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Opioid use in chronic non cancer pain (CNCP) is still controversial regarding their effectiveness and safety. We conducted a 2-year prospective cohort study in 4 multidisciplinary chronic pain clinics to assess long-term opioid effectiveness in CNCP patients. All adult CNCP patients consecutively admitted to their first consultation were recruited. Demographic and clinical data were collected, and propensity score matching was used to adjust for differences between opioid users and nonusers. The Brief Pain Inventory and the Short version of Treatment Outcomes in Pain Survey were used to measure pain outcomes and quality of life. A total of 529 subjects were matched and included in our analysis. Rate of prescription opioid use was 59.7% at baseline, which increased to 70.3% over 2 years, of which 42.7% of the prescriptions were for strong opioids. Opioid users reported no improvement regarding pain symptoms, physical function, emotional function, and social/familiar disability. Opioid users reported higher satisfaction with care and outcomes at 1 year of follow-up, but at 2 years, they only reported improvement in satisfaction with outcomes. Opioids have shown limited effectiveness in long-term CNCP management, as opioid users presented no improvements regarding functional outcomes and quality of life. These findings emphasize the need for proper selection and outcome assessment of CNCP patients prescribed opioids. PERSPECTIVE: This study adds important additional evidence concerning the controversial use of opioids in CNCP management. Opioid users presented no improvement regarding pain relief, functional outcomes and quality of life over 2 years of follow-up. Therefore, our results support and highlight the limited effectiveness of opioids in long-term CNCP management.
Learn More >Sensory functions of the vagus nerve are critical for conscious perceptions and for monitoring visceral functions in the cardio-pulmonary and gastrointestinal systems. Here, we present a comprehensive identification, classification, and validation of the neuron types in the neural crest (jugular) and placode (nodose) derived vagal ganglia by single-cell RNA sequencing (scRNA-seq) transcriptomic analysis. Our results reveal major differences between neurons derived from different embryonic origins. Jugular neurons exhibit fundamental similarities to the somatosensory spinal neurons, including major types, such as C-low threshold mechanoreceptors (C-LTMRs), A-LTMRs, Aδ-nociceptors, and cold-, and mechano-heat C-nociceptors. In contrast, the nodose ganglion contains 18 distinct types dedicated to surveying the physiological state of the internal body. Our results reveal a vast diversity of vagal neuron types, including many previously unanticipated types, as well as proposed types that are consistent with chemoreceptors, nutrient detectors, baroreceptors, and stretch and volume mechanoreceptors of the respiratory, gastrointestinal, and cardiovascular systems.
Learn More >Spinal transmission of pruritoceptive (itch) signals requires transneuronal signaling by gastrin-releasing peptide (GRP) produced by a subpopulation of dorsal horn excitatory interneurons. These neurons also express the glutamatergic marker vGluT2, raising the question of why glutamate alone is insufficient for spinal itch relay. Using optogenetics together with slice electrophysiology and mouse behavior, we demonstrate that baseline synaptic coupling between GRP and GRP receptor (GRPR) neurons is too weak for suprathreshold excitation. Only when we mimicked the endogenous firing of GRP neurons and stimulated them repetitively to fire bursts of action potentials did GRPR neurons depolarize progressively and become excitable by GRP neurons. GRPR but not glutamate receptor antagonism prevented this action. Provoking itch-like behavior by optogenetic activation of spinal GRP neurons required similar stimulation paradigms. These results establish a spinal gating mechanism for itch that requires sustained repetitive activity of presynaptic GRP neurons and postsynaptic GRP signaling to drive GRPR neuron output.
Learn More >The site of action potential initiation in sensory neurons remains poorly understood. In this issue of Neuron, Goldstein et al. (2019) identified the location of the sodium-dependent spike initiation zone (Nav-SIZ) in nociceptive neurons, showing its plasticity under inflammatory conditions.
Learn More >Mast-cell-nerve interactions play an integral role in itch and inflammation. Meixiong et al. (2019) show that the receptors MRGPRB2 and FcεRI mediate distinct types of mast cell activation and nerve interactions and that mast cell activation through MRGPRB2 drives itch in allergic contact dermatitis.
Learn More >We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic non-cancer pain or chronic cancer-related pain. We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with chronic non-cancer pain or chronic cancer-related pain. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with chronic non-cancer pain or chronic cancer-related pain. Seven of those 23 reviews included six trials that involved children with chronic non-cancer pain. There were no RCTs in reviews relating to reducing pain in chronic cancer-related pain. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42017081205. A video accompanying this abstract is available online as Supplemental Digital Content at http://links.lww.com/PAIN/A797.
Learn More >Accumulating evidence has shown that complicated brain systems are involved in the development and maintenance of chronic low back pain (cLBP), but the association between brain functional changes and clinical outcomes remains unclear. Here, we used resting-state functional magnetic resonance imaging (fMRI) and multivariate pattern analysis to identify abnormal functional connectivity (FC) between the default mode, sensorimotor, salience, and central executive brain networks in cLBP and tested whether abnormal FCs are related to pain and comorbid symptoms. Fifty cLBP patients and 44 matched healthy controls (HCs) underwent an fMRI scan, from which brain networks were identified by independent component analysis. Multivariate pattern analysis, graph theory approaches, and correlation analyses were applied to find abnormal FCs that were associated with clinical symptoms. Findings were validated on a second cohort of 30 cLBP patients and 30 matched HCs. Results showed that the medial prefrontal cortex/rostral anterior cingulate cortex had abnormal FCs with brain regions within the default mode network and with other brain networks in cLBP patients. These altered FCs were also correlated with pain duration, pain severity, and pain interference. Finally, we found that resting-state FC could discriminate cLBP patients from HCs with 91% accuracy in the first cohort and 78% accuracy in the validation cohort. Our findings suggest that the medial prefrontal cortex/rostral anterior cingulate cortex may be an important hub for linking the default mode network with the other 3 networks in cLBP patients. Elucidating the altered FCs and their association with clinical outcomes will enhance our understanding of the pathophysiology of cLBP and may facilitate the development of pain management approaches.
Learn More >Diabetic neuropathy is an incapacitating complication in diabetic patients. The cellular and molecular mechanisms involved in this pathology are poorly understood. Previous studies have suggested that the loss of spinal GABAergic inhibition participate in painful diabetic neuropathy. However, the role of extrasynaptic α5 subunit-containing GABAA (α5GABAA) receptors in this process is not known. The purpose of this study was to investigate the role of α5GABAA receptors in diabetes-induced tactile allodynia, loss of rate-dependent depression (RDD) of the Hoffmann reflex (HR), and modulation of primary afferent excitability. Intraperitoneal administration of streptozotocin induced tactile allodynia. Intrathecal injection of α5GABAA receptor inverse agonist, L-655,708, produced tactile allodynia in naive rats, whereas it reduced allodynia in diabetic rats. In healthy rats, electrical stimulation of the tibial nerve at 5 Hz induced RDD of the HR, although intrathecal treatment with L-655,708 (15 nmol) abolished RDD of the HR. Streptozotocin induced the loss of RDD of the HR, while intrathecal L-655,708 (15 nmol) restored RDD of the HR. L-655,708 (15 nmol) increased tonic excitability of the primary afferents without affecting the phasic excitability produced by the primary afferent depolarization. α5GABAA receptors were immunolocalized in superficial laminae of the dorsal horn and L4 to L6 dorsal root ganglion. Streptozotocin increased mean fluorescence intensity and percentage of neurons expressing α5GABAA receptors in dorsal horn and L4 to L6 dorsal root ganglia in 10-week diabetic rats. Our results suggest that spinal α5GABAA receptors modulate the HR, play an antinociceptive and pronociceptive role in healthy and diabetic rats, respectively, and are tonically active in primary afferents.
Learn More >There is an ethical obligation to notify individuals about potential pain associated with diagnoses, treatments, and procedures; however, supplying this information risks inducing nocebo hyperalgesia. Currently there are few empirically-derived strategies for reducing nocebo hyperalgesia. Since nocebo effects are linked to negative affectivity, we tested the hypothesis that a positive affect induction can disrupt nocebo hyperalgesia from verbal suggestion. Healthy volunteers (N =147) were randomly assigned to conditions in a 2 (Affect Induction: Positive vs. Neutral) by 2 (Verbal Suggestion: No Suggestion vs. Suggestion of Pain Increase) between-subjects design. Participants were induced to experience positive or neutral affect by watching movie clips for 15 mins. Next, participants had an inert cream applied to their non-dominant hand and suggestion was manipulated by telling only half the participants the cream could increase the pain of the upcoming cold pressor test. Subsequently, all participants underwent the cold pressor test (8C ±.04C), wherein they submerged the non-dominant hand and rated pain intensity on numerical rating scales every 20 sec up to two mins. In the neutral affect conditions, there was evidence for the nocebo hyperalgesia effect: participants given the suggestion of pain displayed greater pain than participants not receiving this suggestion, ps<.05. Demonstrating a blockage effect, nocebo hyperalgesia did not occur in the positive affect conditions, ps>.5. This is the first study to show that positive affect may disrupt nocebo hyperalgesia thereby pointing to a novel strategy for decreasing nocebo effects without compromising the communication of medical information to patients in clinical settings.
