Papers: 19 Mar 2022 - 25 Mar 2022

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection can cause neurological sequelae after the resolution of symptomatic COVID-19 illness, but the occurrence of peripheral neuropathy symptoms and cranial nerve dysfunction is unknown. This study aimed to characterize the occurrence and severity of pain and peripheral neuropathy symptoms in patients with SARS-CoV-2 infection.An observational cohort study included adults tested for a SARS-CoV-2 infection at an academic medical center (assigned as CV+ or control, based on test results). 30-90 days after the index SARS-CoV-2 test, patients completed a web-based questionnaire assessing pain, peripheral neuropathy-related sensory symptoms, and symptoms in the distribution of cranial nerves (current symptoms, symptoms at testing and two weeks thereafter). Univariate analyses compared the outcomes between the groups. Multivariable analysis was used to determine the odds for neuropathy symptoms after adjusting for key baseline variables.1556 participants were included: 542 CV+ and 1014 controls. CV+ patients reported a higher occurrence of peripheral neuropathy symptoms in the extremities anytime within 90 days post-infection (28.8% vs 12.9%, OR [95%CI] =2.72 [2.10-3.54]), as well as such symptoms persisting up to 90 days after infection (6.1% vs 1.9%, OR=3.39 [1.91-6.03]). The occurrence of pain in the extremities was higher in the CV+ group (24.2% vs 9.8%, OR=2.95 [2.21-3.91]). SARS-CoV-2 infection was also associated with higher occurrence of peripheral neuropathy symptoms, after adjusting for the history of chronic pain and neuropathy (OR=3.19 [2.37-4.29]. The results suggest that SARS-CoV-2 infection was independently associated with an increased risk of pain and peripheral neuropathy symptoms.

In the midst of the COVID-19 pandemic, data has shown that age-adjusted overdose death rates involving synthetic opioids, psychostimulants, cocaine, and heroin have been increasing, including prescription opioid deaths, which were declining, but, recently, reversing the trends. Contrary to widely held perceptions, the problem of misuse, abuse, and diversion of prescription opioids has been the least of all the factors in recent years. Consequently, it is important to properly distinguish between the role of illicit and prescription opioids in the current opioid crisis. Multiple efforts have been based on consensus on administrative policies for certain harm reduction strategies for individuals actively using illicit drugs and reducing opioid prescriptions leading to curbing of medically needed opioids, which have been ineffective. While there is no denial that prescription opioids can be misused, abused, and diverted, the policies have oversimplified the issue by curbing prescription opioids and the pendulum has swung too far in the direction of severely limiting prescription opioids, without acknowledgement that opioids have legitimate uses for persons suffering from chronic pain. Similar to the opioid crisis, interventional pain management procedures have been affected by various policies being applied to reduce overuse, abuse, and finally utilization. Medical policies have been becoming more restrictive with reduction of access to certain procedures, with the pendulum swinging too far in the direction of limiting interventional techniques. Recent utilization assessments have shown a consistent decline for most interventional techniques, with a 18.7% decrease from 2019 to 2020. The causes for these dynamic changes are multifactorial likely including the misapplication of the 2016 Centers for Disease Control and Prevention (CDC) guidelines for prescribing opioids for chronic pain, the relative ease of access to illicit synthetic opioids and more recently issues related to the COVID-19 pandemic. In addition, recent publications have shown association of dose tapering with overdose or mental health crisis among patients prescribed long-term opioids. These findings are leading to the hypothesis that federal guidelines may inadvertently be contributing to an increase in overall opioid deaths and diminished access to interventional techniques. Together, these have resulted in a fourth wave of the opioid epidemic.

Response to analgesic therapy is influenced by several factors including genetics and drug-drug interactions. Pharmacogenetic (PGx) variants in the CYP2D6 gene modify response to opioids by altering drug metabolism. We sought to determine the potential impact of PGx testing on the care of Veterans with noncancer pain prescribed opioids metabolized by CYP2D6 (codeine, hydrocodone, or tramadol). A retrospective analysis was performed within the Veterans Health Administration (VHA) evaluating prescription records for pain medications metabolized by CYP2D6 and interacting drugs from 2012-2017. Among 2,436,654 VHA pharmacy users with at least one opioid prescription, 34% met the definition of chronic use (longer than 90 days with more than 10 prescriptions or 120 days- supply). Opioids were commonly co-prescribed with antidepressants interacting with CYP2D6 (28%). An estimated 21.6% (n=526,905) of these patients are at elevated risk of an undesirable response to their opioid medication based on predicted phenotypes and drug-drug interactions: 3.5% are predicted CYP2D6 ultrarapid metabolizers and at increased risk for toxicity, 5.4% are poor metabolizer at higher risk for nonresponse, and 12.8% are normal or intermediate metabolizers co-prescribed a CYP2D6 inhibitor leading to phenoconversion into poor metabolizer. Despite the high rate of co-prescription of opioids and interacting drugs, CYP2D6 testing was infrequent in the sample (0.02%) and chart review suggest that test results were used to optimize antidepressant treatments rather than pain medications. Using pharmacogenetic testing combined with consideration of phenoconversion may allow for an enhanced precision medicine approach to pain management in Veterans.

