Browse by Audience
Neuropathic pain encompasses a diverse array of clinical entities affecting 7-10% of the population, which is challenging to adequately treat. Several promising therapeutics derived from molecular discoveries in animal models of neuropathic pain have failed to translate following unsuccessful clinical trials suggesting the possibility of important cellular-level and molecular differences between animals and humans. Establishing the extent of potential differences between laboratory animals and humans, through direct study of human tissues and/or cells, is likely important in facilitating translation of preclinical discoveries to meaningful treatments. Patch-clamp electrophysiology and RNA-sequencing was performed on dorsal root ganglia taken from patients with variable presence of radicular/neuropathic pain. Findings establish that spontaneous action potential generation in dorsal root ganglion neurons is associated with radicular/neuropathic pain and radiographic nerve root compression. Transcriptome analysis suggests presence of sex-specific differences and reveals gene modules and signalling pathways in immune response and neuronal plasticity related to radicular/neuropathic pain that may suggest therapeutic avenues and that has the potential to predict neuropathic pain in future cohorts.
Learn More >Negative affective states affect quality of life for patients suffering from pain. These maladaptive emotional states can lead to involuntary opioid overdose and many neuropsychiatric comorbidities. Uncovering the mechanisms responsible for pain-induced negative affect is critical in addressing these comorbid outcomes. The nucleus accumbens (NAc) shell, which integrates the aversive and rewarding valence of stimuli, exhibits plastic adaptations in the presence of pain. In discrete regions of the NAc, activation of the kappa opioid receptor (KOR) decreases the reinforcing properties of rewards and induces aversive behaviors. Using complementary techniques, we report that in vivo recruitment of NAc shell dynorphin neurons, acting through KOR, is necessary and sufficient to drive pain-induced negative affect. Taken together, our results provide evidence that pain-induced adaptations in the kappa opioid system within the NAc shell represent a functional target for therapeutic intervention that could circumvent pain-induced affective disorders.
Learn More >Pain is a hallmark of tissue injury, inflammatory diseases, pathogen invasion and neuropathy. It is mediated by nociceptor sensory neurons that innervate the skin, joints, bones, muscles and mucosal tissues and protects organisms from noxious stimuli. Nociceptors are sensitized by inflammatory mediators produced by the immune system, including cytokines, lipid mediators and growth factors, and can also directly detect pathogens and their secreted products to produce pain during infection. Upon activation, nociceptors release neuropeptides from their terminals that potently shape the function of innate and adaptive immune cells. For some pathogens, neuron-immune interactions enhance host protection from infection, but for other pathogens, neuron-immune signalling pathways can be exploited to facilitate pathogen survival. Here, we discuss the role of nociceptor interactions with the immune system in pain and infection and how understanding these pathways could produce new approaches to treat infectious diseases and chronic pain.
Learn More >Sex differences in gene expression are important contributors to normal physiology and mechanisms of disease. This is increasingly apparent in understanding and potentially treating chronic pain where molecular mechanisms driving sex differences in neuronal plasticity are giving new insight into why certain chronic pain disorders preferentially affect women vs. men. Large transcriptomic resources are now available and can be used to mine for sex differences to gather insight from molecular profiles using donor cohorts. We performed in-depth analysis of 248 human tibial nerve (hTN) transcriptomes from the GTEx Consortium project to gain insight into sex-dependent gene expression in the peripheral nervous system (PNS). We discover 149 genes with sex differential gene expression. Many of the more abundant genes in men are associated with inflammation and appear to be primarily expressed by glia or immune cells, with some genes downstream of Notch signaling. In women, we find the differentially expressed transcription factor SP4 that is known to drive a regulatory program, and may impact sex differences in PNS physiology. Many of these 149 differentially expressed (DE) genes have some previous association with chronic pain but few of them have been explored thoroughly. Additionally, using clinical data in the GTEx database, we identify a subset of DE, sexually dimorphic genes in diseases associated with chronic pain: arthritis and Type II diabetes. Our work creates a unique resource that identifies sexually dimorphic gene expression in the human PNS with implications for discovery of sex-specific pain mechanisms.
Learn More >Current guidelines for addressing opioid cessation in the context of chronic pain management recommend that opioids be discontinued if the risks outweigh the benefits. However, few studies have focused on understanding opioid cessation from the perspective of individuals with chronic pain. This mixed-method study included 49 former opioid users with chronic pain and used quantitative survey data and qualitative focus group data to identify themes pertaining to former opioid user's experience before, during, and after opioid cessation. Participants described several reasons for wanting to stop opioids including lack of efficacy, impact on quality of life, and concerns about addiction. Barriers to cessation included concerns about inadequate pain management and concerns about the impact of stopping opioids on mood. After opioid cessation, the sample was mixed regarding the benefit of cessation. Half of the former opioid users reported their pain to be better or the same after stopping opioids; however, 47% of the sample reported feeling worse pain since stopping their opioids. As the pendulum swings from pain control to drug control, we must ensure that the response to the opioid epidemic does not cause harm to individuals with chronic pain. Novel opioid cessation interventions are needed in combination with methods of addressing individual challenges and barriers to adequate pain relief including access to and provision of nonopioid alternatives for pain management.
