols to enhance the prospect of sleep needs being addressed, and improvement in hospital design to mitigate environmental disturbances. Hospitals and health care providers have a duty to provide, to the greatest extent possible, appropriate preconditions for healing. Accumulating evidence suggests that these preconditions include adequate patient sleep duration and quality. The Society of Anesthesia and Sleep Medicine calls for systematic changes in the approach of hospital leadership and staff to this issue. Measures required include incorporation of optimization of patient sleep into the objectives of perioperative and general patient care guidelines. These steps should be complemented by further research into the impact of hospitalization on sleep, the effects of poor sleep on health outcomes after hospitalization, and assessment of interventions to improve it.

Stigmatized experience is associated with exacerbated pain perception in depressed patients

Patients with depression not only have to cope with depressive and physical symptoms but also face stigmatization due to mental illness. Pain is a clinical symptom of many patients with depression. However, it is unclear whether stigmatized experience associated with mental illness directly affects depressed patients' pain perception. Here, using the event reflection task, Study 1 (N = 95) examined whether stigmatized experiences due to depression would affect patients' self-reported pain assessment. Study 2 (N = 43) further employed thermal stimuli at different intensities to examine whether stigmatization would affect patients' evoked pain. We found that patients with depression who experienced stigmatization based on mental illness reported higher pain catastrophizing and performed increased pain perception for noxious stimuli than those who did not. Our studies provide first-hand experimental evidence of the effect of stigmatized experiences on depressed patients’ pain perception. The findings contribute insights for improving clinical treatment, suggesting that interventions should minimize stigmatization associated with mental illness to help patients maintain healthier physical and psychological states.

Effects of Transcranial Direct Current Stimulation (t-DCS) of the Cerebellum on Pain Perception and Endogenous Pain Modulation: a Randomized, Monocentric, Double-Blind, Sham-Controlled Crossover Study

Accumulating evidence demonstrates a role of the cerebellum in nociception. Some studies suggest that this is mediated via endogenous pain modulation. Here, we used t-DCS to test the effects of modulation of cerebellar function on nociception and endogenous pain modulation. Anodal, cathodal, and sham cerebellar t-DCS were investigated in a cross-over design in 21 healthy subjects. The nociceptive flexor (RIII) reflex, conditioning pain modulation (CPM), and offset analgesia (OA) paradigms were used to assess endogenous pain modulation. Somatosensory evoked potentials (SEPs) and pain ratings were used to assess supraspinal nociception and pain perception, respectively. No significant t-DCS effects were detected when including all t-DCS types and time points (baseline, 0, 30, 60 min post t-DCS) in the analysis. Exploratory analysis revealed an increased RIII reflex size immediately after cathodal t-DCS (compared to sham, P = 0.046, η2p = 0.184), in parallel with a trend for a decrease in electrical pain thresholds (P = 0.094, η2p = 0.134), and increased N120 SEP amplitudes 30 min after cathodal compared to anodal t-DCS (P = 0.007, η2p = 0.374). OA was increased after anodal compared to sham stimulation (P = 0.023, η2p = 0.232). Exploratory results suggested that cathodal (inhibitory) cerebellar t-DCS increased pain perception and reduced endogenous pain inhibition while anodal (excitatory) t-DCS increased endogenous pain inhibition. Results are principally compatible with activation of endogenous pain inhibition by cerebellar excitation. However, maybe due to limited t-DCS skull penetration, effects were small and unlikely to be clinically significant.