Classification of musculoskeletal pain based on underlying pain mechanisms (nociceptive, neuropathic, and nociplastic pain) is challenging. In the absence of a gold standard, verification of features that could aid in discrimination between these mechanisms in clinical practice and research depends on expert consensus. This Delphi expert consensus study aimed to: (1) identify features and assessment findings that are unique to a pain mechanism category or shared between no more than 2 categories and (2) develop a ranked list of candidate features that could potentially discriminate between pain mechanisms. A group of international experts were recruited based on their expertise in the field of pain. The Delphi process involved 2 rounds: round 1 assessed expert opinion on features that are unique to a pain mechanism category or shared between 2 (based on a 40% agreement threshold); and round 2 reviewed features that failed to reach consensus, evaluated additional features, and considered wording changes. Forty-nine international experts representing a wide range of disciplines participated. Consensus was reached for 196 of 292 features presented to the panel (clinical examination-134 features, quantitative sensory testing-34, imaging and diagnostic testing-14, and pain-type questionnaires-14). From the 196 features, consensus was reached for 76 features as unique to nociceptive (17), neuropathic (37), or nociplastic (22) pain mechanisms and 120 features as shared between pairs of pain mechanism categories (78 for neuropathic and nociplastic pain). This consensus study generated a list of potential candidate features that are likely to aid in discrimination between types of musculoskeletal pain.

Neck pain is a common musculoskeletal problem often accompanied by reduced exercise-induced hypoalgesia (EIH) or hyperalgesia compared to an asymptomatic population. This study investigated EIH in a healthy population during experimental neck pain. Forty participants were randomized into this double-blinded parallel-group study. On four separate test days (Day0, Day2, Day4, Day15), participants completed the Neck Disability Index (NDI) and scored neck pain intensity during head movements on a numerical rating scale (NRS). At the end of Day0 and Day2, Nerve Growth Factor (NGF) or isotonic saline (control) was injected into the right splenius capitis muscle. Pressure pain thresholds (PPTs) were recorded bilaterally over splenius capitis (neck), temporalis (head) and tibialis anterior (leg) muscles on all days. On Day0, Day4 and Day15, PPTs were recorded before and after a hand-bike exercise. EIH was defined as the PPT increase caused by the exercise. Compared with the control-group, the NGF-group demonstrated higher NDI scores at Day2 and Day4 (P<0.001,η2>0.557) and higher NRS scores (P<0.03,η2>0.09) along with reduced neck PPTs (P<0.01,d>0.44) at Day2(Right:95%CI[26.0,54.0];Left:95%CI[6.8,26.9]), Day4(Right:95%CI[40.5, 67.9];Left:95%CI[6.9,28.2]) and Day15(Right:95%CI[5.6,37.2];Left:95%CI[6.9,34.8]). Across days, the EIH-effect was reduced at the neck site in the NGF-group compared to the control-group (P<0.001,η2P=0.367,95%CI[-34.5,-13.7]). At the head and leg sites, the NGF-group showed reduced EIH-effect compared to the control-group (P<0.05,d>0.43) on Day4(Head:95%CI[-61.4,-22.9];Leg:95%CI[-154.7,-72.4]) and Day15(Head:95%CI[-54.3,-7.6];Leg:95%CI[-122.7,-34.4]). These results indicate that a few days of clinically comparable neck pain and hyperalgesia might have a negative impact on EIH-responses and may help explain why some neck pain patients do not experience immediate positive effects of exercise.

Pathological sensations caused by peripheral painful neuropathy occurring in Type 2 diabetes mellitus (T2DM) are often described as 'sharp' and 'burning' and are commonly spontaneous in origin. Proposed etiologies implicate dysfunction of nociceptive sensory neurons in dorsal root ganglia (DRG) induced by generation of reactive oxygen species, microvascular defects, and ongoing axonal degeneration and regeneration. To investigate the molecular mechanisms contributing to diabetic pain, DRGs were acquired postmortem from patients who had been experiencing painful diabetic peripheral neuropathy (DPN) and subjected to transcriptome analyses to identify genes contributing to pathological processes and neuropathic pain. DPN occurs in distal extremities resulting in the characteristic "glove and stocking" pattern. Accordingly, the L4 and L5 DRGs, which contain the perikarya of primary afferent neurons innervating the foot, were analyzed from five DPN patients and compared with seven controls. Transcriptome analyses identified 844 differentially expressed genes. We observed increases in levels of inflammation-associated transcripts from macrophages in DPN patients that may contribute to pain hypersensitivity and, conversely, there were frequent decreases in neuronally-related genes. The elevated inflammatory gene profile and the accompanying downregulation of multiple neuronal genes provide new insights into intraganglionic pathology and mechanisms causing neuropathic pain in DPN patients with T2DM.