Learn More >Cross-sectional studies confirm, as expected, a positive association between jaw injury and painful temporomandibular disorders (TMDs), but prospective evaluations are lacking. We prospectively assessed incident jaw injury, injury type, and development of TMD in adults ages 18-44 years.Data were collected from 3,258 individuals from communities surrounding four U.S. academic institutes between 2006 and 2008. At enrollment, participants reported no TMD history and no facial injuries in the previous 6 months. Quarterly follow-up questionnaires assessed incident jaw injury, which was classified as intrinsic (attributed to yawning or prolonged mouth opening) or extrinsic (attributed to other causes). Examiners classified incident TMD during a median follow-up period of 2.8 years (range 0.2-5.2 years). Cox regression models used jaw injury as a time-dependent covariate to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association with incident TMD.Among 1,729 participants with complete data, 175 developed TMD. Eighty percent of injuries were intrinsic. TMD annual incidence was nearly twice as high in those experiencing jaw injury (5.37%) compared to those who did not (3.44%). In the Cox model that accounted for timing of injury, the corresponding HR was 3.94 (95%CI=2.82-5.50) after adjusting for study site, age, race, and gender. Hazard ratios did not differ (p=0.91) for extrinsic injuries (HR=4.03, 95%CI=2.00-8.12) and intrinsic injuries (HR=3.85, 95%CI=2.70-5.49).Jaw injury was strongly associated with incident TMD. If surveillance and intervention following jaw injury is to be effective in preventing TMD, they should focus on both intrinsic and extrinsic injuries.
Learn More >Chronic eye pain, which has previously been assumed to be due to ocular surface abnormalities (i.e., "dry eye disease"), has recently garnered attention as a potential indicator of neuropathic ocular pain in some patients. The purpose of this study was to evaluate the psychometric properties of a modified version of the Neuropathic Pain Symptom Inventory in individuals with eye pain (NPSI-Eye). Enrolled participants (n = 397) completed the NPSI-Eye, general pain severity questionnaires, dry eye symptom report, and psychological health indices. Participants also underwent mechanical pain sensitivity testing of the cornea, tear film assessment, and evaluation of the efficacy of anesthetic eye drops to relieve pain. Short-term test-retest reliability of the NPSI-Eye was excellent (intraclass correlation coefficient = 0.98, p < 0.001). Correlations between the NPSI-Eye and indicators of general eye pain were ≥ 0.65 (p < 0.001), while correlations between the NPSI-Eye and dry eye symptom severity and psychological health indices were lower (rho= 0.56, 0.32, 0.37; all p < 0.001). Individuals who reported little or no decrease in pain after anesthetic eye drops (hypothesized to indicate eye pain with at least partial central involvement) had significantly higher NPSI-Eye scores than participants whose eye pain was completely relieved by anesthetic (p < 0.05). Overall, our results support preliminary validation of the NPSI-Eye, yielding similar metrics to those reported in Bouhassira et al.'s original NPSI publication (2004). However, additional evaluation and refinement of some questions may be desirable, including the potential elimination of items that were not highly endorsed.
Learn More >Risk of opioid use disorder, overdose, and death from prescription opioids increases as dosage, duration, and use of extended-release and long-acting formulations increase. States are well suited to respond to the opioid crisis through legislation, regulations, enforcement, surveillance, and other interventions.
Learn More >The primary objective of preclinical pain research is to improve the treatment of pain. Decades of research using pain-evoked tests has revealed much about mechanisms but failed to deliver new treatments. Evoked pain-tests are often limited because they ignore spontaneous pain and motor or disruptive side effects confound interpretation of results. New tests have been developed to focus more closely on clinical goals such as reducing pathological pain and restoring function. The objective of this review is to describe and discuss several of these tests. We focus on: Grimace Scale, Operant Behavior, Wheel Running, Burrowing, Nesting, Home Cage Monitoring, Gait Analysis and Conditioned Place Preference/ Aversion. A brief description of each method is presented along with an analysis of the advantages and limitations. The pros and cons of each test will help researchers identify the assessment tool most appropriate to meet their particular objective to assess pain in rodents. These tests provide another tool to unravel the mechanisms underlying chronic pain and help overcome the translational gap in drug development.
Learn More >Psychological therapies for parents of children and adolescents with chronic illness aim to improve parenting behavior and mental health, child functioning (behavior/disability, mental health, and medical symptoms), and family functioning.This is an updated version of the original Cochrane Review (2012) which was first updated in 2015.
Learn More >With a widespread opioid epidemic and profound biopsychosocial implications, chronic pain is a multifaceted public health issue requiring urgent attention. The treatment of chronic pain is particularly important to anesthesiologists given our unique role as perioperative physicians and pain medicine specialists. The present review details the recent shift from a neuronal theory of chronic pain to one that includes complex neuron-glia interactions. In particular, we highlight microglia, the myeloid-lineage cells of the central nervous system, as initiators of a postinjury neuroimmune response that contributes to the acute to chronic pain transition. We discuss ever-advancing preclinical studies, wherein significant success has been made through pharmacologic and genetic modulation of microglia, and we emphasize where these approaches have made the transition to the clinical realm. Furthermore, we highlight the most current, novel efforts to visualize glial activation in vivo using positron emission tomography and improve the diagnosis of chronic pain through radiotracer binding of specific targets, like the 18 kDa translocator protein in microglia and myeloid-lineage cells. Our rapidly advancing knowledge about microglia and their involvement in pain suggests that the era of glial-targeted therapeutics is just beginning so long as we refocus our attention on optimizing preclinical studies using a clinically informed approach, before translation.
Learn More >Although critical for informed consent, side effect warnings can contribute directly to poorer patient outcomes because they often induce negative expectations that trigger nocebo side effects. Communication strategies that reduce the development of nocebo side effects whilst maintaining informed consent are therefore of considerable interest. We reviewed theoretical and empirical evidence for the use of framing strategies to achieve this. Framing refers to the way in which information about the likelihood or significance of side effects is presented (e.g., negative frame: 30% experience headache vs. positive frame: 70% will experience headache), with the rationale that positively framing such information could diminish nocebo side effects. Relatively few empirical studies ( = 6) have tested whether framing strategies can reduce nocebo side effects. Of these, four used attribute framing and two message framing. All but one of the studies found a significant framing effect on at least one aspect of side effects (e.g., experience, attribution, threat), suggesting that framing is a promising strategy for reducing nocebo effects. However, our review also revealed some important open questions regarding these types of framing effects, including, the best method of communicating side effects (written, oral, pictorial), optimal statistical presentation (e.g., frequencies vs. percentages), whether framing affects perceived absolute risk of side effects, and what psychological mechanisms underlie framing effects. Future research that addresses these open questions will be vital for understanding the circumstances in which framing are most likely to be effective.