Learn More >Cancer and its surgical treatment are among the most important triggering events for persistent pain, but additional factors need to be present for the clinical manifestation, such as variants in pain-relevant genes. In a cohort of 140 women undergoing breast cancer surgery, assigned based on a three-year follow-up to either a persistent or non-persistent pain phenotype, next generation sequencing was performed for 77 genes selected for known functional involvement in persistent pain. Applying machine learning and item categorization techniques, 21 variants in 13 different genes were found to be relevant to the assignment of a patient to either the persistent pain or the non-persistent pain phenotype group. In descending order of importance for correct group assignment, the relevant genes comprised DRD1, FAAH, GCH1, GPR132, OPRM1, DRD3, RELN, GABRA5, NF1, COMT, TRPA1, ABHD6, and DRD4, of which one in the DRD4 gene was a novel discovery. Particularly relevant variants were found in the DRD1 and GPR132 genes, or in a cis-eCTL position of the OPRM1 gene. Supervised machine learning based classifiers, trained with 2/3 of the data, identified the correct pain phenotype group in the remaining 1/3 of the patients at accuracies and areas under the receiver operator characteristic curves of 65 – 72 %. When using conservative classical statistical approaches, none of the variants passed α-corrected testing. The present data analysis approach, using machine learning and training artificial intelligences, provided biologically plausible results and outperformed classical approaches to genotype phenotype association.
Learn More >Chronic pain is a serious debilitating disease for which effective treatment is still lacking. Acid-sensing ion channel 1a (ASIC1a) has been implicated in nociceptive processing at both peripheral and spinal neurons. However, whether ASIC1a also contributes to pain perception at the supraspinal level remains elusive. Here, we report that ASIC1a in anterior cingulate cortex (ACC) is required for thermal and mechanical hypersensitivity associated with chronic pain. ACC-specific genetic deletion or pharmacological blockade of ASIC1a reduced the probability of cortical long-term potentiation (LTP) induction and attenuated inflammatory thermal hyperalgesia and mechanical allodynia in male mice. Using cell type-specific manipulations, we demonstrate that ASIC1a in excitatory neurons of ACC is a major player in cortical LTP and pain behavior. Mechanistically, we show that ASIC1a tuned pain-related cortical plasticity through protein kinase C lambda-mediated increase of membrane trafficking of AMPA receptor subunit GluA1 in ACC. Importantly, post-application of ASIC1a inhibitors in ACC reversed previously established nociceptive hypersensitivity in both chronic inflammatory pain and neuropathic pain models. These results suggest that ASIC1a critically contributes to higher level of pain processing through synaptic potentiation in ACC, which may serve as a promising analgesic target for treatment of chronic pain. Chronic pain is a debilitating disease that still lacks effective therapy. Ion channels are good candidates for developing new analgesics. Here, we provide several lines of evidence to support an important role of cortically-located ASIC1a channel in pain hypersensitivity through promoting long-term synaptic potentiation in the anterior cingulate cortex. Our results indicate a promising translational potential of targeting ASIC1a to treat chronic pain.
Learn More >Advances in cancer treatment have led to a growing number of survivors. At least 40% of those survivors live with chronic pain and need pain control medication. This coincides with an epidemic of opioid misuse and overdose deaths, resulting in restrictive practices that can impact patients who experience severe pain. Oncologists and other healthcare professionals who treat patients with cancer need to balance considerations of opioid misuse with effective pain control and become better educated about risk factors and management of opioids in cancer survivors.
Learn More >Numerous studies have identified the proinflammatory, pronociceptive effects of morphine which ultimately exacerbate pain. Our novel endomorphin analog ZH853 does not produce proinflammatory effects on its own and gives potent, long-lasting analgesia. This study investigates whether ZH853's lack of interaction with the neuroimmune system reduces the risk of prolonged pain.
Learn More >Chronic pain affects 50% of adults with sickle cell disease (SCD). Although central sensitization is thought to contribute to the pathogenesis of this chronic pain, no studies have examined differences in functional connectivity of the brain between patients with SCD with and without chronic pain. We performed an observational cohort study using resting-state functional MRI (rsfMRI) of the brain on adults with SCD with and without chronic pain. We tested the hypothesis that, compared to those without chronic pain, those with chronic pain would have differences in functional connectivity between the periaqueductal grey (PAG) and other regions of the brain. Twenty-two adults with SCD, 15 with chronic pain and 7 without chronic pain, as well as 10 African-American controls, underwent rsfMRI of the brain. When SCD patients with chronic pain were compared to those without chronic pain, significant differences in connectivity were noted between the PAG and 9 regions of the brain, including several in the default mode network, a network involved in introspection that has been implicated in other chronic pain syndromes. Changes in functional connectivity between patients with SCD with and without chronic pain suggest a mechanism for chronic pain that involves neuro-plastic changes to the brain.
Learn More >In addition to large plexiform neurofibromas (pNF), NF1 patients are frequently disfigured by cutaneous neurofibromas (cNF) and are often afflicted with chronic pain and itch even from seemingly normal skin areas. Both pNFs and cNF consist primarily of benign hyperproliferating nonmyelinating Schwann cells (nSC). While pNF clearly arise within deep nerves and plexuses, the role of cutaneous innervation in the origin of cNF and in chronic itch and pain is unknown. First, we conducted a comprehensive, multi-molecular, immunofluorescence (IF) analyses on 3mm punch biopsies from three separate locations in normal appearing, cNF-free skin in 19 NF1 patients and skin of 16 normal subjects. At least one biopsy in 17 NF1 patients had previously undescribed micro-lesions consisting of a small, dense cluster of nonpeptidergic C-fiber endings and the affiliated nSC consistently adjoining adnexal structures-dermal papillae, hair follicles, sweat glands, sweat ducts, and arterioles-where C-fiber endings normally terminate. Similar micro-lesions were detected in hind paw skin of mice with conditionally-induced SC Nf1-/- mutations. Hypothesizing that these microlesions were pre-cNF origins of cNF, we subsequently analyzed numerous overt, small cNF (s-cNF, 3-6 mm) and discovered that each had an adnexal structure at the epicenter of vastly increased nonpeptidergic C-fiber terminals, accompanied by excessive nSC. The IF and functional genomics assays indicated that neurturin (NTRN) and artemin (ARTN) signaling through cRET kinase and GFRα2 and GFRα3 co-receptors on the aberrant C-fiber endings and nSC may mutually promote the onset of pre-cNF and their evolution to s-cNF. Moreover, TrpA1 and TrpV1 receptors may, respectively, mediate symptoms of chronic itch and pain. These newly discovered molecular characteristics might be targeted to suppress the development of cNF and to treat chronic itch and pain symptoms in NF1 patients.
Learn More >Migraine mechanisms are *These authors contributed equally to this work. only partly known. Some studies have previously described genes differentially expressed between blood from migraineurs and controls. The objective of this study was to describe gene expression in subtypes of migraine outside of attack and in healthy controls.
Learn More >The current understanding of mechanisms behind migraine pain has been greatly enhanced with the recent therapies targeting calcitonin gene-related peptide and its receptor. The clinical efficacy of calcitonin gene-related peptide-blocking drugs indicates that, at least in a considerable proportion of patients, calcitonin gene-related peptide is a key molecule in migraine pain. There are several receptors and molecular pathways that can affect the release of and response to calcitonin gene-related peptide. One of these could be purinergic receptors that are involved in nociception, but these are greatly understudied with respect to migraine.
Learn More >Initiating mechanisms of migraine headache remain poorly understood and a biomarker of migraine does not exist. Inflammation pertaining to the wall of cerebral arteries and brain parenchyma has been suggested to play a role in migraine pathophysiology.
Learn More >Painful diabetic neuropathy (PDN) is a severely debilitating chronic pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of chronic pain induced by peripheral tissue inflammation or nerve injury. In this study we investigated whether CXCL13/CXCR5 mediates PDN and the underlying spinal mechanisms. We used the db/db type 2 diabetes mice, which showed obvious hyperglycemia and obese, long-term mechanical allodynia, and increased expression of CXCL13, CXCR5 as well as pro-inflammatory cytokines TNF-α and IL-6 in the spinal cord. Furthermore, in the spinal cord of db/db mice there is significantly increased gliosis and upregulated phosphorylation of cell signaling kinases, including pERK, pAKT and pSTAT3. Mechanical allodynia and upregulated pERK, pAKT and pSTAT3 as well as production of TNF-α and IL-6 were all attenuated by the noncompetitive NMDA receptor antagonist MK-801. If spinal giving U0126 (a selective MEK inhibitor) or AG490 (a Janus kinase (JAK) -STAT inhibitor) to db/db mice, both of them can decrease the mechanical allodynia, but only inhibit pERK (by U0126) or pSTAT3 (by AG490) respectively. Acute administration of CXCL13 in C57BL/6J mice resulted in exacerbated thermal hyperalgesia and mechanical allodynia, activation of the pERK, pAKT and pSTAT3 pathways and increased production of pro-inflammatory cytokines (IL-1β, TNF-α and IL-6), which were all attenuated by knocking out of Cxcr5. In all, our work showed that chemokine CXCL13 and its receptor CXCR5 in spinal cord contribute to the pathogenesis of PDN and may help develop potential novel therapeutic approaches for patients afflicted with PDN.