Poststroke pain (PSP) is a heterogeneous term encompassing both central neuropathic (ie, central poststroke pain [CPSP]) and nonneuropathic poststroke pain (CNNP) syndromes. Central poststroke pain is classically related to damage in the lateral brainstem, posterior thalamus, and parietoinsular areas, whereas the role of white matter connecting these structures is frequently ignored. In addition, the relationship between stroke topography and CNNP is not completely understood. In this study, we address these issues comparing stroke location in a CPSP group of 35 patients with 2 control groups: 27 patients with CNNP and 27 patients with stroke without pain. Brain MRI images were analyzed by 2 complementary approaches: an exploratory analysis using voxel-wise lesion symptom mapping, to detect significant voxels damaged in CPSP across the whole brain, and a hypothesis-driven, region of interest-based analysis, to replicate previously reported sites involved in CPSP. Odds ratio maps were also calculated to demonstrate the risk for CPSP in each damaged voxel. Our exploratory analysis showed that, besides known thalamic and parietoinsular areas, significant voxels carrying a high risk for CPSP were located in the white matter encompassing thalamoinsular connections (one-tailed threshold Z > 3.96, corrected P value <0.05, odds ratio = 39.7). These results show that the interruption of thalamocortical white matter connections is an important component of CPSP, which is in contrast with findings from nonneuropathic PSP and from strokes without pain. These data can aid in the selection of patients at risk to develop CPSP who could be candidates to pre-emptive or therapeutic interventions.

Transcranial focused ultrasound (tFUS) is regarded as a promising non-invasive stimulation tool for modulating brain circuits. The aim of this study is to explore the feasibility of tFUS stimulation for analgesia application.

Total knee and hip arthroplasty (TKA, THA) surgeries are among the most common elective procedures. Moderate to severe postoperative pain during the subacute period (defined here as the period from hospital discharge to 3 months postoperatively) is a predictor of persistent pain 12 months postoperatively. This review aimed to examine the available post-discharge pharmacological interventions, including educational and prescribing strategies, and their effect on reducing pain during the subacute period after TKA or THA.

Traditional pain assessment methods have significant limitations due to the high variability in patient reported pain scores and perception of pain by different individuals. There is a need for generalized and automatic pain detection and recognition methods. In this paper, state-of-the-art machine learning (ML) and deep learning methods in this field are analyzed as well as pain management techniques.

Chronic spinal pain is the most prevalent chronic disease, with chronic persistent spinal pain lasting longer than one-year reported in 25% to 60% of the patients. Health care expenditures have been escalating and the financial impact on the US economy is growing. Among multiple modalities of treatments available, facet joint interventions and epidural interventions are the most common ones, in addition to surgical interventions and numerous other conservative modalities of treatments. Despite these increasing costs in the diagnosis and management, disability continues to increase. Consequently, algorithmic approaches have been described as providing a disciplined approach to the use of spinal interventional techniques in managing spinal pain. This approach includes evaluative, diagnostic, and therapeutic approaches, which avoids unnecessary care, as well as poorly documented practices.  Recently, techniques involving artificial intelligence and machine learning have been demonstrated to contribute to the improved understanding, diagnosis, and management of both acute and chronic disease in line with well-designed algorithmic approach. The use of artificial intelligence and machine-learning techniques for the diagnosis of spinal pain has not been widely investigated or adopted.

Epidermal growth factors (EGF) play a wide range of roles in embryogenesis, skin development, immune response homeostasis. They are involved in several pathologies as well, including several cancer types, psoriasis, chronic pain and chronic kidney disease. All members share the structural EGF domain, which is responsible for receptor interaction, thereby initiating transduction of signals. EGF growth factors have intense use in fundamental research and high potential for biotechnological applications. However, due to their structural organization with three disulfide bonds, recombinant production of these factors in prokaryotic systems is not straightforward. A significant fraction usually forms inclusion bodies. For the fraction remaining soluble, misfolding and incomplete disulfide bond formation may affect the amount of active factor in solution, which can compromise experimental conclusions and biotechnological applications. In this work, we describe a reliable procedure to produce seven human growth factors of the EGF family in Escherichia coli. Biophysical and stability analyses using limited proteolysis, light scattering, circular dichroism and nanoDSF show that the recombinant factors present folded and stable conformation. Cell proliferation and scratch healing assays confirmed that the recombinant factors are highly active at concentrations as low as 5 ng/ml.

Currently available treatments for neuropathic pain are only modestly efficacious when assessed in randomized clinical trials and only work for some patients in the clinic. Induced-pain or gain-of-function phenotypes, have been shown to predict response to analgesics (vs. placebos) in patients with neuropathic pain. However, the predictive value of these phenotypes has never been studied in post-traumatic neuropathic pain. Mixed-effects model for repeated measures (MMRM) were used to evaluate the efficacy of pregabalin vs. placebo in subgroups with induced-pain phenotypes (i.e., hyperalgesia or allodynia) using data from a recent, multi-national RCT (N = 539) that identified phenotypic subgroups using a structured clinical exam. The difference in mean pain score between active and placebo groups (i.e., delta) after 15 weeks of treatment for the subgroup with hyperalgesia was -0.76 (p = 0.001), compared to 0.19 (p = 0.47) for the subgroup that did not have hyperalgesia. The treatment-by-phenotype interaction, which tests whether subgroups have statistically different treatment responses, was significant (p = 0.0067). The delta for the subgroup with allodynia was -0.31 (p = 0.22), compared to -0.30 (p = 0.22) for the subgroup that did not have allodynia (treatment-by-phenotype interaction p = 0.98). These data suggest that hyperalgesia, but not allodynia predicts response to pregabalin in patients with chronic post-traumatic neuropathic pain. This study extends the growing data supporting the utility of induced-pain phenotypes to predict response to analgesics to post-traumatic neuropathic pain. Sensory phenotyping in large, multi-site trials using a structured clinical exam has the potential to accelerate the development of new analgesics and improve the generalizability of clinical trial results.