Learn More >Pain is a major comorbidity of sickle cell disease (SCD). Opioids are the mainstay for pain treatment but remain suboptimal. We discuss mechanism-based treatable targets devoid of opioids to prevent and/or treat SCD pain.
Learn More >Current definitions of pain do not necessitate tissue damage. This is important because it does justice to the pain patient in whom a nociceptive source is not detectable. However, in conjunction with exciting findings regarding supraspinal pain modulation and a (perceived) failure of identifying nociceptive sources in individual patients, this might have led to a devaluation of the role of nociception for chronic pain. In this review, the relative importance of nociception versus psychological factors for chronic pain is examined by scrutinizing the example of pain present several months following surgical joint replacement for severe osteoarthritis.
Learn More >Each year, over 50 million Americans suffer from persistent pain, including debilitating headaches, joint pain, and severe back pain. Although morphine is amongst the most effective analgesics available for the management of severe pain, prolonged morphine treatment results in decreased analgesic efficacy (i.e., tolerance). Despite significant headway in the field, the mechanisms underlying the development of morphine tolerance are not well understood. The midbrain ventrolateral periaqueductal gray (vlPAG) is a primary neural substrate for the analgesic effects of morphine, as well as for the development of morphine tolerance. A growing body of literature indicates that activated glia (i.e., microglia and astrocytes) facilitate pain transmission and oppose morphine analgesia, making these cells important potential targets in the treatment of chronic pain. Morphine affects glia by binding to the innate immune receptor toll-like receptor 4 (TLR4), leading to the release of proinflammatory cytokines and opposition of morphine analgesia. Despite the established role of the vlPAG as an integral locus for the development of morphine tolerance, most studies have examined the role of glia activation within the spinal cord. Additionally, the role of TLR4 in the development of tolerance has not been elucidated. This review attempts to summarize what is known regarding the role of vlPAG glia and TLR4 in the development of morphine tolerance. These data, together, provide information about the mechanism by which central nervous system glia regulate morphine tolerance, and identify a potential therapeutic target for the enhancement of analgesic efficacy in the clinical treatment of chronic pain.
Learn More >The TRIUMPH study assessed the efficacy and safety of high-purity synthetic trans-capsaicin (CNTX-4975) in subjects with chronic osteoarthritis-associated moderate to severe knee pain.
Learn More >Complex regional pain syndrome (CRPS) is a debilitating condition where trauma to a limb results in devastating persistent pain that is disproportionate to the initial injury. The pathophysiology of CRPS remains unknown; however, accumulating evidence suggests it is an immunoneurological disorder, especially in light of evidence of auto-antibodies in ~ 30% of patients. Despite this, a systematic assessment of all circulating leukocyte populations in CRPS has never been performed.
Learn More >Sex has been speculated to be a predictor of the placebo and nocebo effect for many years, but whether this holds true or not has rarely been investigated. We utilized a placebo literature database on various aspects of the genuine placebo/nocebo response. In 2015, we had extracted 75 systematic reviews, meta-analyses, and meta-regressions performed in major medical areas (neurology, psychiatry, internal medicine). These meta-analyses were screened for whether sex/gender differences had been noted to contribute to the placebo/nocebo effect: in only 3 such analyses female sex was associated with a higher placebo effect, indicating poor evidence for a contribution of sex to it in RCTs. This was updated with another set of meta-analyses for the current review, but did not change the overall conclusion. The same holds true for 18 meta-analyses investigating adverse event (nocebo) reporting in RCT in the placebo arm of trials. We also screened our database for papers referring to sex/gender and the placebo effect in experimental studies, and identified 28 papers reporting 29 experiments. Their results can be summarized as follows: (a) Despite higher sensitivity of pain in females, placebo analgesia is easier to elicit in males; (b) It appears that conditioning is effective specifically eliciting nocebo effects; (c) Conditioning works specifically well to elicit placebo and nocebo effects in females and with nausea; (d) Verbal suggestions are not sufficient to induce analgesia in women, but work in men. These results will be discussed with respect to the question why nausea and pain may be prone to be responsive to sex/gender differences, while other symptoms are less. Lastly, we will discuss the apparent discrepancy between RCT with low relevance of sex, and higher relevance of sex in specific experimental settings. We argue that the placebo response is predominantly the result of a conditioning (learning) response in females, while in males it predominantly may be generated via (verbal) manipulating of expectancies. In RCT therefore, the net outcome of the intervention may be the same despite different mechanisms generating the placebo effect between the sexes, while in experimental work when both pathways are separated and explicitly explored, such differences may surface.