Learn More >It is well documented that pain chronification requires a host of plastic mechanisms at the spinal cord (SC) level, including alterations in neuronal and glial structure and function. Such cellular plasticity necessitates the existence of a plastic extracellular matrix (ECM). Here, we describe a key role for ECM remodeling in the regulation of chronic pain following peripheral injury. Three weeks following tibia fracture in mice, we show increased levels of MMP8 in the SC. Furthermore, we show that the pharmacological or genetic downregulation of MMP8 ameliorates the pain phenotype observed after injury. These results delineate an extracellular mechanism for pain chronification, thereby improving our mechanistic understanding of pain and providing novel therapeutic venues that go beyond targeting individual cell types.
Learn More >The α9 subunit of nicotinic acetylcholine receptors (nAChRs) exists mainly in heteropentameric assemblies with α10. Accumulating data indicate the presence of three different binding sites in α9α10 nAChRs: the α9(+)/α9(-), the α9(+)/α10(-), and the α10(+)/α9(-). The major role of the principal (+) side of the extracellular domain (ECD) of α9 subunit in binding of the antagonists methyllylcaconitine and α-bungarotoxin was shown previously by the crystal structures of the monomeric α9-ECD with these molecules. Here we present the 2.26-Å resolution crystal structure of α9-ECD in complex with α-conotoxin (α-Ctx) RgIA, a potential drug for chronic pain, the first structure reported for a complex between an nAChR domain and an α-Ctx. Superposition of this structure with those of other α-Ctxs bound to the homologous pentameric acetylcholine binding proteins revealed significant similarities in the orientation of bound conotoxins, despite the monomeric state of the α9-ECD. In addition, ligand-binding studies calculated a binding affinity of RgIA to the α9-ECD at the low micromolar range. Given the high identity between α9 and α10 ECDs, particularly at their (+) sides, the presented structure was used as template for molecular dynamics simulations of the ECDs of the human α9α10 nAChR in pentameric assemblies. Our results support a favorable binding of RgIA at α9(+)/α9(-) or α10(+)/α9(-) rather than the α9(+)/α10(-) interface, in accordance with previous mutational and functional data.
Learn More >Routine assessment of photophobia in the clinical setting may underestimate the presence and severity of this condition. We aimed to develop and validate a questionnaire to improve evaluation of the impact of photophobia on activities of daily living, and to determine the relationship of this questionnaire to psychophysical assessment of light sensitivity thresholds.
Learn More >Transmission of pain signals from primary sensory neurons to secondary neurons of the central nervous system is critically dependent on presynaptic voltage-gated calcium channels. Calcium channel-binding domain 3 (CBD3), derived from the collapsin response mediator protein 2 (CRMP2), is a peptide aptamer that is effective in blocking N-type voltage-gated calcium channel (Ca2.2) activity. We previously reported that recombinant adeno-associated virus (AAV)-mediated restricted expression of CBD3 affixed to enhanced green fluorescent protein (EGFP) in primary sensory neurons prevents the development of cutaneous mechanical hypersensitivity in a rat neuropathic pain model. In this study, we tested whether this strategy is effective in treating established pain. We constructed AAV6-EGFP-CBD3A6K (AAV6-CBD3A6K) expressing a fluorescent CBD3A6K (replacing A to K at position 6 of CBD3 peptide), which is an optimized variant of the parental CBD3 peptide that is a more potent blocker of Ca2.2. Delivery of AAV6-CBD3A6K into lumbar (L) 4 and 5 dorsal root ganglia (DRG) of rats 2 weeks following tibial nerve injury (TNI) induced transgene expression in neurons of these DRG and their axonal projections, accompanied by attenuation of pain behavior. We additionally observed that the increased Ca2.2α1b immunoreactivity in the ipsilateral spinal cord dorsal horn and DRG following TNI was significantly normalized by AAV6-CBD3A6K treatment. Finally, the increased neuronal activity in the ipsilateral dorsal horn that developed after TNI was reduced by AAV6-CBD3A6K treatment. Collectively, these results indicate that DRG-restricted AAV6 delivery of CBD3A6K is an effective analgesic molecular strategy for the treatment of established neuropathic pain.
Learn More >The Aids to Management are a product of the Global Campaign against Headache, a worldwide programme of action conducted in official relations with the World Health Organization. Developed in partnership with the European Headache Federation, they update the first edition published 11 years ago.The common headache disorders (migraine, tension-type headache and medication-overuse headache) are major causes of ill health. They should be managed in primary care, firstly because their management is generally not difficult, and secondly because they are so common. These Aids to Management, with the European principles of management of headache disorders in primary care as the core of their content, combine educational materials with practical management aids. They are supplemented by translation protocols, to ensure that translations are unchanged in meaning from the English-language originals.The Aids to Management may be individually downloaded and, as is the case for all products of the Global Campaign against Headache, are available without restriction for non-commercial use.
Learn More >We aimed to test the hypothesis that the effect of chronic pain on depressive symptoms is mediated through hippocampal volume (HV). Participants were 131 non-demented adults over the age of 70 years from the Einstein Aging Study. Smaller right and left HV were both associated with higher depressive symptoms, but only smaller right HV was associated with chronic pain. In mediation models, right HV was a significant mediator for the effect of chronic pain on depression. Our findings suggest presence of a shared brain substrates between chronic pain and depression as reflected by right HV.
Learn More >The Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials demonstrated efficacy/tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. This post hoc analysis assessed time of onset of onabotulinumtoxinA after the first treatment in total and responder populations and consistency weekly through five treatment cycles.
Learn More >Topical application of lidocaine and prilocaine (LP) cream attenuates the functionality of small cutaneous nerve fibers. The aim of this human study was to measure the underlying excitability modulation of small cutaneous nerve fibers using a novel and fast perception threshold tracking (PTT) technique.
Learn More >Efficacy of galcanezumab in chronic migraine has been demonstrated in a pivotal Phase 3 study. Here, we assess efficacy in patients who have failed ≥2 and ≥1 prior migraine preventives for efficacy and/or safety reasons, and in those who never failed.
Learn More >Complex regional pain syndrome type 1 (CRPS-I) is a debilitating pain condition that significantly affects life quality of patients. It remains a clinically challenging condition and the mechanisms of CRPS-I have not been fully elucidated. Here, we investigated the involvement of TRPV1, a non-selective cation channel important for integrating various painful stimuli, in an animal model of CRPS-I. A rat model of chronic post-ischemia pain (CPIP) was established to mimic CRPS-I. TRPV1 expression was significantly increased in hind paw tissue and small to medium-sized dorsal root ganglion (DRG) neurons of CPIP rats. CPIP rats showed increased TRPV1 current density and capsaicin responding rate in small-sized nociceptive DRG neurons. Local pharmacological blockage of TRPV1 with the specific antagonist AMG9810, at a dosage that does not produce hyperthermia or affect thermal perception or locomotor activity, effectively attenuated thermal and mechanical hypersensitivity in bilateral hind paws of CPIP rats and reduced the hyperexcitability of DRG neurons induced by CPIP. CPIP rats showed bilateral spinal astrocyte and microglia activations, which were significantly attenuated by AMG9810 treatment. These findings identified an important role of TRPV1 in mediating thermal and mechanical hypersensitivity in a CRPS-I animal model and further suggest local pharmacological blocking TRPV1 may represent an effective approach to ameliorate CRPS-I.
Learn More >Ischemia-reperfusion (IR)-induced pain hypersensitivity shares features of neuroinflammation and neuropathic pain, accompanied by overproduction of interleukin (IL)-1β. Multiple microRNAs (miRs) are dysregulated during IR; among these miRs, miR-187-3p was recently reported to drive IL-1β release in retinal disease by activating members of the purinergic receptor family. However, the roles of miR-187-3p in the spinal cord are unclear. Thus, we investigated whether miR-187-3p is involved in the pathogenesis of IR-induced pain hypersensitivity by regulating the P2X7R signal and subsequent IL-1β release.
Learn More >The treatment of migraine is impeded by several difficulties, among which insufficient headache relief, side effects, and risk for developing medication overuse headache (MOH). Thus, new acutely acting antimigraine drugs are currently being developed, among which the small molecule CGRP receptor antagonists, gepants, and the 5-HT receptor agonist lasmiditan. Whether treatment with these drugs carries the same risk for developing MOH is currently unknown.