Scientific evidence points to a shared neural representation between performing and observing an action. The action observation notoriously determines a modulation of the observer's sensorimotor system, a phenomenon called Motor Resonance (MR). Fibromyalgia (FM) patients suffer from a condition characterized by generalized musculoskeletal pain in which even simple movement can exacerbate their symptoms. Maladaptive functioning of the primary motor cortex is a common finding in patients with chronic pain. Activation of the motor cortex is known to induce an analgesic effect in patients with chronic pain. In this exploratory study, we intend to verify if the mere observation of a movement could elicit activation of the motor cortical areas in patients with FM. Therefore, the purpose of this study was to examine the presence of MR in patients affected by fibromyalgia. We adopted a behavioral paradigm known for detecting the presence of MR and a neurophysiological experiment. Participants watched videos showing gripping movements towards a graspable or an ungraspable object, respectively, and were asked to press a button the instant the agent touched the object (Time-to-contact detection session). In a different experimental session, participants were only requested to observe and pay attention to the videos (Observation-only session). During each experimental session, the participants' cerebral hemodynamic activity was recorded using the functional Near-Infrared Spectroscopy method. The behavioral task analysis revealed the presence of MR in both FM patients and healthy controls. Moreover, neurophysiological findings suggested that the observation of movement during the Observation-only session provoked activation and modulation of the cortical motor networks of FM patients. These results could represent evidence of the possible beneficial effects of movement observation in restarting motor activation, notoriously reduced, in FM patients.

Initial clinical studies have shown that the stimulation of the dorsal root ganglion (DRG) can significantly reduce chronic intractable pain. However, clinical data on long-term results and complications of these systems are limited. The aim of this prospective study is to report on a single center long-term follow-up of DRG stimulation for intractable chronic pain. Participants were implanted with DRG stimulation devices between 2013 and 2015 with an observation period of 24 months. Patients were contacted again in 2020 for a final follow-up (ie, between 5 and 7 years postimplantation). Forty-two participants were recruited, of whom 32 received the fully implantable pulse generator (IPG). At the final follow-up, 50% (16/32) of participants were still using DRG stimulation. Two participants still had the original IPG and 14 had received a replacement IPG. Pain scores were significantly reduced at 24 months, mean difference 1.7 (95% confidence interval: 0.2-3.3, P = 0.03), and at the last follow-up, mean difference 2.1 (95% confidence interval: 0.3-4, P = 0.03). Significant improvements were observed for health-related quality of life. The findings were generally robust to imputation methods of missing data. Implantable pulse generators of 8 patients were explanted because of dissatisfaction with pain relief. In conclusion, DRG stimulation can provide effective pain relief and improved quality of life in patients suffering with neuropathic pain, although this study had a revision rate of 42% within the first 24 months, and 56% of IPGs that were replaced because of battery depletion had a shorter than expected battery life.

Acute pain is a physiological response that causes an unpleasant sensory and emotional experience in the presence of actual or potential tissue injury. Anatomically and symptomatically, chronic pathological pain can be divided into three distinct but interconnected pathways, a lateral "painfulness" pathway, a medial "suffering" pathway and a descending pain inhibitory circuit. Pain (fullness) can exist without suffering and suffering can exist without pain (fullness). The triple network model is offering a generic unifying framework that may be used to understand a variety of neuropsychiatric illnesses. It claims that brain disorders are caused by aberrant interactions within and between three cardinal brain networks: the self-representational default mode network, the behavioral relevance encoding salience network and the goal oriented central executive network. A painful stimulus usually leads to a negative cognitive, emotional, and autonomic response, phenomenologically expressed as pain related suffering, processed by the medial pathway. This anatomically overlaps with the salience network, which encodes behavioral relevance of the painful stimuli and the central sympathetic control network. When pain lasts longer than the healing time and becomes chronic, the pain- associated somatosensory cortex activity may become functionally connected to the self-representational default mode network, i.e., it becomes an intrinsic part of the self-percept. This is most likely an evolutionary adaptation to save energy, by separating pain from sympathetic energy-consuming action. By interacting with the frontoparietal central executive network, this can eventually lead to functional impairment. In conclusion, the three well-known pain pathways can be combined into the triple network model explaining the whole range of pain related co-morbidities. This paves the path for the creation of new customized and personalized treatment methods.