Learn More >Clinically, osteoarthritis (OA) pain is significantly associated with synovial inflammation. Identification of the mechanisms driving inflammation could reveal new targets to relieve this prevalent pain state. Herein, a role of polyadenylation in OA synovial samples was investigated, and the potential of the polyadenylation inhibitor cordycepin (3' deoxyadenosine) to inhibit inflammation as well as to reduce pain and structural OA progression were studied. Joint tissues from people with OA with high or low grade inflammation and non-arthritic post-mortem controls were analysed for the polyadenylation factor CPSF4 and inflammatory markers. Effects of cordycepin on pain behavior and joint pathology were studied in models of OA (intra-articular injection of monosodium iodoacetate in rats and surgical destabilisation of the medial meniscus in mice). Human monocyte-derived macrophages and a mouse macrophage cell line were used to determine effects of cordycepin on nuclear localisation of the inflammatory transcription factor NFĸB and polyadenylation factors (WDR33 and CPSF4). CPSF4 and NFκB expression were increased in synovia from OA patients with high grade inflammation. Cordycepin reduced pain behaviour, synovial inflammation and joint pathology in both OA models. Stimulation of macrophages induced nuclear localisation of NFĸB and polyadenylation factors, effects inhibited by cordycepin. Knockdown of polyadenylation factors also prevented nuclear localisation of NFĸB. The increased expression of polyadenylation factors in OA synovia indicates a new target for analgesia treatments. This is supported by the finding that polyadenylation factors are required for inflammation in macrophages and by the fact that the polyadenylation inhibitor cordycepin attenuates pain and pathology in models of OA.
Learn More >Migraine is a primary headache disorder and one of the most common and disabling neurological diseases worldwide. Genome-wide association studies have identified ≈40 genetic loci associated with migraine. How these and other genetic findings are used to expand our knowledge on the pathophysiological mechanism of common migraine and rare migraine variants will be discussed.
Learn More >Migraine causes more years of life lived with disability than almost any other condition in the world and can significantly impact the lives of individuals with migraine, their families, and society. The use of medication for the prevention of migraine is an integral component to reducing disability caused by migraine. There are many different drug classes that have been investigated and shown efficacy in migraine prophylaxis. This article examines several of the classes of medications that are used for migraine preventive treatment, specifically, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, serotonin antagonists, alpha-adrenergic agonists, and N-methyl-D-aspartic acid receptor antagonists.
Learn More >Neurological disorders are increasingly recognised as major causes of death and disability worldwide. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 is to provide the most comprehensive and up-to-date estimates of the global, regional, and national burden from neurological disorders.
Learn More >Biomarkers indicating characteristic alterations in the brains of pain patients would in comparison to behavioral examinations allow for earlier diagnoses of pain disease development, a more immediate monitoring of pain disease progression, and for the development of interventions to reverse or compensate for the alterations. To reveal causal relations between an observed alteration and the pain disease longitudinal examinations are essential. Resting-state fMRI examinations can readily be included in large longitudinal cohorts allowing to achieve sufficiently large patient samples even for rare diseases. Our literature review on longitudinal resting-state fMRI examinations of pain patients indicates that pain chronicity is predicted by alterations to the brain's reward system and default mode network. A brain wide reorganization of the resting-state networks is associated with the emergence of the chronic pain state. The functional connectivity of the left frontoparietal network predicts the evolution of pain intensity in the chronic state. Further investigations are necessary concerning the generalization of the biomarkers across the phases in pain development especially for the healthy state, across different pain etiologies, and their specificity to chronic pain. The currently acquired representative longitudinal cohorts will allow for clarification of those issues within the next decades.
Learn More >Depressive symptoms are common among individuals with chronic pain. Previous work suggests that chronic pain patients have difficulty regulating emotional responses, which is a risk factor for the development of major depressive disorder (MDD). Function of the mesocorticolimbic system, a neural network associated with reward processing, contributes to emotion regulation. This network's dysfunction has been described in chronic pain and MDD research and potentially underlies the relationship among emotion dysregulation, chronic pain, and MDD development. Given that mood induction paradigms have been used to measure emotion regulation, the present study examined intrinsic mesocorticolimbic functional connectivity (FC) after induced sad mood in individuals with and without chronic low back pain (cLBP). Thirty-three MDD-free individuals (17 cLBP) underwent resting-state scanning before and after sad memory-evoked mood induction. A Group [cLBP, healthy control (HC)] x Mood (Neutral, Sadness) repeated measures ANCOVA was conducted on seed-based FC data using a mesolimbic a priori region of interest. Interaction effects were identified in the orbital frontal cortex and inferior frontal gyrus [F = 21.07, p < .05. h = .5]. Whereas cLBP showed significantly greater FC between these two regions and the mesolimbic seed under neutral mood, FC among these regions increased in HC and decreased in cLBP under sad mood. Exploratory graph theory analyses further describe between-group differences in mesocorticolimbic network properties. Findings support previous literature describing mesocorticolimbic dysfunction in cLBP and demonstrate aberrant function in emotion regulation. Mesocorticolimbic dysfunction during emotion regulation might contribute to the development of certain depressive phenotypes in chronic pain patients.
Learn More >Therapeutic plasma exchange (PE) or plasmapheresis is an extracorporeal procedure employed to treat immunological disorders. Exosomes, nanosized vesicles of endosomal origin, mediate intercellular communication by transferring cargo proteins and nucleic acids and regulate many pathophysiological processes. Exosomal miRNAs are potential biomarkers due to their stability and dysregulation in diseases including complex regional pain syndrome (CRPS), a chronic pain disorder with persistent inflammation. A previous study showed that a subset of CRPS patients responded to PE.
Learn More >The methodology used for the application of repetitive transcranial magnetic stimulation (TMS) is such that it may induce a placebo effect. Respectively, adverse events (AEs) can occur when using a placebo, a phenomenon called nocebo. The primary aim of our meta-analysis is to establish the nocebo phenomena during TMS. Safety and tolerability of TMS were also studied.
Learn More >This review describes the pharmacology of each antidepressant class as it applies to migraine prevention, summarizes the evidence base for each medication, and describes relevant side effects and clinical considerations. Use of antidepressants for migraine prevention in clinical practice is also discussed.
Learn More >To compare somatosensory function profiles and psychologic factors in patients with primary burning mouth syndrome (BMS) and healthy controls and to evaluate correlations of subjective pain ratings with somatosensory and psychologic parameters.
Learn More >Descriptive analysis of secondary data.
Learn More >Cluster headache stands among the worst debilitating pain conditions. Available treatments for cluster headache have often disabling side effects, are not tolerated, or are ineffective. The management of drug-refractory chronic forms is challenging. New treatments are warranted and reported here.
Learn More >Background and aims Recent research indicates a previously unknown low-grade systemic or neurogenic inflammation in groups of chronic pain (CP) patients. Low-grade inflammation may have an important role in symptoms that have previously not been well depicted: widespread pain, tiredness and cognitive dysfunctions frequently seen in severely impaired CP patients. This study aimed to investigate the plasma inflammatory profile in a group of very complex CP patients at baseline and at a 1-year follow-up after participation in a cognitive behavior therapy (CBT)-based multimodal pain rehabilitation program (PRP). Methods Blood samples were collected from 52 well-characterized CP patients. Age- and sex-matched healthy blood donors served as controls. The samples were analyzed with a multiple Proximal Extension Analysis allowing a simultaneous analysis of 92 inflammation-related proteins consisting mainly of cytokines, chemokines and growth-factors. At follow-up, 1-year after participation in the RPR samples from 28 patients were analyzed. The results were confirmed by a multi-array technology that allows quantitative estimation. Results Clear signs of increased inflammatory activity were detected in the CP patients. Accepting a false discovery rate (FDR) of 5%, there were significant differences in 43/92 inflammatory biomarkers compared with the controls. In three biomarkers (CXCL5, SIRT2, AXIN1) the expression levels were elevated more than eight times. One year after the PRP, with the patients serving as their own controls, a significant decrease in overall inflammatory activity was found. Conclusions Our results indicate that the most impaired CP patients suffer from low-grade chronic systemic inflammation not described earlier with this level of detail. The results may have implications for a better understanding of the cluster of co-morbid symptoms described as the "sickness-syndrome" and the wide-spread pain seen in this group of patients. The decrease in inflammatory biomarkers noted at the follow-up after participation in the PRP may reflect the positive effects obtained on somatic and psycho-social mechanisms involved in the inflammatory process by a rehabilitation program. Besides the PRP, no major changes in medication or lifestyle factors were implemented during the same period. To our knowledge, this is the first study reporting that a PRP may induce inflammatory-reducing effects. Further studies are needed to verify the objective findings in CP patients and address the question of causality that remains to be solved. Implications The findings offer a new insight into the complicated biological processes underlying CP. It may have implications for the understanding of symptoms collectively described as the "sickness-syndrome" – frequently seen in this group of patients. The lowering of cytokines after the participation in a PRP indicate a new way to evaluate this treatment; by measuring inflammatory biomarkers.
Learn More >Tanezumab, a humanized monoclonal anti-NGF antibody, has demonstrated efficacy and safety profiles in Phase III clinical trials of chronic pain. In a 24-week study in non-human primates, morphological observations of sympathetic ganglia showed decreased ganglia volume, decreased neuronal size, and increased glial cell density compared with controls after 3 tanezumab treatments. Using stereological techniques to quantify glial cells, the present 26-week study found no significant difference after weekly treatments in total cervicothoracic ganglia satellite glial cell number between placebo- or tanezumab-treated cynomolgus monkeys. These findings suggest that tanezumab treatment does not result in a true gliosis in sympathetic ganglia.
Learn More >Herpes simplex virus-type 1 (HSV-1) infection of sensory neurons may lead to a significant reduction in the expression of voltage-activated Na and Ca channels, which can disrupt the transmission of pain information. Viral infection also results in the secretion of various pro-inflammatory cytokines, including interleukin (IL)-6. In this work, we tested whether IL-6 regulates the expression of Na and Ca channels post HSV-1 infection in ND7/23 sensory-like neurons. Our results demonstrate that HSV-1 infection causes a significant decrease in the protein expression of the Cav3.2 T-type Ca channel subunit, despite increasing Cav3.2 mRNA synthesis. Neither Cav3.2 mRNA nor total protein content was affected by IL-6 treatment post HSV-1 infection. In ND7/23 cells, HSV-1 infection caused a significant reduction in the expression of Na and T-type Ca channels within 48 h. Exposure of ND7/23 cells to IL-6 for 24 h post infection reverses the effect of HSV-1, resulting in a significant increase in T-type Ca current density. However, Na currents were not restored by 24 h-treatment with IL-6 post HSV-1 infection of ND7/23 cells. The ability of IL-6 to increase the functional expression of T-type Ca channels on the membrane was blocked by inhibition of protein trafficking with brefeldin-A and ERK1/2 activation. These results indicate that IL-6 release following HSV-1 infection regulates the expression of T-type Ca channels, which may alter the transmission of pain information. This article is protected by copyright. All rights reserved.
Learn More >Self-management interventions are well recognised and widely used in chronic conditions. Their application to chronic headaches has been limited and generally of low quality. We describe here our process for developing an evidence based, and theory driven, education and self-management intervention for those living with chronic headache.
Learn More >Neuropathic pain in cancer is common and debilitating. It is important to differentiate neuropathic pain from other cancer-related pains as it is associated with worse pain outcomes and requires different treatment strategies. This review summarises recent updates to pain classification, aetiology, pain assessment and current recommendations for treatment in patients with cancer-related neuropathic pain.
Learn More >Complex regional pain syndrome (CRPS) is a rare but refractory pain disorder. Recent advanced information retrieval studies using text-mining and network analysis have suggested nuclear factor kappa B (NFκB) as a possible central mediator of CRPS. The brain is also known to play important roles in CRPS. The aim of this study was to evaluate changes in cerebral NFκB in rats with CRPS.