Learn More >Neuropathic pain can develop after nerve injury, leading to a chronic condition with spontaneous pain and hyperalgesia. Pain is typically restricted to the side of the injured nerve, but may occasionally spread to the contralateral side, a condition that is often referred to as mirror-image pain. Mechanisms leading to mirror-image pain are not completely understood, but cannabinoid CB2 receptors have been implicated. In this study, we use genetic mouse models to address the question if CB2 receptors on neurons or on microglia/macrophages are involved. First, we show that a GFP reporter protein under control of the CB2 promoter is induced upon partial sciatic nerve ligation in spinal cord, dorsal root ganglia, and highest in sciatic nerve macrophages, but not in neurons. Mice which lack CB2 receptors specifically on myeloid cells (microglia, macrophages) developed a mirror-image allodynia [treatment F = 45.69, p < 0.0001] similar to constitutive CB2 receptor knockout mice [treatment F = 92.41, p < 0.0001]. Such a phenotype was not observed after the deletion of CB2 from neurons [treatment F = 0.1315, p = 0.7180]. This behavioral pain phenotype was accompanied by an increased staining of microglia in the dorsal horn of the spinal cord, as evidenced by an enhanced Iba 1 expression [CB2KO, p = 0.0175; CB2-LysM, p = 0.0425]. Similarly, myeloid-selective knockouts showed an increased expression of the leptin receptor in the injured ipsilateral sciatic nerve, thus further supporting the notion that leptin signaling contributes to the increased neuropathic pain responses of CB2 receptor knockout mice. We conclude that CB2 receptors on microglia and macrophages, but not on neurons, modulate neuropathic pain responses.
Learn More >Despite being one of the most common presenting dermatological symptoms, itching continues to perplex health care professionals because it is notoriously difficult to control.
Learn More >Long-term stress was suggested to cause visceral hypersensitivity and promote functional gastrointestinal disorders (FGIDs). Some brain regions such as the anterior cingulate cortex (ACC) may play an important role for generating visceral hypersensitivity; however, its molecular mechanisms are not clear. This study aimed to explore the role of 5-HT1A receptors (HTR1As) in activating ACC and corresponding mechanism, in stress-induced visceral hyperalgesia rats.
Learn More >Poor reporting quality may contribute to irreproducibility of results and failed 'bench-to-bedside' translation. Consequently, guidelines have been developed to improve the complete and transparent reporting of in vivo preclinical studies. To examine the impact of such guidelines on core methodological and analytical reporting items in the preclinical anesthesiology literature, we sampled a cohort of studies. Preclinical in vivo studies published in Anesthesiology, Anesthesia & Analgesia, Anaesthesia, and the British Journal of Anaesthesia (2008-2009, 2014-2016) were identified. Data was extracted independently and in duplicate. Reporting completeness was assessed using the National Institutes of Health Principles and Guidelines for Reporting Preclinical Research. Risk ratios were used for comparative analyses. Of 7615 screened articles, 604 met our inclusion criteria and included experiments reporting on 52 490 animals. The most common topic of investigation was pain and analgesia (30%), rodents were most frequently used (77%), and studies were most commonly conducted in the United States (36%). Use of preclinical reporting guidelines was listed in 10% of applicable articles. A minority of studies fully reported on replicates (0.3%), randomization (10%), blinding (12%), sample-size estimation (3%), and inclusion/exclusion criteria (5%). Statistics were well reported (81%). Comparative analysis demonstrated few differences in reporting rigor between journals, including those that endorsed reporting guidelines. Principal items of study design were infrequently reported, with few differences between journals. Methods to improve implementation and adherence to community-based reporting guidelines may be necessary to increase transparent and consistent reporting in the preclinical anesthesiology literature.
Learn More >Chronic pain states have resulted in an overreliance on opioid pain relievers, which can carry significant risks when used long term. As such, alternative pain treatments are increasingly desired. Although emerging research suggests that cannabinoids have therapeutic potential regarding pain, results from studies across pain populations have been inconsistent. To provide meta-analytic clarification regarding cannabis's impact on subjective pain, we identified studies that assessed drug-induced pain modulations under cannabinoid and corresponding placebo conditions. A literature search yielded 25 peer-reviewed records that underwent data extraction. Baseline and end-point data were used to compute standardized effect size estimates (Cohen's d) across cannabinoid administrations (k = 39) and placebo administrations (k = 26). Standardized effects were inverse-variance weighted and pooled across studies for meta-analytic comparison. Results revealed that cannabinoid administration produced a medium-to-large effect across included studies, Cohen's d = -0.58, 95% confidence interval (CI) [-0.74, -0.43], while placebo administration produced a small-to-medium effect, Cohen's d = -0.39, 95% CI [-0.52, -0.26]. Meta-regression revealed that cannabinoids, β = -0.43, 95% CI [-0.62, -0.24], p < .05, synthetic cannabinoids, β = -0.39, 95% CI [-0.65, -0.14], p < .05, and sample size, β = 0.01, 95% CI [0.00, 0.01], p < .05, were associated with marked pain reduction. These outcomes suggest that cannabinoid-based pharmacotherapies may serve as effective replacement/adjunctive options regarding pain, however, additional research is warranted. Additionally, given demonstrated neurocognitive side effects associated with some constituent cannabinoids (i.e., THC), subsequent work may consider developing novel therapeutic agents that capitalize on cannabis's analgesic properties without producing adverse effects. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Learn More >Studies in rodents suggest that cutaneous beta-2 adrenoceptors (β2-ARs) mediate inflammation and pain after tissue injury and that inflammation and peripheral nerve injury trigger increases in neuronal β2-AR expression. Hence, the aim of this study was to investigate the expression of β2-ARs on keratinocytes and dermal nerves in patients with complex regional pain syndrome (CRPS).
Learn More >Cancer pain is a common symptom experienced by patients, caused either by the disease or its treatment. Morphine remains the most effective and recommended treatment for cancer pain. However, cancer patients still do not receive appropriate management for their pain, and under-treatment is common. Lack of knowledge and negative attitudes towards cancer pain and analgesia among professionals, patients and family caregivers are reported as one of the most common barriers to effective cancer pain management (CPM). To systematically review research on the nature and impact of attitudes and knowledge towards CPM, a systematic literature search of 6 databases (the Cochrane library, MEDLINE, PsycINFO, CINAHL, Web of Science and EMBASE) was undertaken in July 2018. Additionally, hand-searching of Google, Google Scholar and reference lists was conducted. The inclusion criteria were adult (18-65 years of age), studies which included attitudes and knowledge towards CPM, studies written in English, published literature only and cross-sectional design. Included studies were critically appraised by two researchers independently using the Joanna Briggs Institute Analytical Cross Sectional Studies Assessment (JBI-ACSSA). A total of 36 studies met the inclusion criteria. The main finding was that among professionals, patients, caregivers and the public there were similar attitudinal barriers to effective CPM. The most commonly cited barriers were fear of drug addiction, tolerance of medication and side effects of opioids. We also found differences between professional groups (physicians versus nurses) and between different countries based on their potential exposure to palliative care training and services. There are still barriers to effective CPM, which might result in unrelieved cancer pain. Therefore, more educational programmes and training for professionals on CPM are needed. Furthermore, patients, caregivers, and the public need more general awareness and adequate level of knowledge about CPM.
Learn More >Since the discovery of the NOP receptor and N/OFQ as the endogenous ligand, evidence has appeared demonstrating the involvement of this receptor system in pain. This was not surprising for members of the opioid receptor and peptide families, particularly since both the receptor and N/OFQ are highly expressed in brain regions involved in pain, spinal cord, and dorsal root ganglia. What has been surprising is the complicated picture that has emerged from 25 years of research. The original finding that N/OFQ decreased tail flick and hotplate latency, when administered i.c.v., led to the hypothesis that NOP receptor antagonists could have analgesic activity without abuse liability. However, as data accumulated, it became clear that not only the potency but the activity per se was different when N/OFQ or small molecule NOP agonists were administered in the brain versus the spinal cord and it also depended upon the pain assay used. When administered systemically, NOP receptor agonists are generally ineffective in attenuating heat pain but are antinociceptive in an acute inflammatory pain model. Most antagonists administered systemically have no antinociceptive activity of their own, even though selective peptide NOP antagonists have potent antinociceptive activity when administered i.c.v. Chronic pain models provide different results as well, as small molecule NOP receptor agonists have potent anti-allodynic and anti-hyperalgesic activity after systemic administration. A considerable number of electrophysiological and anatomical experiments, in particular with NOP-eGFP mice, have been conducted in an attempt to explain the complicated profile resulting from NOP receptor modulation, to examine receptor plasticity, and to elucidate mechanisms by which selective NOP agonists, bifunctional NOP/mu agonists, or NOP receptor antagonists modulate acute and chronic pain.