Cluster headache is the most common primary headache disorder of the trigeminal autonomic cephalalgias, and it is highly disabling.

Chronic pain, with a prevalence of at least 17%, is a costly health problem associated with a high burden of disease. Musculoskeletal chronic pain is particulary common, which in many cases is treated with physiotherapy.

The efficacy of pain therapies can be substantially modulated by treatment expectations, which is reflected by the substantial placebo effects observed in pain (so called placebo analgesia).

Spinal Anesthesia was the first regional anesthetic technique to be performed. It was performed by Dr. August Bier, known for the Bier block, and his colleagues on August 16, 1898. Dr. Bier opted for, what he referred to at the time as "cocainization of the spinal cord" by introducing 15 mg of cocaine intrathecally prior to the operation. The surgery was largely uneventful and painless. The patient only experienced some vomiting and a headache postoperatively. Dr. Bier's use of neuraxial anesthesia aimed to directly inject local anesthetics in and around the central nervous system (CNS) for more direct control of pain and anesthesia. Local anesthetics were an important discovery in anesthesiology. However, since the advent of local anesthetics and spinal anesthesia as an alternative technique to general anesthesia, much has been learned about both the benefits and adverse effects of local anesthetics. It was quickly learned that use of local anesthetics would be limited by their potential for life-threatening toxic effects. For this reason, there was a push towards development of novel local anesthetics that had a larger therapeutic window with less likelihood of serious side effects. In addition to developing newer local anesthetics, the idea of adding adjuvants provided an opportunity to potentially limit the life-threatening events. These adjuvants would include medications such as epinephrine and alpha-2 agonists, such as clonidine and dexmedetomidine. Other adjuvants include opioids, glucocorticoids, and mineralocorticoids.

This study was performed amongst trigeminal neuralgia (TN) patients with neurovascular contact (NVC) to 1) investigate the association of the demographic and radiologic factors/variables with TN occurrence, and 2) develop a screening tool for TN/TN-affected nerves based on the factors/variables associated with it.

Sex differences exist in the prevalence, progression and treatment efficacy of a wide array of medical conditions. While the placebo and nocebo effects have become increasingly relevant in the clinical arena, little is known about the influence of biological sex on placebo and nocebo effects. This paper discusses the existing, relatively limited and sometimes conflicting evidence about how sex impacts the occurrence and magnitude of the placebo and nocebo effects, mainly focusing on pain studies. We present recent evidence that when compared to men, women suffering from chronic orofacial pain may derive greater benefit from the placebo effect for analgesia. Nonetheless, we broadly argue that the field is not currently positioned to draw definitive conclusions and propose several important factors that may explain the inconsistency in the literature and that should be taken into account in future research. These include the specific target symptom of the placebo or nocebo manipulation and whether or not the target is related to the medical condition, the placebo or nocebo induction method, the sex of the experimenter or physician, and so forth. Future research should intentionally include sex a biological variable to favor translation of placebo and nocebo mechanisms into clinical applications.

The malfunction and misregulation of voltage-gated sodium channels (Na s) underlie in large part the electrical hyperexcitability characteristic of chronic inflammatory and neuropathic pain. Na s are responsible for the initiation and propagation of electrical impulses (action potentials) in cells. Tissue and nerve injury alter the expression and localization of multiple Na isoforms, including Na 1.1, 1.3, and 1.6-1.9, resulting in aberrant action potential firing patterns. To better understand the role of Na regulation, localization, and trafficking in electrogenesis and pain pathogenesis, a number of chemical and biological reagents for interrogating Na function have been advanced. The development and application of such tools for understanding Na physiology are the focus of this review.

Neuropeptide Y (NPY) is a highly conserved endogenous peptide in the central and peripheral nervous systems, which has been implicated in nociceptive signaling in neuropathic pain. However, downstream mechanistic actions remain uncharacterized. In this study, we sought to investigate the mechanism of NPY and its receptor NPY2R in the amygdala in rats with neuropathic pain-like behaviors induced by chronic constriction injury (CCI) of the sciatic nerve. The expression of NPY and NPY2R was found to be aberrantly up-regulated in neuropathic pain-related microarray dataset. Further, NPY was found to act on NPY2R in the basolateral amygdala (BLA). As reflected by the decrease in mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) as well as the increase of NPY expression in the amygdala of rats with neuropathic pain-like behaviors, NPY was closely related to the effect of amygdala nerve activity in neuropathic pain. Subsequently, mechanistic investigations indicated that NPY2R activated the MAPK signaling pathway in the amygdala. NPY2R-induced decrease of MWT and TWL were also restored in the presence of MAPK signaling pathway antagonist. Moreover, it was revealed that NPY2R overexpression promoted the viability while inhibiting the apoptosis of microglia. Taken together, NPY in the amygdala interacts with NPY2R to activate the MAPK signaling pathway, thereby promoting the occurrence of neuropathic pain.

We examined the functional connectivity (FC) in migraine compared with healthy subjects before and after C2 peripheral nerve field stimulation using electroacupuncture (EA-C2-PNfS), to evaluate the effect of EA-C2-PNfS, and elucidate the mechanism of migraine.