Learn More >Chronic pain patients frequently suffer from psychological symptoms. There is no consensus concerning the prevalence of severe anxiety and depressive symptoms and the strength of the associations between pain intensity and psychological distress. Although an important aspect of the clinical picture is understanding how the pain condition impacts life, little is known about the relative importance of pain and psychological symptoms for individual's life impact. The aims of this study were to identify subgroups of pain patients; to analyze if pain, psychological distress, and life impact variables influence subgrouping; and to investigate how patients in the subgroups benefit from treatments.
Learn More >Antiepileptic drugs (AEDs) are an important class of agents used in the treatment of migraine, a neurological disorder that imparts significant socioeconomic burden. It is important for neurologists to understand the rationale for AEDs in migraine-preventive treatment, as well as each agent's efficacy and tolerability profile, in order to best determine clinical care.
Learn More >In the course of investigating how common clinical treatments and adaptive technologies affect recovery after spinal cord injury (SCI), we discovered that a clinically-modeled hindlimb stretching protocol dramatically, but transiently, reduces locomotor function. Nociceptive sensory input is capable of altering motor output at the spinal level, and nociceptive neurons are sensitized after SCI. Here we tested the possibility that the stretch-induced motor deficits required the presence of nociceptors using neonatal capsaicin induced depletion of TRPV1+ nociceptive neurons. Following maturation, animals received 25 g-cm contusive SCI at T10. After plateau of locomotor recovery at 6 weeks, daily stretching was performed for 3 weeks, followed by 2 weeks without stretch, and again for two additional weeks. Animals were sacrificed 2 h after the last stretching session for histological assessments. The expected stretch-induced drops in locomotor function were observed in nociceptor-intact animals but were nearly absent in nociceptor-depleted animals. These functional changes were accompanied by corresponding increases in the number of c-Fos + nuclei throughout the lumbar enlargement. As expected, nociceptor-depleted animals had very little CGRP+ axonal innervation of the dorsal horn. However, in nociceptor-intact animals the expected post-SCI increase in CGRP+ innervation was significantly enhanced in animals that received stretching, implying additional stretch-induced intraspinal sprouting. These results indicate that locomotor dysfunction following hindlimb muscle stretch in animals with incomplete SCI involves C-fibers, adding a negative post-SCI role to their adaptive roles (e.g., bladder control), and suggesting that the clinical use of muscle stretching to combat contractures and spasticity may be unintentionally detrimental to locomotor function.
Learn More >Increasing knowledge about the role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology has led to the development of antibodies against this peptide or its receptor. However, CGRP is widely expressed throughout the body, participating not only in pathophysiological conditions but also in several physiological processes and homeostatic responses during pathophysiological events. Therefore, in this chapter, the risks of long-term blockade of the CGRP pathway will be discussed, with focus on the cardiovascular system, as this peptide has been described to have a protective role during ischemic events, and migraine patients present a higher risk of stroke and myocardial infarction.
Learn More >Pregabalin is a psychoactive drug indicated in the treatment of epilepsy, neuropathic pain, and generalized anxiety disorders. Pregabalin acts on different neurotransmission systems by inactivating the alpha2-delta subunit of voltage-gated calcium channels. In light of this pharmacological property, the hypothesis has been raised that pregabalin may regulate the mesolimbic dopamine pathway and thereby display a potential for misuse or abuse as recently observed in humans. Although some preclinical data support this possibility, the rewarding properties of gabapentinoid are still a matter for debate.
Learn More >The commercial formulation of sumatriptan nasal spray is an effective option for migraine patients requiring or preferring a non-oral route of drug administration, but its utility is limited by poor absorption and tolerability issues. DFN-02, a new formulation of sumatriptan 10 mg nasal spray, is co-formulated with a permeation enhancer that gives it pharmacokinetics comparable to subcutaneous sumatriptan. As reported previously, DFN-02 was significantly better than placebo on multiple efficacy endpoints at 2 h postdose, including pain freedom, absence of the most bothersome symptom, and pain relief, and its safety and tolerability profiles were excellent.
Learn More >Opioids are potent analgesic drugs, but their use has been limited due to their side effects. Antinociceptive effects of D2-like receptor agonists such as quinpirole have been shown at the spinal cord level; however, their efficacy is not as high as that of opioids. Dopaminergic agonists are long-prescribed and well-tolerated drugs that have been useful to treat clinically and experimentally painful conditions. Because current pain treatments are not completely effective, the aim of this work was to determine if a D2-like receptor agonist improves the antinociceptive effects of a μ-opioid receptor agonist. Drugs were intrathecally administered in adult rats; mechanonociceptive and thermonociceptive tests were carried out. Intraplantar injection of complete Freund's adjuvant (CFA) and sciatic loose ligation (SLL) were used for inflammatory and neuropathic models of pain, respectively. In intact animals, D-Ala2, N-MePhe4, Gly-ol-enkephalin (DAMGO; a µ-opioid receptor agonist) increased the paw withdrawal latencies (PWL) in thermal and mechanical nociceptive tests in a dose-dependent manner. Quinpirole (D2-like receptor agonist) increased PWL only in mechanonociception. In the presence of quinpirole (1 nmol), the ED of the mechanical antinociceptive effect of DAMGO was significantly decreased (8-fold). Coadministration of 1 nmol quinpirole and 30 pmol DAMGO completely reversed hyperalgesia in the CFA model, whereas 100pmol DAMGO plus 1 nmol quinpirole reversed the allodynia in the SLL model. This work offers evidence about a synergistic antinociceptive effect between opioidergic and dopaminergic drugs. This combination may relieve painful conditions resistant to conventional treatments, and it may reduce the adverse effects of chronic opioid administration.