Learn More >Amputation of a sensory peripheral nerve induces severe anatomical and functional changes along the afferent pathway as well as perception alterations and neuropathic pain. In previous studies we showed that electrical stimulation applied to a transected infraorbital nerve protects the somatosensory cortex from the above-mentioned sensory deprivation-related changes. In the present study we focus on the initial tract of the somatosensory pathway and we investigate the way weak electrical stimulation modulates the neuroprotective-neuroregenerative and functional processes of trigeminal ganglia primary sensory neurons by studying the expression of neurotrophins (NTFs) and Glia-Derived Neurotrophic Factors (GDNFs) receptors. Neurostimulation was applied to the proximal stump of a transected left infraorbitary nerve using a neuroprosthetic micro-device 12 h/day for 4 weeks in freely behaving rats. Neurons were studied by hybridization and immunohistochemistry against RET (proto-oncogene tyrosine kinase "rearranged during transfection"), tropomyosin-related kinases (TrkA, TrkB, TrkC) receptors and IB4 (Isolectin B4 from Griffonia simplicifolia). Intra-group (left vs. right ganglia) and inter-group comparisons (between Control, Axotomization and Stimulation-after-axotomization groups) were performed using the mean percentage change of the number of positive cells per section [100(left-right)/right)]. Intra-group differences were studied by paired -tests. For inter-group comparisons ANOVA test followed by LSD test (when < 0.05) were used. Significance level (α) was set to 0.05 in all cases. Results showed that (i) neurostimulation has heterogeneous effects on primary nociceptive and mechanoceptive/proprioceptive neurons; (ii) neurostimulation affects RET-expressing small and large neurons which include thermo-nociceptors and mechanoceptors, as well as on the IB4- and TrkB-positive populations, which mainly correspond to non-peptidergic thermo-nociceptive cells and mechanoceptors respectively. Our results suggest (i) electrical stimulation differentially affects modality-specific primary sensory neurons (ii) artificial input mainly acts on specific nociceptive and mechanoceptive neurons (iii) neuroprosthetic stimulation could be used to modulate peripheral nerve injuries-induced neuropathic pain. These could have important functional implications in both, the design of effective clinical neurostimulation-based protocols and the development of neuroprosthetic devices, controlling primary sensory neurons through selective neurostimulation.
Learn More >We examined whether diabetic polyneuropathy (DPN) and diabetic foot ulcers in type 2 diabetes can be accurately identified using International Classification of Diseases, 10th revision discharge diagnosis codes, surgery codes, and drug prescription codes. We identified all type 2 diabetes patients in the Central Denmark region, 2009-2016, who had ≥1 primary/secondary diagnosis code of "diabetes with neurological complication" (E10.4-E14.4), "diabetic polyneuropathy" (G63.2), or "polyneuropathy, unspecified" (G62.9). Patients with potential painful DPN and non-painful DPN were identified based on prescription history for serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, or gabapentinoids. Likewise, type 2 diabetes patients with potential foot ulcers were identified based on diagnosis or surgery codes. We used medical record review as the reference standard and calculated positive predictive values (PPVs). Of 53 randomly selected patients with potential painful DPN, 38 were classified as having DPN when validated against medical records; of these, 18 also had neuropathic pain, yielding a PPV of 72% (95% CI: 58-83%) for DPN and 34% (95% CI: 22-48%) for painful DPN. Likewise, among 54 randomly selected patients with potential non-painful DPN, 30 had DPN based on medical record data; of these, 27 had non-painful DPN, yielding PPVs of 56% (95% CI: 41-69%) and 50% (95% CI: 36-64%), respectively. Secondary E-chapter codes often denoted stroke or mononeuropathies, rather than DPN. Excluding secondary E-chapter codes from the algorithm increased the PPV for DPN to 78% (95% CI: 63-89%) for the painful DPN cohort and to 74% (95% CI: 56-87%) for the non-painful DPN cohort. Of 53 randomly selected patients with potential diabetic foot ulcer, only 18 diagnoses were confirmed; PPV=34% (95% CI: 22-48%). G-chapter and primary E-chapter diagnosis codes can detect type 2 diabetes patients with hospital-diagnosed DPN, and may be useful in epidemiological research. In contrast, our diabetic foot ulcer algorithm did not perform well.
Learn More >To synthesize the evidence regarding the effect of spinal cord stimulation (SCS) on opioid and pain medication reduction in patients with intractable spine or limb pain. A comprehensive literature search was conducted to identify RCTs of patients with chronic back and/or limb pain of greater than one year duration. Only comparative studies were included (ie, conventional SCS vs medical therapy, conventional SCS vs high-frequency SCS) and were required to have a minimum follow-up period of 3 months. Random effect meta-an alysis was used to compare the three interventions. Results were expressed as odds ratio (OR) or weighted mean difference (WMD) with 95% confidence intervals (CI). We identified five trials enrolling 489 patients. Three of the trials reported the results as a number of patients who were able to reduce or eliminate opioid consumption in the SCS vs medical therapy group. The odds of reducing opioid consumption were significantly increased in the SCS group compared to medical therapy (OR 8.60, CI {1.93-38.30}). Two of the trials reported the results as mean medication dose reduction as measured by the Medication Quantification Scale (MQS) in the SCS group vs medical therapy group. MQS score significantly decreased in the SCS group and not in the medical group (WMD -1.97, 95% CI {-3.67, -0.27}). One trial reported a number of patients in high-frequency SCS who were able to reduce opioids vs number of patients in conventional SCS group who were able to reduce opioids. Thirty-four percent of the patients in the high-frequency group and 26% of the patients in the conventional SCS group were able to reduce opioid consumption; however, there was not a significant difference between groups (OR 1.43, 95% CI {0.74, 2.78}). This trial also quantified the opioid reduction in morphine equivalent dosage (MED). In the high-frequency SCS group, average MED decreased by 24.8 mg vs average MED decrease of 7.3 mg in the conventional SCS group. Again, the difference between groups did not reach statistical significance (-17.50, CI {-66.27, 31.27}). In patients with intractable spine/limb pain, SCS was associated with increased odds of reducing pain medication consumption. However, results should be treated with caution as available data were limited, and clinical significance of these findings requires further study.
Learn More >Injury of peripheral nerves may quickly induce severe pain, but the mechanism remains obscure. We observed a rapid onset of spontaneous pain and evoked pain hypersensitivity after acute transection of the L5 spinal nerve (SNT) in awake rats. The outburst of pain was associated with a rapid development of spontaneous activities and hyperexcitability of nociceptive neurons in the adjacent uninjured L4 dorsal root ganglion (DRG), as revealed by both in vivo electrophysiological recording and high-throughput calcium imaging in vivo. Transection of the L4 dorsal root or intrathecal infusion of aminobutyrate aminotransferase inhibitor attenuated the spontaneous activity, suggesting that retrograde signals from the spinal cord may contribute to the sensitization of L4 DRG neurons after L5 SNT. Electrical stimulation of low-threshold afferents proximal to the axotomized L5 spinal nerve attenuated the spontaneous activities in L4 DRG and pain behavior. These findings suggest that peripheral axotomy may quickly induce hyperexcitability of uninjured nociceptors in the adjacent DRG that drives an outburst of pain.
Learn More >Background and aims Chronic pain after traumatic injury and surgery is highly prevalent, and associated with substantial psychosocial co-morbidities and prolonged opioid use. It is currently unclear whether predicting chronic post-injury pain is possible. If so, it is unclear if predicting chronic post-injury pain requires a comprehensive set of variables or can be achieved only with data available from the electronic medical records. In this prospective study, we examined models to predict pain at the site of injury 3-6 months after hospital discharge among adult patients after major traumatic injury requiring surgery. Two models were developed: one with a comprehensive set of predictors and one based only on variables available in the electronic medical records. Methods We examined pre-injury and post-injury clinical variables, and clinical management of pain. Patients were interviewed to assess chronic pain, defined as the presence of pain at the site of injury. Prediction models were developed using forward stepwise regression, using follow-up surveys at 3-6 months. Potential predictors identified a priori were: age; sex; presence of pre-existing chronic pain; intensity of post-operative pain at 6 h; in-hospital opioid consumption; injury severity score (ISS); location of trauma, defined as body region; use of regional analgesia intra- and/or post-operatively; pre-trauma PROMIS Depression, Physical Function, and Anxiety scores; in-hospital Widespread Pain Index and Symptom Severity Score; and number of post-operative non-opioid medications. After the final model was developed, a reduced model, based only on variables available in the electronic medical record was run to understand the "value add" of variables taken from study-specific instruments. Results Of 173 patients who completed the baseline interview, 112 completed the follow-up within 3-6 months. The prevalence of chronic pain was 66%. Opioid use increased from 16% pre-injury to 28% at 3-6 months. The final model included six variables, from an initial set of 24 potential predictors. The apparent area under the ROC curve (AUROC) of 0.78 for predicting pain 3-6 months was optimism-corrected to 0.73. The reduced final model, using only data available from the electronic health records, included post-surgical pain score at 6 h, presence of a head injury, use of regional analgesia, and the number of post-operative non-opioid medications used for pain relief. This reduced model had an apparent AUROC of 0.76, optimism-corrected to 0.72. Conclusions Pain 3-6 months after trauma and surgery is highly prevalent and associated with an increase in opioid use. Chronic pain at the site of injury at 3-6 months after trauma and surgery may be predicted during hospitalization by using routinely collected clinical data. Implications If our model is validated in other populations, it would provide a tool that can be easily implemented by any provider with access to medical records. Patients at risk of developing chronic pain could be selected for studies on preventive strategies, thereby concentrating the interventions to patients who are most likely to transition to chronic pain.