Fibromyalgia (FM) is a chronic pain condition that is characterized by hypersensitivity to multimodal sensory stimuli, widespread pain, and fatigue. We have previously proposed explosive synchronization (ES), a phenomenon wherein a small perturbation to a network can lead to an abrupt state transition, as a potential mechanism of the hypersensitive FM brain. Therefore, we hypothesized that converting a brain network from ES to general synchronization (GS) may reduce the hypersensitivity of FM brain. To find an effective brain network modulation to convert ES into GS, we constructed a large-scale brain network model near criticality (i.e., an optimally balanced state between order and disorders), which reflects brain dynamics in conscious wakefulness, and adjusted two parameters: local structural connectivity and signal randomness of target brain regions. The network sensitivity to global stimuli was compared between the brain networks before and after the modulation. We found that only increasing the local connectivity of hubs (nodes with intense connections) changes ES to GS, reducing the sensitivity, whereas other types of modulation such as decreasing local connectivity, increasing and decreasing signal randomness are not effective. This study would help to develop a network mechanism-based brain modulation method to reduce the hypersensitivity in FM.

Conventional neurostimulation typically involves a brief (eg, ≤10-day) trial to assess presumed effectiveness prior to permanent implantation. Low trial conversion rates and high explant rates due to inadequate pain relief highlight the need for improved patient identification strategies. The development of a 60-day percutaneous peripheral nerve stimulation (PNS) system enables evaluation of outcomes following an extended temporary treatment period of up to 60 days, that may obviate or validate the need for permanent implant. The present study provides the first real-world evidence regarding patient response throughout a 60-day PNS treatment period.

It has been reported that degenerated and herniated lumbar intervertebral discs show high expression of IL-17, suggesting that local immune reactions occur in patients with low back pain. While clinical sample analyses from different laboratories confirm this, it is not deeply not known on how IL-17 is induced in the pathology and their interactions with other inflammatory responses. This conscience review organizes current laboratory findings on this topic and present trajectory for full understanding on the role of IL-17 in pathology of intervertebral disc disease.

Though it has been shown that men have a higher lifetime prevalence of substance use disorder and a lower prevalence of chronic pain than women, there is little research to date focusing on gender differences in the relationship between chronic pain and substance use disorder. This study examined whether gender moderates the relationship of chronic pain and substance use disorder. We also sought to examine the gender differences in the associations between specific pain types-arthritis, migraine, and back pain, and substance use disorder.

Exposure to aversive stimuli such as stress results in profound analgesia named stress-induced analgesia (SIA). We previously showed that D1- and D2-like dopamine receptors within the nucleus accumbens (NAc) mediated the SIA in chronic pain. Since the neurophysiological mechanisms responsible for the various pain conditions are different, the present study aimed to examine the role of dopamine receptors within the NAc in the forced swim stress (FSS)-induced analgesia in the tail-flick test as an animal model of acute pain. Ninety-six adult male Wistar rats weighing 200-230 g were unilaterally implanted with a cannula into the NAc. SCH23390 or Sulpiride (0.25, 1, and 4 μg/0.5 μl vehicle), as D1- and D2-like dopamine receptor antagonists, respectively, were microinjected into the NAc, 5 min before exposure to FSS. The vehicle groups received saline or DMSO instead of SCH23390 or Sulpiride, respectively. The tail-flick test was performed in time set intervals after animals were subjected to FSS. The results showed that FSS produces analgesia during the tail-flick test. However, intra-accumbal injection of SCH23390 or Sulpiride attenuated the FSS-induced analgesia. D1-and D2-like dopamine receptor antagonists contributed almost equally to attenuating the antinociceptive responses induced by FSS. It seems that the mesolimbic dopamine system might act as a potential endogenous pain control system in stress conditions. Besides, an improved understanding of this endogenous pain inhibitory system can develop pharmacological and psychological approaches to treat pain.

Spinal cord injury (SCI) frequently results in immediate and sustained neurological dysfunction, including intractable neuropathic pain in approximately 60-80% of individuals. SCI induces immediate mechanical damage to spinal cord tissue followed by a period of secondary injury in which tissue damage is further propagated, contributing to the development of anatomically unique lesions. Variability in lesion size and location influences the degree of motor and sensory dysfunction incurred by an individual. We predicted that variability in lesion parameters may also explain why some, but not all, experimental animals develop mechanical sensitivity after SCI. To characterize the relationship of lesion anatomy to mechanical allodynia, we utilized a mouse cervical hemicontusion model of SCI that has been shown to lead to the development and persistence of mechanical allodynia in the ipsilateral forelimb after injury. At four weeks post-SCI, the numbers and locations of surviving neurons were quantified along with total lesion volume and nociceptive fiber sprouting. We found that the subset of animals exhibiting mechanical allodynia had significantly increased neuronal sparing in the ipsilateral dorsal horn around the lesion epicenter compared to animals that did not exhibit mechanical allodynia. Additionally, we failed to observe significant differences between groups in nociceptive fiber density in the dorsal horn around the lesion epicenter. Notably, we found that impactor probe displacement upon administration of the SCI surgery was significantly lower in sensitive animals compared with not-sensitive animals. Together, our data indicate that lesion severity negatively correlates with the manifestation of at-level mechanical hypersensitivity and suggests that sparing of dorsal horn neurons may be required for the development of neuropathic pain.