Learn More >The purpose of the following review is to summarize the most recent understanding of migraine pathophysiology, as well as of basic and clinical science pharmacologic literature regarding the development of calcitonin gene receptor peptide (CGRP) antagonists as a novel therapeutic modality for the treatment of migraine headaches. A review is provided of erenumab, the first of its class FDA approved CGRP antagonist.
Learn More >Drug discovery research on new pain targets with human genetic validation, including the voltage-gated sodium channel NaV1.7, is being pursued to address the unmet medical need for chronic pain and the rising opioid epidemic. As part of early research efforts on this front, we have previously developed NaV1.7 inhibitory peptide-antibody conjugates with tarantula venom-derived GpTx-1 toxin peptides with extended half-life (80 h) in rodents but only moderate in vitro activity (hNaV1.7 IC50 = 250 nM) and without in vivo activity. We identified the more potent peptide JzTx-V from our natural peptide collection and improved its selectivity against other sodium channel isoforms through positional analoging. Here we report utilization of the JzTx-V scaffold in a peptide-antibody conjugate and architectural variations in linker, peptide loading, and antibody attachment site. We found conjugates with 100x improved in vitro potency relative to complementary GpTx-1 analogs, but pharmacokinetic and bioimaging analyses of these JzTx-V conjugates revealed a shorter than expected plasma half-life in vivo with accumulation in the liver. In an attempt to increase circulatory serum levels, we sought the reduction of the net +6 charge of the JzTx-V scaffold whilst retaining a desirable NaV in vitro activity profile. The conjugate of a JzTx-V peptide analog with a +2 formal charge maintained NaV1.7 potency with 18-fold improved plasma exposure in rodents. Balancing the loss in peptide and conjugate potency associated with the reduction of net charge necessary for improved target exposure resulted in a compound with moderate activity in a NaV1.7-dependent pharmacodynamic model but requires further optimization to identify a conjugate that can fully engage NaV1.7 in vivo.
Learn More >Neuropathic pain (NP) is among the most intractable comorbidities of spinal cord injury. Dysregulation of non-coding RNAs has also been implicated in the development of neuropathic pain. Here, we identified a novel lncRNA, PKIA-AS1, by using lncRNA array analysis in spinal cord tissue of spinal nerve ligation (SNL) model rats, and investigated the role of PKIA-AS1 in SNL-mediated neuropathic pain. We observed that PKIA-AS1 was significantly upregulated in SNL model rats and that PKIA-AS1 knockdown attenuated neuropathic pain progression. Alternatively, overexpression of PKIA-AS1 was sufficient to induce neuropathic pain-like symptoms in uninjured rats. We also found that PKIA-AS1 mediated SNL-induced neuropathic pain by directly regulating the expression and function of CDK6, which is essential for the initiation and maintenance of neuroinflammation and neuropathic pain. Therefore, our study identifies PKIA-AS1 as a novel therapeutic target for neuroinflammation related neuropathic pain.
Learn More >The nociceptive withdrawal reflex (NWR) is a polysynaptic spinal reflex protecting the body from harmful stimuli. Two different methods to assess its' threshold (NWR-T) have been part of clinical trials concerning the evaluation of the nociceptive system in the human body. NWR-T's are gathered by stimulation at the sole of the foot and over the sural pathway. Consequently, EMG analyzes the muscle activity over the biceps femoris and tibialis anterior muscle. Past studies favor stimulation at the sole of the foot.
Learn More >To estimate the prevalence of use of analgesics in Brazil; and to characterize this use, according to sociodemographic and health-related characteristics.
Learn More >The opioid epidemic is a significant public health crisis, and this problem is particularly prevalent among individuals with chronic pain. Accordingly, there is an urgent need for interventions to mitigate the risk for opioid misuse and opioid use disorder among people with pain. Given that mental health problems, specifically anxiety, are common among people who misuse opioids, it is important to examine factors that link mental health problems with opioid misuse to ultimately inform the development of novel interventions. Anxiety sensitivity, a transdiagnostic vulnerability factor defined as the fear of anxiety-related physical sensations, may be one important mechanism in elevated opioid misuse among persons with chronic pain.
Learn More >To investigate whether physician-patient agreement of potential patient problem areas impacts subsequent patient enrollment in an interdisciplinary pain management program.
Learn More >Gabapentin has analgesic efficacy for neuropathic pain and is increasingly used in burn care. This study investigated the effect of a neuropathic pain control protocol, as well as early gabapentin initiation (< 72 hours from injury) on total inpatient opioid use, chronic pain, and itch. This is a single-institution retrospective cohort study of patients over age 14 admitted between 2006 and 2016 with burns. We compared patients who did not receive gabapentin with those who had early gabapentin initiation vs. late initiation. We also compared patients who used gabapentin prior to initiation of a neuropathic pain protocol (February 2015) to those after. Primary outcomes were total inpatient gabapentin, morphine equivalents (MED), longitudinal pain and itch, as well as SF-12v2 Health Survey mental and physical component scores (MCS/PCS) at discharge, 6, 12, and 24 months post-injury. Ordinal logistic regression analysis was used to examine pain and itch scores. Linear regression models examined MCS and PCS between groups. Models were adjusted for age, sex, TBSA burned, area grafted, MED, and ICU stay. There was no significant difference in MED with early initiation, yet inpatient gabapentin use increased from 43.9 g to 59.5 g (p<0.001) with late initiation. The neuropathic pain protocol did not significantly change total gabapentin use (p = 0.184) in patients receiving gabapentin but decreased opioid use from 58.1 g to 17.4 g MED (p = 0.008). Our results suggest neither early gabapentin nor its use in a standardization neuropathic pain protocol improves long-term pain, itch, PCS or MCS scores.
Learn More >Neuropathic pain following surgery could be a useful model for the study of the genetic mechanisms of peripheral neuropathic pain.
Learn More >Burning mouth syndrome (BMS) is a chronic orofacial pain disorder of unknown cause. It is more common in peri- and postmenopausal women, and sex hormone dysregulation is believed to be an important causative factor. Psychosocial events often trigger or exacerbate symptoms, and persons with BMS appear to be predisposed toward anxiety and depression. Atrophy of small nerve fibers in the tongue epithelium has been reported, and potential neuropathic mechanisms for BMS are now widely investigated. Historically, BMS was thought to comprise endocrinological, psychosocial, and neuropathic components. Neuroprotective steroids and glial cell line-derived neurotrophic factor family ligands may have pivotal roles in the peripheral mechanisms associated with atrophy of small nerve fibers. Denervation of chorda tympani nerve fibers that innervate fungiform buds leads to alternative trigeminal innervation, which results in dysgeusia and burning pain when eating hot foods. With regard to the central mechanism of BMS, depletion of neuroprotective steroids alters the brain network related mood and pain modulation. Peripheral mechanistic studies support the use of topical clonazepam and capsaicin for the management of BMS, and some evidence supports the use of cognitive behavioral therapy. Hormone replacement therapy may address the causes of BMS, although adverse effects prevent its use as a first-line treatment. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) may have important benefits, and well-designed controlled studies are expected. Other treatment options to be investigated include brain stimulation and TSPO (translocator protein 18 KDa) ligands. This article is protected by copyright. All rights reserved.
Learn More >Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) is one of the essential signaling pathways for the development and maintenance of neuropathic pain.
Learn More >To describe and analyze Twitter activity associated with American Headache Society (AHS) conferences and evaluate the potential for Twitter to promote education and public outreach.
Learn More >The US National Pain Strategy focused attention on high-impact chronic pain and its restrictions. Although many interventions have been studied for chronic low-back pain, results are typically reported for heterogeneous samples. To better understand chronic pain and target interventions to those who most need care, more granular classifications recognizing chronic pain's impact are needed.
Learn More >Oliceridine is a novel G protein-biased µ-opioid receptor agonist designed to provide intravenous (IV) analgesia with a lower risk of opioid-related adverse events (ORAEs) than conventional opioids.
Learn More >Exercise is known to be an important component of treatment programs for individuals with neck pain. The study aimed to compare the effects of semispinalis cervicis (extensor) training, deep cervical flexor (flexor) training, and usual care (control) on functional disability, pain intensity, craniovertebral (CV) angle, and neck-muscle strength in chronic mechanical neck pain.
Learn More >Many leaders in the field of chronic pain treatment consider interdisciplinary pain management programs to be the most effective treatments available for chronic pain. As programs are instituted and expanded to address demands for nonpharmacological chronic pain interventions, we need to better understand how patients experience program impacts, as well as the challenges and supports patients encounter in trying to maintain and build on intervention gains.
Learn More >The purpose of this review is to summarize the current understanding of opioid pathways in mediating and/or modulating analgesia and adverse effects. Oliceridine is highlighted as a novel mu-opioid receptor agonist with selective activation of G protein and β-arrestin signaling pathways.
Learn More >Dexmedetomidine (DEX) is a high-selectivity α2 adrenergic receptor agonist. The present study aimed to characterize the analgesic effects of DEX on TNBS-induced chronic inflammatory visceral pain (CIVP) in rats and to evaluate whether its antinociceptive effect is regulated by microRNAs (miRNAs) and the ERK pathway. TNBS with or without DEX was administered to 60 male Sprague-Dawley rats. These rats were randomly classified into four groups: control, TNBS, vehicle, and DEX groups. Pain behaviors were assessed by the abdominal withdrawal reflex (AWR), thermal withdrawal latency (TWL), and mechanical withdrawal threshold (MWT). qPCR, ELISA, and western blotting results showed increased serum IL-1β, TNF-α, and IL-6 levels. RNA microarray and qPCR results indicated that miR-211 was downregulated by CIVP induction but upregulated by DEX administration. ERK signaling was decreased in the TNBS+miR-211 group and increased in the DEX + miR-211 group, indicating that miR-211 targeted the 3'-UTR of the ERK gene. Moreover, ectopic expression of miR-211 in these two groups ameliorated pain behaviors and reduced proinflammatory cytokine production. Therefore, DEX exhibited an analgesic effect on CIVP in rats through a miR-211-mediated MEK/ERK/CREB pathway, suppressing visceral hypersensitivity.
Learn More >Attachment theory provides a useful framework for understanding individual differences in pain patients, especially with insecure attachment shown to be more prevalent in chronic pain patients compared to the general population. Nevertheless, there is little evidence of attachment-informed treatment approaches for this population. The present study compares outcomes from two different attachment-informed treatment modalities for clinicians, with outcomes from treatment as usual (TAU). In both intervention groups (IG1 and IG2), clinicians received bi-monthly training sessions on attachment. Additionally, clinicians in IG1 had access to the attachment diagnostics of their patients. All treatments lasted for four weeks and included a 6-month follow up. A total of 374 chronic pain patients were recruited to participate in this study (TAU = 159/IG1 = 163/IG2 = 52). Analyses were carried out using multilevel modeling with pain intensity as the outcome variable. Additionally, working alliance was tested as a mediator of treatment efficacy. The study was registered under the trial number DRKS00008715 on the German Clinical Trials Register (DRKS). Findings show that while IG2 was efficient in enhancing treatment outcomes, IG1 did not outperform TAU. In IG2, working alliance was a mediator of outcome. Results of the present study indicate that attachment-informed treatment of chronic pain can enhance existing interdisciplinary pain therapies; however, caveats are discussed.
Learn More >