Learn More >Previous research has shown that self-compassion is associated with improved functioning and health outcomes among multiple chronic illnesses. However, the role of self-compassion in chronic pain-related functioning is understudied. The present study sought to understand the association between self-compassion and important measures of functioning within a sample of patients with chronic pain. Treatment-seeking individuals (N= 343 with chronic pain) that were mostly White (97.9%) and female (71%) completed a battery of assessments that included the Self-Compassion Scale (SCS), as well as measures of pain-related fear, depression, disability, pain acceptance, success in valued activity, and use of pain coping strategies. Cross-sectional multiple regression analyses that controlled for age, sex, pain intensity, and pain duration, revealed that self-compassion accounted for a significant and unique amount of variance in all measures of functioning (r range: .07 – .32, all p < .001). Beta weights indicated that higher self-compassion was associated with lower pain-related fear, depression, and disability, as well as greater pain acceptance, success in valued activities, and utilization of pain coping strategies. These findings suggest that self-compassion may be a relevant adaptive process in those with chronic pain. Targeted interventions to improve self-compassion in those with chronic pain may be useful. SIGNIFICANCE: Self-compassion is associated with better functioning across multiple general and pain-specific outcomes, with the strongest associations among measures related to psychological functioning and valued living. These findings indicate that self-compassion may be an adaptive process that could minimize the negative impact of chronic pain on important areas of life. This article is protected by copyright. All rights reserved.
Learn More >To investigate the prevalence of anxiety, depression and mixed anxiety and depressive disorder (MADD) and factors associated with these conditions in women with chronic pelvic pain (CPP) compared to a pain-free control group. A cross-sectional study was conducted with 100 women with CPP and 100 without CPP. The Hospital Anxiety and Depression Scale (HADS) was used to evaluate the presence of anxiety and depression. Sociodemographic, behavioral and clinical characteristics were investigated. Fisher's exact test was used to compare characteristics between groups. A log-binomial regression model was used, with adjustment for age, skin color, schooling, body mass index and pain. Prevalence ratios (PR), together with their 95% confidence intervals (CI), were calculated to investigate factors associated with anxiety, depression and MADD. The prevalence of anxiety was 66% in the CPP group and 49% in the controls (=0.02). Depression was identified in 63% of the women with CPP and in 38% of the controls (<0.01). MADD was present in 54% of the CPP group and in 28% of the controls (<0.01). In the adjusted analysis, CPP (PR=1.3; 95%CI: 1.1-1.6), physical abuse (PR=1.5; 95%CI: 1.2-1.8) and sexual abuse (PR=1.5; 95%CI: 1.1-1.8) were independently associated with anxiety. Women of 25 to 34 years of age were less likely to have anxiety (PR=0.6; 95%CI: 0.4-0.8). CPP (PR=1.6; 95%CI: 1.2-2.2), physical abuse (PR=1.3; 95%CI: 1.1-1.7) and sexual abuse (PR=1.7; 95%CI: 1.3-2.2) were independently associated with depression. CPP (PR=1.9; 95%CI: 1.3-2.7), smoking (PR=1.5; 95%CI: 1.1-2.1), physical abuse (PR=1.4; 95%CI: 1.1-1.9) and sexual abuse (PR=1.4; 95%CI: 1.1-1.8) were independently associated with MADD. The prevalence of anxiety, depression and MADD was higher in women with CPP compared to the pain-free controls. Factors associated with mental disorders were identified. The independent association between CPP and anxiety, depression and MADD was noteworthy. These findings suggest that systematic management of psychological factors could contribute towards improving the mental health of these women.
Learn More >Complex regional pain syndrome type-I (CRPS-I) is a progressive and devastating pain condition, which remains clinically challenging. The mechanisms of CRPS-I still remain largely unknown. We aim to identify transcriptome profiles of genes relevant to pain mechanisms and major pathways involved in CRPS-I. A rat model of chronic post-ischemia pain (CPIP) was established to mimic CRPS-I. RNA-sequencing (RNA-Seq) was used to profile transcriptome of L4-6 dorsal root ganglia (DRGs) of a rat model of CRPS-I. CPIP model rats developed persistent mechanical/thermal hyperalgesia in ipsilateral hind paw. RNA-Seq identified a total of 295 differentially expressed genes (DEGs), including 195 up- and 100 downregulated, in ipsilateral DRGs of CPIP rats compared with sham rats. The expression of several representative genes was confirmed by qPCR. Functional analysis of DEGs revealed that the most significant enriched biological processes of upregulated genes include response to lipopolysaccharide, inflammatory response and cytokine activity, which are all important mechanisms mediating pain. We further screened DEGs implicated in pain progress, genes enriched in small- to medium-sized sensory neurons and enriched in TRPV1-lineage nociceptors. By comparing our dataset with other published datasets of neuropathic or inflammatory pain models, we identified a core set of genes and pathways that extensively participate in CPIP and other neuropathic pain states. Our study identified transcriptome gene changes in DRGs of an animal model of CRPS-I and could provide insights into identifying promising genes or pathways that can be potentially targeted to ameliorate CRPS-I.
Learn More >Pain catastrophizing is reliably associated with pain reports during experimental pain in healthy, pain-free subjects and in people with chronic pain. It also correlates with self-reports of clinical pain intensity/severity in a variety of disorders characterized by chronic pain in adults, adolescents and children. However, processes, through which it exerts its effects are yet unclear. In this paper, our primary aim was to synthesize neuroimaging research to open a window to possible mechanisms underlying pain catastrophizing in both chronic pain patients and healthy controls. We also aimed to compare whether the neural correlates of pain catastrophizing are similar in these two groups. PubMed and the Web of Science were searched for magnetic resonance imaging (MRI) studies that explored neural correlates of pain catastrophizing. Twenty articles met the inclusion criteria. The results of our review show a connection between pain catastrophizing and brain areas tightly connected to pain perception (including the somatosensory cortices, anterior insula, anterior cingulate cortex and thalamus) and/or modulation (eg, the dorsolateral prefrontal cortex). Our results also highlight that these processes – in relation to pain catastrophizing – are more pronounced in chronic pain patients, suggesting that structural and functional brain alterations (and perhaps mechanisms) related to pain catastrophizing may depend on prior and/or relatively stable/constant pain experience. However, we also found methodological issues and differences that could lead to divergent results. : Based on our results, pain catastrophizing might be related to salience detection, pain processing, and top-down attentional processes. More research is recommended to explore neural changes to specific types of catastrophizing thoughts (eg, experimentally induced and/or state). Furthermore, we provide ideas regarding pain catastrophizing studies in the future for a more standardized approach.
Learn More >The diagnosis of neuropathic pruritus (NP) may be difficult. The aim of this study was to compare the characteristics of both neuropathic pruritus and non-neuropathic pruritus (NNP) in order to elaborate a tool to help the diagnosis of NP without clinical examination. One hundred and seven patients were included: Fifty three in the NP group and Fifty four in the NNP group. In multiple regression, presence of twinges, absence of burning, worsening with activity, no worsening with stress, and relief with cold ambient temperature were independent factors that were associated with NP. A score of two criteria out of five was optimal to discriminate NP from NNP with a sensitivity of 76% and a specificity of 77%. Alloknesis, hyperknesis, or the ice cube test were not included because their evaluation is based on clinical examination. Future high-powered studies are needed to confirm the results of the present study.
Learn More >There is an unmet medical need for non-opioid pain therapies in human populations; several pathways are under investigation for possible therapeutic intervention. Tetrahydrobiopterin (BH4) has received attention recently as a mediator of neuropathic pain. Recent reports have implicated sepiapterin reductase (SPR) in this pain pathway as a regulator of BH4 production. To evaluate the role of SPR inhibition on BH4 reduction, we developed analytical methods to monitor the relationship between the plasma concentration of test article and endogenous pterins and applied these in the rat spinal nerve ligation pain model. Sepiapterin is an endogenous substrate, which accumulates upon inhibition of SPR. In response to a potent inhibitor of SPR, plasma concentrations of sepiapterin increased proportionally with exposure. An indirect effect PK/PD model was developed to describe the relationship between the plasma PK of test article and plasma sepiapterin levels in the rat, which was used to determine an in vivo SPR IC value. Evaluation of SPR inhibition and mechanical allodynia was assessed coordinately with pterin biomarkers in plasma and at the site of neuronal injury (i.e., dorsal root ganglion). Upon QD p.o. administration for 3 consecutive days, unbound plasma concentrations of test article exceeded the unbound in vivo rat SPR IC throughout the dose intervals leading to a 60% reduction in BH4 in the dorsal root ganglion. Despite evidence for pharmacological modulation of the BH4 pathway, there was no significant effect on the tactile paw withdrawal threshold relative to vehicle-treated controls. SIGNIFICANCE STATEMENT: N/A.
Learn More >The progressive increase in the prevalence of obesity in the population has resulted in increased healthcare costs and demands. Recent studies have revealed a positive correlation between pain and obesity, although the underlying mechanisms still remain unknown. Here, we aimed to clarify the role of microglia in altered pain behaviors induced by a high-fat diet (HFD) in male mice. We found that C57BL/6CR mice on a HFD exhibited spinal microglial reaction (increased cell number and up-regulated expression of p-p38 and CD16/32), increased tumor necrosis factor-α (TNF-α) mRNA and brain-derived neurotrophic factor (BDNF) protein as well as a polarization of spinal microglial toward a pro-inflammatory phenotype. Moreover, we found that when applied PLX3397 (a selective colony-stimulating factor-1 receptor (CSF1R) kinase inhibitor) to eliminate microglia of HFD-induced obesity mice, inflammation in the spinal cord was rescued, as were abnormal pain hypersensitivity. Intrathecal injection of Mac-1-saporin (a saporin-conjugated anti-mac1 antibody) resulted in decreased microglia and attenuated both mechanical allodynia and thermal hyperalgesia in HFD-fed mice. These results indicate that the pro-inflammatory functions of spinal microglia have a special relevance to abnormal pain hypersensitivity in HFD-induced obesity mice. In conclusion, our data suggest that HFD induces a classical reaction of microglia, characterized by an enhanced phosphorylation of p-38 and increased CD16/32 expression, which may in part contribute to increased nociceptive responses in HFD-induced obesity mice.
Learn More >Case reports and a case series have described relief of neuropathic pain (NP) after treatment with epidermal growth factor receptor inhibitors (EGFR-Is). These observations are supported by preclinical findings. The aim of this trial was to explore a potential clinical signal supporting the therapeutic efficacy of EGFR-Is in NP.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a progressive, often irreversible condition that produces severe neurological deficits. Emerging data suggest that chemotherapy also exerts detrimental effects on gut microbiota composition and intestinal permeability, contributing to dysbiosis and inflammation. Compared with other complications associated with chemotherapy, such as diarrhoea and mucositis, CIPN is of particular concern because it is the most common reason for terminating or suspending treatment. However, specific and effective curative treatment strategies are lacking. In this review, we provide an update on current preclinical and clinical understandings about the role of gut microbiota in CIPN. The gut microbiota serves as an intersection between the microbiome-gut-brain and the neuroimmune-endocrine axis, forming a complex network that can directly or indirectly affect key components involved in the manifestations of CIPN. Herein, we discuss several potential mechanisms within the context of the networks and summarize alterations in gut microbiome induced by chemotherapeutic drugs, providing great potential for researchers to target pathways associated with the gut microbiome and overcome CIPN.
Learn More >The phase III research evaluating migraine prophylaxis therapy (PREEMPT) protocol was developed in low-risk migraine patients. We studied longitudinal response to treatment in a sequential retrospective observational cohort to evaluate predictors of effectiveness in patients with multiple overlapping pain syndromes treated in a quaternary pain management clinic.
Learn More >Long-term trials are key to understanding chronic symptoms such as pain and itch. However, challenges such as high attrition rates and poor recruitment are common when conducting research. The aim of this work is to explore these issues within a long-term randomized control trial using transcranial direct current stimulation to treat pain and itch. This parallel double blinded, placebo-controlled randomized trial was comprised of 15 transcranial direct current stimulation visits and 7 follow-up visits. Participants were over the age of 18, had a burn injury that occurred at least 3 weeks prior to enrollment, and reported having pain and/or itch that was moderate to severe in intensity. A total of 31 subjects were randomized into either an active or sham transcranial direct current stimulation groups. There were no significant differences between the groups in terms of age, race, education, baseline depression, or anxiety. The median dropout time was at visit 19 [visit 16 (SE=1.98) for the sham group and visit 19 (SE=1.98) for the active group]. Analysis showed no differences in the dropout rate between groups (χ2(1)=0.003, p=0.954). The dropout rate was 46.7% for the sham group and 43.8% for the active group. Overall, 45.2% of the subjects dropped out of the trial. Long-term clinical trials are an essential part of evaluating interventions for symptoms such as chronic pain and itch. However, as seen in this trial, long-term studies in the burn population often face recruitment and adherence challenges.
Learn More >Neuropathic pain, resulting from injury to the peripheral or central nervous system, is due to upregulation of aberrant sodium channels with neuronal hyperexcitability. Lidocaine blocks these channels and several studies show that intravenous (IV) lidocaine infusion provides significant relief in patients with chronic peripheral neuropathic pain in the short term (for up to six hours). Our objective was to determine if IV lidocaine provides significant pain relief and overall improvement in quality of life in the longer term (for up to four weeks).
Learn More >Osteoarthritis, the leading cause of chronic joint pain, is studied through different animal models, but none of them is ideal in terms of reliability and translational value. In this pilot study of female rats, 3 surgical models of osteoarthritic pain, destabilization of the medial meniscus (DMM), cranial cruciate ligament transection (CCLT), and the combination of both surgical models (COMBO) and 1 chemical model [intra-articular injection of monosodium iodoacetate (MIA)] were compared for their impact on functional pain outcomes [static weight-bearing (SWB) and punctate tactile paw withdrawal threshold (PWT)] and spinal neuropeptides [substance P (SP), calcitonin gene-related peptide (CGRP), bradykinin (BK), and somatostatin (SST)]. Six rats were assigned to each model group and a sham group. Both the chemical model (MIA) and surgical COMBO model induced functional alterations in SWB and PWT, with the changes being more persistent in the surgical combination group. Both models also produced an increase in levels of pro-nociceptive and anti-nociceptive neuropeptides at different timepoints. Pain comparison with the MIA model showed the advantage of a surgical model, especially the combination of the DMM and CCLT models, whereas each surgical model alone only led to temporary functional alterations and no change in neuropeptidomics.
Learn More >Brainstem raphe (BR) hypoechogenicity in transcranial sonography (TCS) has been depicted in patients with major depression (MD) and in depressed patients with different neurodegenerative diseases. But, up to date, the association of BR alterations in TCS with depression in migraineurs has never been reported. This study was to investigate the possible role of BR examination via TCS in migraineurs with depression.
Learn More >Vasculitic peripheral neuropathy (VPN) is characterized by acute-to-subacute onset of painful sensory and motor disturbances that result from inflammatory obliteration of nerve blood vessels and subsequent ischaemic injury. Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of various peripheral neuropathies, and 4-phenylbutyric acid (4-PBA) is a chemical chaperone that inhibits ER stress signaling. We investigated the effects of 4-PBA on neuropathic pain associated with VPN induced by ischaemia-reperfusion (IR) and its underlying mechanisms. Male Sprague-Dawley rats were allocated to one of the following groups: sham, sham + 4-PBA, IR, and IR + 4-PBA. IR was achieved by occluding the femoral artery for 4 h followed by reperfusion. The behavioral parameters were assessed, and the expression of ER stress markers and nuclear factor (NF)-κB in sciatic nerves was measured. The behavioral data confirmed that VPN induced by IR leads to hindpaw mechano-allodynia and heat hyperalgesia as well as impaired hindpaw grip strength, indicating the development of neuropathic pain and debilitating symptoms of VPN. The molecular data revealed that VPN induced by IR activated ER stress sensors and effector molecules as well as NF-κB in the sciatic nerves, indicating the involvement of ER stress and NF-κB-mediated neuroinflammation. Notably, 4-PBA significantly reduced the expression of all these markers and improved all behavioral changes induced by IR. This study demonstrated that ER stress and NF-κB-mediated neuroinflammation contribute to VPN induced by IR and that 4-PBA has protective potential against neuropathic pain associated with VPN.
Learn More >Preemptive analgesia encompasses different perioperative interventions that have the final aim of decreasing postoperative pain and improving recovery. Recently, peripheral analgesic effects of oxytocinergic modulation have been suggested. In this regard, we tested the potential analgesic effects of subcutaneous oxytocin (OT) infiltration in patients submitted to laparoscopic cholecystectomy.
Learn More >This study was designed to investigate the expression of transient receptor potential melastatin 3 (TRPM3) and transient receptor potential vanilloid type 4 (TRPV4) in the trigeminal spinal subnucleus caudalis of a rat model of trigeminal neuralgia (TN). The influence of botulinum toxin type A (BTX-A) on the expression of these channels was also explored. In this study, a model was established involving chronic constriction injury to the infraorbital nerve (ION-CCI), inducing TN. To explore the effects of BTX-A and whether it was dose related, rats were divided randomly into four groups: a control group, an ION-CCI group, a 3 U group, and a 10 U group (which received 3 and 10 U/kg BTX-A injections, respectively). Von Frey hairs were used to determine the pain threshold of the rats. The expression of TRPM3 and TRPV4 in the trigeminal spinal subnucleus caudalis was detected using western blots and immunohistochemistry. The pain thresholds of rats decreased to a minimum 14 days after ION-CCI. Compared with the ION-CCI group, the pain thresholds of the 3 and 10 U groups were significantly higher 4 days after the subcutaneous injection of BTX-A (P<0.05). The expression of TRPM3 and TRPV4 in the ION-CCI group was significantly higher than that in the control group (P<0.05). TRPM3 and TRPV4 expression in the 3 and 10 U groups was significantly lower than that in the ION-CCI group (P<0.05). In conclusion, overexpression of TRPM3 and TRPV4 can jointly mediate the occurrence of mechanical hyperalgesia in TN. The analgesic effects of BTX-A may be related to the inhibition of TRPM3 and TRPV4 expression.
Learn More >Medically unexplained pain in children and adolescents is a common and increasing health care problem. Primary care is usually the first point of contact for these patients. It is the overall objective of this study to investigate treatment outcome of medically unexplained pain in pediatric primary care and to identify predictors of treatment failure.
Learn More >Periodontitis (PD) and chronic migraine (CM) have been recently linked, and inflammatory processes and vascular endothelial changes are hypothesized as potential mediators of this relationship. The aim of this cross-sectional analysis was to investigate the potential association of PD with vascular systemic inflammation and complement activation in patients with CM.
Learn More >High mobility group box-1 (HMGB1), a representative damage associated-molecular pattern (DAMP), has been reported to be involved in many inflammatory diseases. Several drugs are thought to have potential to control the translocation and secretion of HMGB1, or to neutralize extracellular HMGB1 by binding to it. One of these drugs, anti-HMGB1 monoclonal antibody (mAb), is highly specific for HMGB1 and has been shown to be effective for the treatment of a wide range of CNS diseases when modeled in animals, including stroke, traumatic brain injury, Parkinson's disease, epilepsy and Alzheimer's disease. Thus, anti-HMGB1 mAb not only is useful for target validation but also has extensive potential for the treatment of the above-mentioned diseases. In this review, we summarize existing knowledge on the effects of anti-HMGB1 mAb on CNS and PNS diseases, the common features of translocation and secretion of HMGB1 and the functional roles of HMGB1 in these diseases. The existing literature suggests that anti-HMGB1 mAb therapy would be effective for a wide range of CNS and PNS diseases.
Learn More >The American College of Rheumatology (ACR) 2016 criteria for fibromyalgia (FM) is recommended for use in primary and referral setting. However, neither the ACR 2016 nor its predecessor ACR 2010 criteria have been validated in a referral setting. We hypothesized that the presence of higher comorbidities in the referral care setting may affect the performance of the ACR 2016. All patients referred to a tertiary care hospital with widespread pain for more than 3 months were screened using (1) the ACR 2016 criteria and (2) by a blinded expert physician (using ACR 1990 criteria). Using the ACR 1990 as reference standard, the sensitivity and specificity were calculated. Also, concomitant depression (BPHQ: Brief Patient Health Questionnaire), anxiety disorder (GAD7: Generalized Anxiety Disorder-7) and alexithymia (TAS-20: Toronto Alexithymia Scale-20) were screened for using standardized instruments. Other central sensitization syndromes were also screened clinically. Of 147 patients (132 females; median age 36 [30-45] years, median symptom duration 4 [1-6] years), 112 met the ACR 1990 criteria while 93 met the ACR 2016 criteria. There was disagreement between the two criteria in 47 patients. The sensitivity and specificity of ACR 2016 were 71% and 60%, respectively. Patients diagnosed by ACR 2016 criteria alone, had higher GAD7 scores than those diagnosed by the ACR 1990 alone. However, BPHQ and TAS-20 did not differ between the groups. Patients diagnosed by the ACR 2016 criteria had a greater odds (OR 5.2 CI 1.3-21.7, p = 0.022) of having concomitant restless leg syndrome or post-traumatic stress disorder or chronic fatigue syndrome. The sensitivity/specificity of the ACR 2016 in tertiary settings matched those found in previous primary care-based studies. Thus, the ACR 2016 criteria are valid for use in the tertiary setting. However, patients diagnosed by only the ACR 2016 criteria (and not by the ACR 1990) have high probability of having another concomitant comorbidity.
Learn More >Mitragyna speciosa (kratom) may hold promise as both an analgesic and treatment for opioid use disorder. Mitragynine, its primary alkaloid constituent, is an opioid receptor ligand. However, the extent to which the in vivo effects of mitragynine are mediated by opioid receptors, or whether mitragynine interacts with other opioid agonists, is not fully established.
Learn More >OBJECTIVETrigeminal neuralgia (TN) is facial pain that is usually caused by neurovascular compression syndrome and is characterized by suddenly intense and paroxysmal pain. Radiofrequency lesioning (RFL) is one of the major treatments for TN, but the treatment response for RFL is sometimes inconsistent, and the recurrence of TN is not uncommon. This study aimed to estimate the outcome predictors of TN treated with RFL by using the parameters of diffusion tensor imaging (DTI).METHODSFifty-one patients with TN who were treated with RFL were enrolled in the study. MRI was performed in all patients within 1 week before surgery. The visual analog scale was used to evaluate symptom severity at three time points: before, 1 week after, and 3 months after RFL. The involved cisternal segment of the trigeminal nerves was manually selected, and the histograms of each of the diffusivity metrics-including the apparent diffusion coefficient (ADC), fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD)-were measured. The differences in the means, as well as the kurtosis and skewness of each of the diffusivity metrics between the nonrecurrent and recurrent groups, were then analyzed using the Mann-Whitney U-test.RESULTSThere were significantly lower kurtosis values (a broader peak of the distributional curves) for both FA and ADC in the recurrent group (p = 0.0004 and 0.015, respectively), compared to the nonrecurrent group. The kurtoses of AD and RD, as well as the mean and skewness of all other diffusivity metrics, did not show significant differences between the two groups.CONCLUSIONSThe pretreatment diffusivity metrics of DTI and ADC may be feasible imaging biomarkers for predicting the outcome of TN after RFL. A clarification of the kurtosis value of FA and ADC is helpful for determining the prognosis of patients after RFL.
Learn More >The administration of opioids has been used for centuries as a viable option for pain management. When administered at appropriate doses, opioids prove effective not only at eliminating pain but further preventing its recurrence in long-term recovery scenarios. Physicians have complied with the appropriate management of acute and chronic pain; however, this short or long-term opioid exposure provides opportunities for long-term opioid misuse and abuse, leading to addiction of patients who receive an opioid prescription and/or diversion of this pain medication to other people without prescription. Several reviews attempted to summarize the epidemiology and management of opioid misuse, this integrative review seeks to summarize the current literature related with responsible parties of this opioid abuse crisis and discuss potential associations between demographics (ethnicity, culture, gender, religion) and opioid accessibility, abuse and overdose.
Learn More >Intervertebral disc degeneration is a major cause of chronic low back pain, and excessive loading contributes to intervertebral disc degeneration. However, the lack of an effective bipedal in vivo animal model limits research about this condition.
Learn More >Neuropathic pain (NP) is ranked as one of the major forms of chronic pain and emerges as a direct consequence of a lesion or disease affecting the somatosensory nervous system. Despite great advances into the mechanisms of NP, clinical practice is still not satisfactory. Fortunately, progress in elucidating unique features and multiple molecular mechanisms of long non-coding RNAs (lncRNAs) in NP has emerged in the past 10 years, suggesting that novel therapeutic strategies for pain treatment may be proposed. In this review, we will concentrate on recent studies associated with lncRNAs in NP. First, we will describe the alterations of lncRNA expression after spinal cord injury (SCI) and peripheral nerve injury (PNI), and then we illustrate the role of some specific lncRNAs in detail, which may offer new insights into our understanding of the etiology and pathophysiology of NP. Finally, we put special emphasis on the altered expression of lncRNAs in the diverse biological process of NP. Recent advances we summarized above in the development of NP may facilitate translation of these findings from bench to bedside in the future.
Learn More >Although biomechanics play a role in the development of low back pain (LBP), and perhaps in the persistent and/or recurrent nature of LBP, there is debate regarding whether biomechanics alone can provide the basis for intervention. Biomechanics, which refers to the mechanics of the body including its neuromuscular control, has been extensively studied in LBP. But, can gains be made in understanding LBP by research focused on this component of the biology in the multifactorial bio-psycho-social problem of LBP? This commentary considers whether biomechanics research has the potential to advance treatment of LBP, and how likely it is that this research will lead to better treatment strategies for LBP. A viewpoint-counterpoint format is taken to present both sides of the argument. This is considered first from the perspective of the challenges faced by an approach that considers biomechanics in isolation. Second, 3 models are described that place substantial emphasis on biomechanical factors. Third, reactions to each viewpoint are presented as a foundation for further research and clinical practice to progress understanding of the place for biomechanics in guiding treatment for LBP. .
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