Motor training is a widely used therapy in many pain conditions. The brain's capacity to undergo functional and structural changes i.e., neuroplasticity is fundamental to training-induced motor improvement and can be assessed by transcranial magnetic stimulation (TMS). The aim was to investigate the impact of pain on training-induced motor performance and neuroplasticity assessed by TMS. The review was carried out in accordance with the PRISMA-guidelines and a Prospero protocol (CRD42020168487). An electronic search in PubMed, Web of Science and Cochrane until December 13, 2019, identified studies focused on training-induced neuroplasticity in the presence of experimentally-induced pain, 'acute pain' or in a chronic pain condition, 'chronic pain'. Included studies were assessed by two authors for methodological quality using the TMS Quality checklist, and for risk of bias using the Newcastle-Ottawa Scale. The literature search identified 231 studies. After removal of 71 duplicates, 160 abstracts were screened, and 24 articles were reviewed in full text. Of these, 17 studies on acute pain (n = 7) or chronic pain (n = 10), including a total of 258 patients with different pain conditions and 248 healthy participants met the inclusion criteria. The most common types of motor training were different finger tasks (n = 6). Motor training was associated with motor cortex functional neuroplasticity and six of seven acute pain studies and five of ten chronic pain studies showed that, compared to controls, pain can impede such trainings-induced neuroplasticity. These findings may have implications for motor learning and performance and with putative impact on rehabilitative procedures such as physiotherapy.

Experimental pain during gait has been shown to interfere with learning a new locomotor task. However, very few studies have investigated the impact of clinical pain on motor learning due to the challenges associated with clinical populations.

Infrared radiation (IR) is a promising complementary treatment for musculoskeletal conditions and chronic pain. By means of a systematic review, we evaluated the contribution of IR to the management of these ailments. PubMed-MEDLINE, Scopus, and Cochrane Library-Cochrane Central Register of Controlled Trials were systematically searched until 20 December 2021. The literature search yielded 233 relevant records. Following the screening of titles and abstracts, 42 full-texts were evaluated. As per inclusion/exclusion criteria, 13 publications were entered into the qualitative assessment. These studies described the effects of IR in humans: three studies focused on osteoarthritis, four studies on fibromyalgia, and six encompassed a wider range of diseases (ankylosing spondylitis, recovery from sports injuries, myofascial pain syndrome). Based on the findings of our systematic review, we noted a decrease in pain levels, as evaluated by the visual analog scale (VAS), in patients suffering from musculoskeletal disorders treated with IR. In addition, IR use led to a decrease in Fibromyalgia Impact Questionnaire (FiQ) scores in subjects diagnosed with fibromyalgia. Nevertheless, IR has failed to facilitate muscle recovery following athletic injuries.

Approximately half of the patients with long-standing diabetes are known to have diabetic peripheral neuropathy (DPN). Pain from DPN deteriorates quality of life and hinders activities of daily living.

Knee osteoarthritis (KOA) is a common chronic debilitating disease with an estimated prevalence of 23.9% in the general adult population. The condition is characterised by joint pain, functional impairment and significant reduction in quality of life. Management for KOA can generally be divided into conservative (non-operative) and surgical (operative) measures. Conservative management broadly compromises pharmacological and non-pharmacological options and is conventionally the first line treatment to avoid or delay the need for surgical management. The aim of this study is to provide an overview of the current recommendations, efficacy and safety profile of different conservative treatments through a review of the literature.

The activation of mast cells (MCs) and mediator release are closely related to the pathophysiology of irritable bowel syndrome (IBS). However, the exact underlying mechanisms are still not completely understood. The nuclear receptor subfamily 4a (Nr4a) is a family of orphan nuclear receptors implicated in regulating MC activation, degranulation, cytokine/chemokine synthesis and release. Acute and chronic stress trigger hypothalamic-pituitaryadrenal axis (HPA) activation to induce the release of corticotropin-releasing hormone (CRH), resulting in MC activation and induction of the Nr4a family. Our newest data showed that Nr4a members were specially over-expressed in colonic MCs of the chronic water-avoidance stress (WAS)-induced visceral hyperalgesia mice, suggesting that Nr4a members might be involved in the pathophysiology of visceral hypersensitivity. In this review, we highlight the present knowledge on roles of Nr4a members in the activation of MCs and the pathophysiology of IBS, and discuss signaling pathways that modulate the activation of Nr4a family members. We propose that a better understanding of Nr4a members and their modulators may facilitate the development of more selective and effective therapies to treat IBS patients.

Fabry disease (FD) is a rare chronic genetic disorder that presents under a paucity of symptoms. Gastrointestinal (GI) involvement is a common event and can sometimes be debilitating, but relatively often it is overlooked. We aimed to provide a systematic review of main GI symptoms in FD patients and treatment possibilities.

Axial Spondyloarthritis is a rheumatic condition affecting young patients with social and occupational consequences. Diagnosis delay is associated with functional impairment and impact on quality of life, requiring a multidisciplinary approach.

Abnormalities of mast cell structure or function may play prominent roles in irritable bowel syndrome (IBS) symptom genesis. Mast cells show close apposition to sensory nerves and release bioactive substances in response to varied stimuli including infection, stress, and other neuroendocrine factors. Most studies focus on patients who develop IBS after enteric infection or who report diarrhea-predominant symptoms. Three topics underlying IBS pathogenesis have been emphasized in recent investigations. Visceral hypersensitivity to luminal stimulation is found in most IBS patients and may contribute to abdominal pain. Mast cell dysfunction also may disrupt epithelial barrier function which alters mucosal permeability potentially leading to altered bowel function and pain. Mast cell products including histamine, proteases, prostaglandins, and cytokines may participate in hypersensitivity and permeability defects, especially with diarrhea-predominant IBS. Recent experimental evidence indicates that the pronociceptive effects of histamine and proteases are mediated by the generation of prostaglandins in the mast cell. Enteric microbiome interactions including increased mucosal bacterial translocation may activate mast cells to elicit inflammatory responses underlying some of these pathogenic effects. Therapies to alter mast cell activity (mast cell stabilizers) or function (histamine antagonists) have shown modest benefits in IBS. Future investigations will seek to define patient subsets with greater potential to respond to therapies that address visceral hypersensitivity, epithelial permeability defects, and microbiome alterations secondary to mast cell dysfunction in IBS.

Pain is an unpleasant sensation associated with injury, inflammation, and infection. It has been demonstrated that communication between immune cells and neurons plays a vital role in pain and pain-related diseases (e.g. multiple sclerosis, osteoarthritis, irritable bowel syndrome). Growing data from preclinical and clinical studies have established that the bilateral regulations between peripheral immune cells and nociceptive neurons could be beneficial or detrimental for the development of pain and immune defense. We here review the mechanisms underlying neuroimmune crosstalk between circulating immune cells (e.g. macrophages, T cells, mast cells, neutrophils, monocytes) and nociceptors in the peripheral nervous system and the spinal cord. Deciphering the mechanisms by which neuroimmune interaction integrates neuronal inputs and immune responses helps to understand the pathogenesis of pain-related diseases and develop effective medications.

Chronic pain affects almost 20% of the European adult population and it significantly reduces patients' quality of life. Chronic pain is considered a multidimensional experience determined by the interaction of several genetic and environmental factors. The effect of specific genetic contributions is often unclear, and the interpretation of the results from studies focused on genetic influences on pain has been complicated by the existence of multiple pain phenotypes. A step forward from genetics could be given by the application of metabolomics and microbiomics tools. Metabolomics is a powerful approach for hypothesis generation in biology, and it aims to analyze low molecular weight compounds, either metabolic intermediates or metabolic end-products, resulting from human or microbial metabolism. Microbiomics is a fast-growing field in which all the microbes are examined together, and as a result, its perturbation may indicate the development of chronic diseases. By applying these methodologies for the study of chronic pain, several differences have been identified. The alteration of the choline-PAF pathway is an intriguing finding recognized by several groups. In our opinion, metabolomics and microbiomics techniques will allow significant progress into the medical field. Patients may benefit from the possibility of being stratified and classified based on their metabolic and microbial profile, which, in the next future, may lead to personalized therapy.

Recent studies have linked activated spinal glia to neuropathic pain. Here, using a positron emission tomography (PET) scanner with high spatial resolution and sensitivity, we evaluated the feasibility and sensitivity of N,N-diethyl-2-(2-(4-([F]fluoro)phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl)acetamide ([F]F-DPA) imaging for detecting spinal cord microglial activation after partial sciatic nerve ligation (PSNL) in rats.

Although psychosocial factors have a profound impact on the experience of pain and pain recovery, the transfer to clinical application has so far been insufficient. With this article, a task force of the special interest group "Psychosocial Aspects of Pain" of the German Pain Society (Deutsche Schmerzgesellschaft e. V.) would like to draw attention to the considerable discrepancy between existing scientific evidence on the importance of psychosocial factors in the development of chronic pain disorders and the translation of these findings into the care of pain patients. Our objective is a stronger integration of psychological and psychosomatic expertise in pain treatment and research, as well as the improvement of structural and institutional conditions, to achieve an increased consideration of psychosocial aspects. In this way, modern, integrative and complex pain concepts can reach the patient. Based on these fundamental findings on the importance of psychosocial factors in pain and pain treatment, implications for the transfer to clinic and further research will be shown.

To determine whether glibenclamide, a non-selective adenosine 5'-triphosphate-sensitive K (K) channel blocker, attenuates pituitary adenylate cyclase-activating polypeptide-38 (PACAP38)-induced headache and vascular changes in healthy volunteers.