Procedural Pain and Serious Adverse Events Following Bone Marrow Aspiration and Biopsy: Analysis from an Academic Center in India

Background: The Bone Marrow Aspiration and Biopsy (BMAB) is an important and frequent investigative procedure for hematological diseases. Although thought to be safe and well tolerated; data is limited on the complications and degree of pain experienced by patients undergoing BMAB. Further scarce is data from India and other regions from the developing world especially given the evidence that cultural factors that could shape pain perception. Adverse events following bone marrow biopsy are rare but poorly documented. Aims: To estimate the level of pain and frequency of serious adverse events experienced by patients undergoing BMAB at our center. We also attempted to identify factors associated with increased pain perception. Study Setting: This study was conducted at a tertiary level teaching hospital, the Christian Medical College &amp; Hospital, Ludhiana. Ethics approval was obtained from the Institutional research committee (CMC/1495). Study Period: 01 April 2015 through 30 Nov 2019 Study Design: This is a comparative cross sectional study where comparison of those with relatively more pain to those with less was done to elicit the factors associated with pain perception. Results: A total of 942 BMAB procedures were performed in this period (Table 1). The major serious adverse event was hemorrhage, which comprised 2 of the 9 serious adverse events. Those with prior BMAB had very low odds of pain (OR (95% CI): 0.23 (0.15–0.37)). However, when more than one attempt of biopsy was made the odds of pain was much higher (OR (95% CI): 1.62 (1.29–2.05)).

The Interplay between Pain, Anxiety and Depression

Pain is a subjective experience with two inseparable components: sensory and emotional. The personal property of pain experience makes it difficult to manage and treat due to the influence of genetics, age, gender, spiritual beliefs, social-economic status, and cultural factors. Similarly, medical care methods partly control pain experience and regulate pain progression. Contrary to chronic pain, which is continuous and recurrent, acute pain is primarily due to trauma, acute medical conditions, or treatment. Whatever the case, both can cause mood disorders. The interplay between mood disorders and pain upholds a progressively significant bidirectional link, as mood disorders and pain are risk factors for each other. Depression and anxiety heighten pain perception or decrease pain tolerance. Acute or chronic pain can also increase the chances of mood dysregulation. Although depression and anxiety have a close relationship with acute pain, the interplay between depression and acute pain is more comprehensively studied. Most depressed patients present pain as their sole complaint in primary care practices, which unfortunately is overlooked by physicians. Howbeit, reports on experimentally induced pain perception in depressed patients are mixed, presenting both an amplified and reduced pain threshold and tolerance. Although there are less published data about pain and anxiety, the association is regular because increased anxiety equally increases pain perception while decreasing tolerance. The aim of this review was to elucidate more on the mechanisms delineating the interconnectivity of pain and mood disorders.

Transcranial Direct Current Stimulation (tDCS) in chronic low back pain: Systematic review with meta-analysis

Background and objective. Changes in grey matter of cortex and other parts of brain leads to increased pain perception in chronic low back pain (CLBP) patients which could be reduced by electrical application on these areas. The objective of the present review was to evaluate the efficacy of transcranial direct current stimulation (tDCS) alone as well as tDCS in combination with other interventions on pain in chronic low back pain patients. Method. PubMed and Cochrane search engines was used to locate the literature. The eligibility criterion for the study includes articles published in English language, published till March 2020 and the application of tDCS alone as well as in combination with other interventions on CLBP patients. Pain intensity was measured by visual analogue scale (VAS), numeric rating scale (NRS) or defense and veteran pain rating scale (DVPRS). Mean difference with 95% CI for the active tDCS, sham tDCS and tDCS in combination with other interventions was calculated. Result. 7 articles, with 427 patients, were included in the quantitative meta-analysis. The result showed statistically significant reduction in pain in tDCS alone as compared to sham tDCS Z= 1.93. P= 0.05 and insignificant reduction in pain in tDCS when used in combination with other intervention as compared to sham tDCS, Z= 0.72, P= 0.47 with heterogeneity of 84 % in the included studies. Conclusion. It can be concluded that there is significant reduction of pain in patients of chronic low back pain when tDCS is applied in isolation.

Sodium-calcium exchanger-3 regulates pain “wind-up”: From human psychophysics to spinal mechanisms

SummaryRepeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is “wind-up,” in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca2+ efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting.