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To demonstrate that calcitonin gene-related peptide (CGRP) induces headache exacerbation with migraine-like features in patients with persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI).
Learn More >Migraine is the most common neurological disorder worldwide and it has been shown to have complex polygenic origins with a heritability of estimated 40-70%. Both common and rare genetic variants are believed to underlie the pathophysiology of the prevalent types of migraine, migraine with typical aura and migraine without aura. However, only common variants have been identified so far. Here we identify for the first time a gene module with rare mutations through a systems genetics approach integrating RNA sequencing data from brain and vascular tissues likely to be involved in migraine pathology in combination with whole genome sequencing of 117 migraine families. We found a gene module in the visual cortex, based on single nuclei RNA sequencing data, that had increased rare mutations in the migraine families and replicated this in a second independent cohort of 1930 patients. This module was mainly expressed by interneurons, pyramidal CA1, and pyramidal SS cells, and pathway analysis showed association with hormonal signalling (thyrotropin-releasing hormone receptor and oxytocin receptor signalling pathways), Alzheimer's disease pathway, serotonin receptor pathway and general heterotrimeric G-protein signalling pathways. Our results demonstrate that rare functional gene variants are strongly implicated in the pathophysiology of migraine. Furthermore, we anticipate that the results can be used to explain the critical mechanisms behind migraine and potentially improving the treatment regime for migraine patients.
Learn More >Activation of nociceptor sensory neurons by noxious stimuli both triggers pain and increases capillary permeability and blood flow to produce neurogenic inflammation, but whether nociceptors also interact with the immune system remains poorly understood. Here we report a neurotechnology for selective epineural optogenetic neuromodulation of nociceptors and demonstrate that nociceptor activation drives both protective pain behavior and inflammation. The wireless optoelectronic system consists of sub-millimeter-scale light-emitting diodes embedded in a soft, circumneural sciatic nerve implant, powered and driven by a miniaturized head-mounted control unit. Photostimulation of axons in freely moving mice that express channelrhodopsin only in nociceptors resulted in behaviors characteristic of pain, reflecting orthodromic input to the spinal cord. It also led to immune reactions in the skin in the absence of inflammation and potentiation of established inflammation, a consequence of the antidromic activation of nociceptor peripheral terminals. These results reveal a link between nociceptors and immune cells, which might have implications for the treatment of inflammation.
Learn More >Pain, temperature and itch are conventionally thought to be exclusively transduced by the intraepidermal nerve endings. While recent studies have shown that epidermal keratinocytes also participate in sensory transduction, the mechanism underlying keratinocyte communication with intraepidermal nerve endings remains poorly understood. We sought to demonstrate the synaptic character of the contacts between keratinocytes and sensory neurons and their involvement in sensory communication between keratinocytes and sensory neurons.
Learn More >Pain is a major source of global suffering, with women bearing the greatest burden. Alongside biology, psychological and social factors, including gender, help explain these differences. However, there has been no direct attempt to develop a unified social psychological model of men and women's pain. By drawing on approaches to both gender and pain, a gender context model of pain is presented. It proposes that pain is partly influenced by the gender context in which it occurs, which operates at both individual and interpersonal levels. The model is used to structure an appraisal of the existing evidence around gender and pain, and explore whether the model helps explain why such variation occurs. It is argued that despite evidence for an association between gender and pain, there are empirical gaps that need to be addressed. Implications and directions for future investigations into sex, gender and pain are considered.
Learn More >Many patients who require migraine preventive treatment have not been able to tolerate or have not responded to multiple previous preventive medications. We aimed to assess the safety and efficacy of galcanezumab, an antibody to calcitonin gene-related peptide, in patients with migraine who had not benefited from preventive medications from two to four categories.
Learn More >More than 50 million adults in America suffer from chronic pain. Opioids are commonly prescribed for their effectiveness in relieving many types of pain. However, excessive prescribing of opioids can lead to abuse, addiction, and death. Non-steroidal anti-inflammatory drugs (NSAIDs), another major class of analgesic, also have many problematic side effects including headache, dizziness, vomiting, diarrhea, nausea, constipation, reduced appetite, and drowsiness. There is an urgent need for the understanding of molecular mechanisms that underlie drug abuse and addiction to aid in the design of new preventive or therapeutic agents for pain management. To facilitate pain related small-molecule signaling pathway studies and the prediction of potential therapeutic target(s) for the treatment of pain, we have constructed a comprehensive platform of pain domain-specific chemogenomics knowledgebase (Pain-CKB) with integrated data mining computing tools. Our new computing platform describes the chemical molecules, genes, proteins, and signaling pathways involved in pain regulation. Pain-CKB is implemented with a friendly user-interface for the prediction of the relevant protein targets and analysis and visualization of the outputs, including HTDocking, TargetHunter, BBB predictor, and Spider Plot. Combining with other novel tools, we performed three case studies to systematically demonstrate how further studies can be conducted based on the data generated from Pain-CKB and its algorithms/tools. First, systems pharmacology target mapping was carried out for four FDA approved analgesics in order to identify the known target and predict off-targets. Subsequently, the target mapping outcomes were applied to build physiologically based pharmacokinetic (PBPK) models for acetaminophen and fentanyl to explore the drug-drug interaction (DDI) between this pair of drugs. Finally, pharmaco-analytics was conducted to explore the detailed interaction pattern of acetaminophen reactive metabolite and its hepatotoxicity target thioredoxin reductase.
Learn More >This prospective study examined 1) whether antenatal pain is associated with postnatal maternal bonding disorder (MBD) through postnatal depression and 2) whether intimate partner violence (IPV) has a moderating effect on the association between antenatal pain and postnatal MBD. We analyzed 77,326 pregnancies of women who completed self-report questionnaires including the SF-8 bodily pain item, the Edinburgh Postnatal Depression Scale, the Mother-to-Infant Bonding Scale, and an assessment of IPV. We conducted a mediation analysis to assess whether postnatal depression mediated the association between antenatal pain and MBD 1 year after delivery. A moderated mediation model was used to examine the conditional effect of IPV during pregnancy on the association between antenatal pain and postnatal MBD, operating through postnatal depression. All analyses were adjusted for demographic factors, socioeconomic factors, perinatal and infant factors, medical history, and psychological status. Of the 77,326 pregnancies, 5,420 (7.0%) were characterized by persistent moderate-to-severe pain. The total effect of antenatal pain on MBD was significant (standardized path coefficient = 0.06, 95% CI, 0.05-0.06) and postnatal depression dominantly mediated the association between antenatal pain and postnatal MBD (70.8% mediation). Contrary to our hypothesis, IPV during pregnancy did not moderate the association between antenatal pain and postnatal MBD. However, IPV during pregnancy did have independent negative effects on both postnatal depression and MBD. Our findings suggest that antenatal pain and postnatal depression should be assessed and treated with consideration of the presence of IPV during pregnancy to better monitor and prevent the development of MBD.
Learn More >Previous meta-analyses investigating attentional biases towards pain have utilized reaction time measures. Eye-tracking methods have been adopted to more directly and reliably assess biases, but this literature has not been synthesized in relation to pain. This meta-analysis aimed to investigate the nature and time-course of attentional biases to pain-related stimuli in participants of all ages with and without chronic pain using eye-tracking studies; and determine the role of task parameters and theoretically relevant moderators. After screening, 24 studies were included with a total sample of 1425 participants. Between-group analyses revealed no significant overall group differences for people with and without chronic pain on biases to pain-related stimuli. Results indicated significant attentional biases towards pain related words or pictures across both groups on probability of first fixation (k = 21, g = 0.43, 95% CI 0.15: 0.71, p = 0.002), how long participants looked at each picture in the first 500ms (500ms epoch dwell: k = 5, g = 0.69, 95% CI 0.034: 1.35, p = 0.039) and how long participants looked at each picture overall (total dwell time: k = 25, g = 0.44, 95% CI 0.15: 0.72, p = 0.003). Follow-up analyses revealed significant attentional biases on probability of first fixation, latency to first fixation and dwell time for facial stimuli, and number of fixations for sensory word stimuli. Moderator analyses revealed substantial influence of task parameters and some influence of threat status and study quality. Findings support biases in both vigilance and attentional maintenance for pain-related stimuli but suggest attentional biases towards pain are ubiquitous and not related to pain status.
Learn More >For decades the broad role of opioids in addiction, neuropsychiatric disorders, and pain states has been somewhat well established. However, in recent years, with the rise of technological advances, not only is the existing dogma being challenged, but we are identifying new disease areas in which opioids play a critical role. This review highlights four new areas of exploration in the opioid field. The most recent addition to the opioid family, the nociceptin receptor system, shows promise as the missing link in understanding the neurocircuitry of motivation. It is well known that activation of the kappa opioid receptor system modulates negative affect and dysphoria, but recent studies now implicate the kappa opioid system in the modulation of negative affect associated with pain. Opioids are critical in pain management; however, the often-forgotten delta opioid receptor system has been identified as a novel therapeutic target for headache disorders and migraine. Lastly, changes to the gut microbiome have been shown to directly contribute to many of the symptoms of chronic opioid use and opioid related behaviors. This review summarizes the findings from each of these areas with an emphasis on identifying new therapeutic targets. SIGNIFICANCE STATEMENT: The focus of this minireview is to highlight new disease areas or new aspects of disease in which opioids have been implicated; this includes pain, motivation, migraine, and the microbiome. In some cases, this has resulted in the pursuit of a novel therapeutic target and resultant clinical trial. We believe this is very timely and will be a refreshing take on reading about opioids and disease.
Learn More >As one of the thalamic midline nuclei, the thalamic paraventricular nucleus (PVT) is considered to be an important signal integration site for many descending and ascending pathways that modulate a variety of behaviors, including feeding, emotions and drug-seeking. A recent study has demonstrated that the PVT is implicated in the acute visceral pain response, but it is unclear whether the PVT plays a critical role in the central processing of chronic pain. Here, we report that the neurons in the posterior portion of the PVT (pPVT) and their downstream pathway are involved in descending nociceptive facilitation regarding the development of neuropathic pain conditions in male rats. Lesions or inhibition of pPVT neurons alleviated mechanical allodynia induced by spared nerve injury (SNI). The excitability of pPVT-central amygdala (CeA) projection neurons was significantly increased in SNI rats. Importantly, selective optogenetic activation of the pPVT-CeA pathway induced obvious mechanical hypersensitivity in naïve rats. In addition, we used rabies virus-based and cell-type-specific retrograde transsynaptic tracing techniques to define a novel neuronal circuit in which glutamatergic neurons in the vlPAG were the target of the pPVT-CeA descending facilitation pathway. Our data suggest that this pPVT-CeA-vlPAG circuit mediates central mechanisms of descending pain facilitation underlying persistent pain conditions.Studies have shown that the interactions between the posterior portion of the thalamic paraventricular nucleus (pPVT) and central amygdala (CeA) play a critical role in pain-related emotional regulation. However, most reports have associated this circuit with fear and anxiety behaviors. Here, an integrative approach of behavioral tests, electrophysiology, and immunohistochemistry was used to advance the novel concept that the pPVT-CeA pathway activation facilitates neuropathic pain processing. Using rabies virus-based and cell-type-specific retrograde transsynaptic tracing techniques, we found that glutamatergic neurons in the vlPAG were the target of the pPVT-CeA pathway. Thus, this study indicates the involvement of a pPVT-CeA-vlPAG pathway in a descending facilitatory mechanism underlying neuropathic pain.
Learn More >Neuropathic cancer pain (NcP) is associated with worse treatment responses and specific therapy indications, but a standardized clinical diagnosis of NcP is still lacking.This is a prospective observational study on cancer outpatients, comparing different clinical approaches to NcP evaluation. A three-step assessment of NcP was performed using DN4 (cut-off of 4), palliative care physician Clinical Impression, including etiology and pain syndrome identification, and Retrospective Clinical Classification by a board of specialists with the IASP Neuropathic Pain Special Interest Group criteria. NcP classification was specifically referred to pain directly due to cancer.350 patients were assessed, NcP prevalence was 20%, 95%CI [15.9% – 24.6%], 36,9%, (95% CI 31.6% – 42.1%) and 28.6%, (95%CI 23.8% – 33.9%) according respectively to DN4, Clinical Impression and Retrospective Clinical Classification. Cohen's Kappa concordance coefficient between DN4 and Retrospective Clinical Classification was 0.57, 95%CI [0.47 – 0.67], indicating moderate concordance. Higher percentages of discordance were found for specific pain syndromes like pain due to deep soft tissue infiltration and pain associated with tenesmus. Disagreement among clinicians accounted also for different NcP diagnoses and highlighted lack of homogeneous clinical criteria. Rigorous application of etiological and syndrome diagnosis to explain pain cause, associated with standardized diagnostic criteria and assessment of pain characteristics, that is also specific of the cancer pain condition could improve clinical classification of NcP.
Learn More >Approximately one-half of patients with substance use disorders (SUD) experience chronic pain. Yet how patients perceive the relationship between their substance use and chronic pain remains poorly understood. We sought to identify how patients with comorbid SUD and chronic pain describe the relationship between, and mechanisms linking, these conditions. We conducted qualitative interviews with 34 patients engaged in SUD treatment who were also diagnosed with chronic pain. Interviews were transcribed verbatim and coded by both primary and secondary coders. Qualitative content analysis guided coding and analysis. Patient interviews revealed three primary pathways. One group of participants described SUD as developing independently from their experiences of chronic pain. A second group of participants described turning to substances to self-manage or cope with the physical and emotional aspects of chronic pain. A third group of participants described encounters with opioid medications as the causal agent initiating a SUD. Our findings build upon research that has identified chronic pain and SUD as developmentally similar and mutually reinforcing, by revealing the ways in which patients themselves understand and experience the interconnections between their substance use and chronic pain.
Learn More >While clinical studies support the suggestion that stress is a risk factor for painful chemotherapy-induced peripheral neuropathy (CIPN), there is little scientific validation to support this link. Here, we evaluated the impact of stress on CIPN induced by oxaliplatin, and its underlying mechanisms, in male and female rats. A single dose of oxaliplatin produced mechanical hyperalgesia of similar magnitude in both sexes, still present at similar magnitude in both sexes, on day 28. Adrenalectomy mitigated oxaliplatin-induced hyperalgesia, in both sexes. To confirm the role of neuroendocrine stress axes in CIPN, intrathecal administration of antisense oligodeoxynucleotide (AS-ODN) targeting β2-adrenergic receptor mRNA both prevented and reversed oxaliplatin-induced hyperalgesia, only in males. In contrast, glucocorticoid receptor AS-ODN, prevented and reversed oxaliplatin-induced hyperalgesia in both sexes. Unpredictable sound stress enhanced CIPN, in both sexes. The administration of stress hormones, epinephrine, corticosterone and their combination, at stress levels, mimicked the effects of sound stress on CIPN, in males. In females, only corticosterone mimicked the effect of sound stress. Also a risk factor for CIPN, early life stress, was evaluated by producing both stress-sensitive (produced by neonatal limited bedding, NLB) and stress-resilient (produced by neonatal handling, NH) phenotypes in adults. While NLB significantly enhanced CIPN only in female adults, NH significantly attenuated CIPN, in both sexes. Our study demonstrates a sexually dimorphic role of the two major neuroendocrine stress axes in oxaliplatin-induced neuropathic pain.
Learn More >The fear-avoidance model of chronic pain predicts that catastrophic (mis)interpretation of pain elicits pain-related fear that in turn may spur avoidance behaviour leading to chronic pain disability. Here we investigated whether performing a movement to avoid a painful stimulus in the context of a novel movement increases threat and pain-related fear towards this novel movement, and whether avoidance behaviour persisted when given the choice between performing the acquired movement to avoid a painful stimulus or an alternative, novel movement. Applying a robotic arm-reaching task, participants could choose between two movements to reach a target location: a short, but painful movement trajectory, or a longer non-painful movement trajectory. After avoidance acquisition, the option to choose the painful trajectory was removed. The Experimental Group (N=50) could choose between the longest trajectory or a novel intermediate trajectory, whereas the Control Group (N=50) was allowed to only perform the novel trajectory. In a final test, participants of both groups were allowed to choose any of the three trajectories. Post-acquisition, Experimental Group participants showed elevated pain-expectancy and pain-related fear towards the novel trajectory, compared to the Control Group. During test, the Experimental Group participants persisted in performing the longest pain-free (avoidance) trajectory, and were less likely to choose the novel trajectory. In addition, these participants maintained higher levels of pain-related fear for the novel trajectory compared to the Control Group. These findings suggest that avoidance in the context of other neutral activities/movements may lead to the development and maintenance of threat appraisals and irrational fears.
Learn More >Surgical procedures are necessary in up to 50% of trigeminal neuralgia (TN) patients. While radiofrequency (RF) is more widely used, it is associated with high intra-procedural costs and long technical learning time. Other simpler procedures such as balloon compression (BC) require a lower training period and have significant lower costs. We evaluated the effects of BC and RF in pain control in primary TN in a randomized, double-blinded, head-to-head trial. Individuals were randomly allocated in one of two groups: BC and RF. Throughout pain, psychological and quality of life measurements were performed at baseline and after surgery. The main outcome was the worst pain in the last 24 hours (0-10) at six months postoperatively. After the inclusion of half of the estimated sample, a pre-planned interim analysis was performed when thirty-three patients (62.1 ± 9.4 y.) completed the study. Pain intensity (CI95% 0.6-3.8, and -0.6-2.2, for BC and RF) did not significantly differ. Complications, interference of pain in daily life (CI95% -0.1-2.3 and -0.4-2.3, for BC and RF), neuropathic pain symptoms (CI95% 1.7-3.6 and 3.0-5.7, for BC and RF), mood (CI95% 4.8-11.5 and 5.5-15.1, BC and RF, respectively), medication use and quality of life (CI95% 80.4-93.1 and 83.9-94.2, for BC and RF) were also not different. RF presented more paresthetic symptoms than BC at 30 days following intervention. Based on these results, the study was halted due to futility as BC was not superior do RF.
Learn More >Many chronic pain conditions show sex differences in their epidemiology. This could be attributed to sex-dependent differential expression of genes (DEGs) involved in nociceptive pathways, including sensory neurons. This study aimed to identify sex-dependent DEGs in estrous female versus male sensory neurons, which were prepared by using different approaches and ganglion types. RNA-seq on non-purified sensory neuronal preparations, such as whole dorsal root ganglion (DRG) and hindpaw tissues, revealed only a few sex-dependent DEGs. Sensory neuron purification increased numbers of sex-dependent DEGs. These DEG sets were substantially influenced by preparation approaches and ganglion types [DRG vs trigeminal ganglia (TG)]. Percoll-gradient enriched DRG and TG neuronal fractions produced distinct sex-dependent DEG groups. We next isolated a subset of sensory neurons by sorting DRG neurons back-labeled from paw and thigh muscle. These neurons have a unique sex-dependent DEG set, yet there is similarity in biological processes linked to these different groups of sex-dependent DEGs. Female-predominant DEGs in sensory neurons relate to inflammatory, synaptic transmission and extracellular matrix reorganization processes that could exacerbate neuro-inflammation severity, especially in TG. Male-selective DEGs were linked to oxidative phosphorylation and protein/molecule metabolism and production. Our findings catalog preparation-dependent sex differences in neuronal gene expressions in sensory ganglia.
Learn More >Preclinical and clinical evidence suggests a role for the dysregulation of the endocannabinoid system in migraine pain, particularly in subjects with chronic migraine.
Learn More >The shared representations account of empathy suggests that sharing other people's emotions relies on neural processes similar to those engaged when directly experiencing such emotions. Recent research corroborated this by showing that placebo analgesia induced for first-hand pain resulted in reduced pain empathy and decreased activation in shared neural networks. However, those studies did not report any placebo-related variation of somatosensory engagement during pain empathy. The experimental paradigms used in these studies did not direct attention towards a specific body part in pain, which may explain the absence of effects for somatosensation. The main objective of this preregistered study was to implement a paradigm overcoming this limitation, and to investigate whether placebo analgesia may also modulate the sensory-discriminative component of empathy for pain. We induced a localized, first-hand placebo analgesia effect in the right hand of 45 participants by means of a placebo gel and conditioning techniques, and compared this to the left hand as a control condition. Participants underwent a pain task in the MRI scanner, receiving painful or non-painful electrical stimulation on their left or right hand, or witnessing another person receiving such stimulation. In contrast to a robust localized placebo analgesia effect for self-experienced pain, the empathy condition showed no differences between the two hands, neither for behavioral nor neural responses. We thus report no evidence for somatosensory sharing in empathy, while replicating previous studies showing overlapping brain activity in the affective-motivational component for first-hand and empathy for pain. Hence, in a more rigorous test aiming to overcome limitations of previous work, we again find no causal evidence for the engagement of somatosensory sharing in empathy. Our study refines the understanding of the neural underpinnings of empathy for pain, and the use of placebo analgesia in investigating such models.
Learn More >This meta-analysis evaluates pressure pain sensitivity values in symptomatic and distant pain-free areas comparing individuals with tension-type headache to controls.
Learn More >Previously reported increases in serum levels of vasodilating neuropeptides pituitary adenylate cyclase-activating peptide-38 (PACAP38) and vasoactive intestinal peptide (VIP) during attacks of cluster headache could indicate their involvement in cluster headache attack initiation. We investigated the attack-inducing effects of PACAP38 and vasoactive intestinal peptide in cluster headache, hypothesising that PACAP38, but not vasoactive intestinal peptide, would induce cluster-like attacks in episodic active phase and chronic cluster headache patients.
Learn More >Clinical guidelines recommend that healthcare providers assist children to understand their experience of persistent pain, with pain science education a key component of clinical management in pediatric pain clinics. Currently, no tool exists to assess a child's concept of pain. The aim of this study was to develop such a tool and to evaluate its psychometric properties.
Learn More >To evaluate the association between the degree of response to placebo in migraine studies and the observed difference between drug and placebo across studies of preventative treatments for migraine.
Learn More >Predicting the response to a triptan in migraine using deep attack phenotyping: A feasibility study.
Triptans, specific symptomatic medications for migraine, are not effective in a proportion of patients, or in all attacks, hence the importance of identifying predictors of response. Our aim was to investigate the association between the efficacy of oral frovatriptan 2.5 mg and clinical characteristics of migraine attacks.
Learn More >The Rutgers Acquired Equivalence Test is a visually guided equivalence learning paradigm that involves rule acquisition and generalization. Earlier we found impaired performance in this paradigm among adult migraine patients without aura. The aim of the study was to investigate if similar impairments can be found already in the pediatric form of the disease and to compare the performance of the pediatric study population with that of an adult study population. We hypothesized that the deficits observed in adults would be observable already in the pediatric population.
Learn More >Drugs that block voltage-gated sodium channels (Nas) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved Na blocking drugs (Comprehensive Medicinal Chemistry III; (Elsevier, 2017; pp 131-175). We report the identification of a novel class of brain penetrant and voltage-gated sodium channel blockers, leading to the discovery of vixotrigine, a use-dependent sodium channel blocker with activity in models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.
Learn More >Pain assessment that fully represents patients' pain experiences is essential for chronic pain research and management. The traditional primary outcome measure has been a patient's average pain intensity over a time period. In this series of three articles, we examine whether pain assessment can be enhanced by considering additional outcome measures capturing temporal aspects of pain, such as pain maxima, duration, and variability. Ecological momentary assessment (EMA) makes the assessment of such indices readily available. In this first article, we discuss the rationale for considering additional pain indices derived from EMA and examine which are most important to stakeholders. Patients (n=32), clinicians (n=20), and clinical trialists (n=20) were interviewed about their preference rankings for Average, Worst, and Least Pain, Time in High Pain, Time in No/Low Pain, Pain Variability, and Pain Unpredictability. Each stakeholder group displayed a distinct preference hierarchy for different indices, and there were few commonalities between groups. Patients favored Worst Pain and Time in High Pain, followed by Pain Variability and Unpredictability. Trialists favored Average Pain, whereas clinicians favored Worst Pain. Results suggest that multiple temporal aspects of pain are relevant for stakeholders and should be considered when evaluating the efficacy of pain management. PERSPECTIVE: Examining which aspects of pain are most important to measure from the perspective of different stakeholders can facilitate efforts to include all relevant treatment outcomes. Our study suggests that multiple temporal aspects of pain intensity are important to stakeholders. This should be considered when evaluating the efficacy of pain management.
Learn More >Chronic pain alters cortical and subcortical plasticity, causing enhanced sensory and affective responses to peripheral nociceptive inputs. Previous studies have shown that ketamine had the potential to inhibit abnormally amplified affective responses of single neurons by suppressing hyperactivity in the anterior cingulate cortex (ACC). However, the mechanism of this enduring effect has yet to be understood at the network level. In this study, we recorded local field potentials from the ACC of freely moving rats. Animals were injected with complete Freund's adjuvant (CFA) to induce persistent inflammatory pain. Mechanical stimulations were administered to the hind paw before and after CFA administration. We found a significant increase in the high-gamma band (60-100 Hz) power in response to evoked pain after CFA treatment. Ketamine, however, reduced the high-gamma band power in response to evoked pain in CFA-treated rats. In addition, ketamine had a sustained effect on the high-gamma band power lasting up to five days after a single dose administration. These results demonstrate that ketamine has the potential to alter maladaptive neural responses in the ACC induced by chronic pain.
Learn More >We sought to assess the safety and tolerability of 3 calcitonin gene-related peptide (CGRP) monoclonal antibodies in patients with chronic migraine who have failed multiple classes of migraine preventive therapies.
Learn More >Advances in proton magnetic resonance spectroscopy (MRS) allow for the non-invasive examination of neuroinhibitory and neuroexcitatory processes in humans. In particular, these methods have been used to understand changes across chronic pain conditions. While a recent meta-analysis supports the idea that underlying brain metabolite levels may be unique to different pain conditions and may serve as biomarkers for specific pain conditions, the lack of consideration of differential brain aging processes across heterogenous pain conditions introduces a significant source of bias. Future studies need to address the interactions between pain and brain aging across different MRS metabolite measures.
Learn More >Almost a half century of research has elaborated the discoveries of the central mechanisms governing the analgesic responses of opiates, including their receptors, endogenous peptides, genes and their putative spinal and supraspinal sites of action. One of the central tenets of "gate-control theories of pain" was the activation of descending supraspinal sites by opiate drugs and opioid peptides thereby controlling further noxious input. This review in the Special Issue dedicated to the research of Dr. Gavril Pasternak indicates his contributions to the understanding of supraspinal mediation of opioid analgesic action within the context of the large body of work over this period. This review will examine (a) the relevant supraspinal sites mediating opioid analgesia, (b) the opioid receptor subtypes and opioid peptides involved, (c) supraspinal site analgesic interactions and their underlying neurophysiology, (d) molecular (particularly AS) tools identifying opioid receptor actions, and (e) relevant physiological variables affecting site-specific opioid analgesia. This review will build on classic initial studies, specify the contributions that Gavril Pasternak and his colleagues did in this specific area, and follow through with studies up to the present.
Learn More >We evaluated the efficacy of fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, in patients with chronic migraine (CM) with and without medication overuse (MO).
Learn More >Guidelines for acute postoperative pain management recommend administering analgesics in multimodal combination to facilitate synergistic benefit, reduce opioid requirements and decrease side-effects. However, limited observational research has examined the extent to which multimodal analgesics are prescribed and administered postoperatively following joint replacement.
Learn More >Recently, an additional trigeminothalamic tract – the dorsal trigeminothalamic tract – has been described in human brainstems by our group next to the known ventral trigeminothalamic tract. As various elements of the trigeminal system are known to be organised in a somatotopic fashion, the question arose whether the fibres within the trigeminal root show specific distributions patterns in their contribution to the ventral trigeminothalamic tract and dorsal trigeminothalamic tract specifically.
Learn More >A major portion of individuals affected by traumatic spinal cord injury (SCI) experience one or more types of chronic neuropathic pain (NP), which is often intractable to currently available treatments. The availability of reliable behavioral assays in pre-clinical models of SCI-induced NP is therefore critical to assess the efficacy of new potential therapies. Commonly used assays to evaluate NP-related behavior in rodents, such as Hargreaves thermal and von Frey mechanical testing, rely on the withdrawal response to an evoked stimulus. However, other assays that test spontaneous/non-evoked NP-related behavior or supraspinal aspects of NP would be highly useful for a more comprehensive assessment of NP following SCI. The Mouse Grimace Scale (MGS) is a tool to assess spontaneous, supraspinal pain-like behaviors in mice; however, the assay has not been characterized in a mouse model of SCI-induced chronic NP, despite the critical importance of mouse genetics as an experimental tool. We found that beginning 2 weeks after cervical contusion, SCI mice exhibited increased facial grimace features compared to laminectomy-only control mice, and this grimace phenotype persisted to the chronic time point of 5 weeks post-injury. We also found a significant relationship between facial grimace score and the evoked forepaw withdrawal response in both the Hargreaves and von Frey tests at 5 weeks post-injury when both laminectomy-only and SCI mice were included in the analysis. However, within only the SCI group, there was no correlation between grimace score and Hargreaves or von Frey responses. These results indicate both that facial grimace analysis can be used as an assay of spontaneous NP-related behavior in the mouse model of SCI and that the information provided by the MGS may be different than that provided by evoked tests of sensory function.
Learn More >Overactivity in the context of chronic pain (i.e. activity engagement that significantly exacerbates pain) is an important clinical issue that has gained empirical attention in the last decade. Current assessment concepts of overactivity tend to focus on frequency to quantify the severity of the pain behaviour. This study aimed to develop and validate a more comprehensive self-assessment, the Overactivity in Persistent Pain Assessment (OPPA).
Learn More >Conditioned pain modulation (CPM) methods are experimental procedures to assess presumed descending nociceptive modulatory pathways. Various CPM-methods are currently used, making the comparison of results difficult. The aim of this study was to compare five conditioning stimuli and to evaluate the influencing effects of personal factors on CPM-efficacy.
Learn More >Paclitaxel (PCX) is the first-line choice for the treatment of several types of cancer, including breast, ovarian and lung cancers. However, patients who receive even a single dose with PCX commonly develop mechanical and cold allodynia, a symptom known as PCX-associated acute pain syndrome (P-APS). Here we assessed possible involvement of kinin-kallikrein and renin-angiotensin systems in P-APS in mice.
Learn More >Treatment based on the Fear-Avoidance (FA) model has been found to be effective with chronic low back pain (CLBP), and in-vivo exposure of fear evoking movements is proposed as a key change mechanism. Exposure tasks may be conducted in the session (in-session exposure; ISE), in other real life situations (between sessions exposure) as part of homework assignments, or both. Utilizing a randomized, controlled dismantling study design, the aim of this study was to examine the unique effects of ISE in FA-treatment of CLBP.
Learn More >High risks of falls have been reported in older adults with chronic pain but chronic pain similarly affects adults of all ages. This cross-sectional study aimed to determine the prevalence of falls and associated risk factors in adults of all ages living with chronic pain.
Learn More >Recently programmed death-ligand 1 (PD-L1) receptor PD-1 was found in dorsal root ganglion (DRG) neurons, and PD-L1 activates PD-1 to inhibit inflammatory and neuropathic pain by modulating neuronal excitability. However, the downstream signaling of PD-1 in sensory neurons remains unclear. Here, we show that PD-L1 activates Src homology 2 domain-containing tyrosine phosphatase-1 (SHP-1) to downregulate transient receptor potential vanilloid 1 (TRPV1) in DRG neurons and inhibit bone cancer pain in mice. Local injection of PD-L1 produced analgesia. PD-1 in DRG neurons colocalized with TRPV1 and SHP-1. PD-L1 induced the phosphorylation of SHP-1 in DRG TRPV1 neurons and inhibited TRPV1 currents. Loss of TRPV1 in mice abolished bone cancer-induced thermal hyperalgesia and PD-L1 analgesia. Conditioned deletion of SHP-1 in NaV1.8+ neurons aggravated bone cancer pain and diminished the inhibition of PD-L1 on TRPV1 currents and pain. Together, our findings suggest that PD-L1/PD1 signaling suppress bone cancer pain via inhibition of TRPV1 activity. Our results also suggest that SHP-1 in sensory neurons is an endogenous pain inhibitor and delayed the development of bone cancer pain via suppressing TRPV1 function.
Learn More >The aim of this study was to assess clinical pain, pain sensitization, and physical performances to profile patients with chronic painful knee osteoarthritis (OA) or pain after total knee arthroplasty (TKA). Examining the interactions between pain mechanisms and physical performances would enable us to investigate the underlying explanatory relationships between these parameters.
Learn More >Although pediatric chronic pain is common, it is not yet clear which individuals with chronic pain are likely to seek health care for their pain. The aims of this study were to summarize the current evidence of characteristics of children and adolescents with chronic pain who consult a physician or use medication for their pain. Additionally, we aimed to expand knowledge by further investigating key, and promising, factors in a large community sample of adolescents.
Learn More >The discovery and development of new and potentially nonaddictive pain therapeutics requires rapid, yet clinically relevant assays of nociception in preclinical models. A reliable and scalable automated scoring system for nocifensive behavior of mice in the formalin assay would dramatically lower the time and labor costs associated with experiments and reduce experimental variability. Here, we present a method that exploits machine learning techniques for video recordings that consists of three components: key point detection, per frame feature extraction using these key points, and classification of behavior using the GentleBoost algorithm. This approach to automation is flexible as different model classifiers or key points can be used with only small losses in accuracy. The adopted system identified the behavior of licking/biting of the hind paw with an accuracy that was comparable to a human observer (98% agreement) over 111 different short videos (total 284 min) at a resolution of 1 s. To test the system over longer experimental conditions, the responses of two inbred strains, C57BL/6NJ and C57BL/6J, were recorded over 90 min post formalin challenge. The automated system easily scored over 80 h of video and revealed strain differences in both response timing and amplitude. This machine learning scoring system provides the required accuracy, consistency, and ease of use that could make the formalin assay a feasible choice for large-scale genetic studies.
Learn More >Psychological factors such as fear avoidance beliefs, depression, anxiety, catastrophic thinking and familial and social stress, have been associated with high disability levels in people with chronic low back pain (LBP). Guidelines endorse the integration of psychological interventions in the management of chronic LBP. However, uncertainty surrounds the comparative effectiveness of different psychological approaches. Network meta-analysis (NMA) allows comparison and ranking of numerous competing interventions for a given outcome of interest. Therefore, we will perform a systematic review with a NMA to determine which type of psychological intervention is most effective for adults with chronic non-specific LBP.
Learn More >There is strong evidence showing that the activation of peripheral proteinase-activated receptors type 2 (PAR-2) can initiate hyperalgesic and inflammatory responses in the joint. However, to date, there is no report of functional spinal PAR-2 receptors in arthritis models. The primary aim of this study was to evaluate the activity of PAR-2 receptors at the spinal cord by using a potent agonist (FLIGRL) in naïve animals, and an antagonist (GB83) in different models of joint pain. Saline or FLIGRL (10 nmol) were injected intrathecally in naïve animals and nociceptive behaviour was evaluated over a 24 h time period by von Frey hair algesiometry. Paw withdrawal threshold decreased from 3 to 24 h and this allodynic effect was blocked by GB83 (90 nmol; i.p.). Acute inflammatory joint pain was induced by injecting 0.5% kaolin/carrageenan (50 μL each) into the right knee joint of male Wistar rats (24 hr recovery). Chronic inflammatory joint pain was modelled by intraarticular injection of Freund's complete adjuvant (FCA; 50 μL; 7 days recovery) or chronic osteoarthritis pain by sodium monoiodoacetate (MIA; 3 mg; 14 days recovery). Animals were then treated with either intrathecal vehicle or 10 nmol of GB83 (10 μL); joint pain was evaluated throughout the subsequent 3 h period. The acute inflammatory pain induced by kaolin/carrageenan was not affected by treatment with GB83. Conversely, both chronic arthritis models demonstrated increased hind paw withdrawal threshold after spinal injection of the PAR-2 antagonist. Based on these results, spinal PAR-2 receptors are involved in joint nociceptive processing in chronic but not acute arthritic conditions.
Learn More >In the central nervous system, hyperpolarization-activated, cyclic nucleotide-gated (HCN1-4) channels have been implicated in neuronal excitability and synaptic transmission. It has been reported that HCN channels are expressed in the spinal cord, but knowledge about their physiological roles, as well as their distribution profiles, appear to be limited. We generated a transgenic mouse in which the expression of HCN4 can be reversibly knocked down using a genetic tetracycline-dependent switch and conducted genetically validated immunohistochemistry for HCN4. We found that the somata of HCN4-immunoreactive (IR) cells were largely restricted to the ventral part of the inner lamina II and lamina III. Many of these cells were either parvalbumin- or protein kinase Cγ (PKCγ)-IR. By using two different mouse strains in which reporters are expressed only in inhibitory neurons, we determined that the vast majority of HCN4-IR cells were excitatory neurons. Mechanical and thermal noxious stimulation did not induce c-Fos expression in HCN4-IR cells. PKCγ-neurons in this area are known to play a pivotal role in the polysynaptic pathway between tactile afferents and nociceptive projection cells that contributes to tactile allodynia. Therefore, pharmacological and/or genetic manipulations of HCN4-expressing neurons may provide a novel therapeutic strategy for the pain relief of tactile allodynia.
Learn More >Given the role of Ca3.2 isoform among T-type Ca channels (T-channels) in somatic and visceral nociceptive processing, we analyzed the contribution of Ca3.2 to butyrate-induced colonic pain and nociceptor hypersensitivity in mice, to evaluate whether Ca3.2 could serve as a target for treatment of visceral pain in irritable bowel syndrome (IBS) patients. Mice of ddY strain, and wild-type and Ca3.2-knockout mice of a C57BL/6J background received intracolonic administration of butyrate twice a day for 3 days. Referred hyperalgesia in the lower abdomen was assessed by von Frey test, and colonic hypersensitivity to distension by a volume load or chemicals was evaluated by counting nociceptive behaviors. Spinal phosphorylated ERK was detected by immunohistochemistry. Ca3.2 knockdown was accomplished by intrathecal injection of antisense oligodeoxynucleotides. Butyrate treatment caused referred hyperalgesia and colonic hypersensitivity to distension in ddY mice, which was abolished by T-channel blockers and/or Ca3.2 knockdown. Butyrate also increased the number of spinal phosphorylated ERK-positive neurons following colonic distension in the anesthetized ddY mice. The butyrate-treated ddY mice also exhibited T-channel-dependent colonic hypersensitivity to intracolonic NaS, known to enhance Ca3.2 activity, and TRPV1, TRPA1 or proteinase-activated receptor 2 (PAR2) agonists. Wild-type, but not Ca3.2-knockout, mice of a C57BL/6J background, after treated with butyrate, mimicked the T-channel-dependent referred hyperalgesia and colonic hypersensitivity in butyrate-treated ddY mice. Our study provides definitive evidence for an essential role of Ca3.2 in the butyrate-induced colonic pain and nociceptor hypersensitivity, which might serve as a target for treatment of visceral pain in IBS patients.
Learn More >Chronic pain studies investigating the ability to detect sensory processing differences related to thalamic gating using electroencephalographic (EEG) alpha have yielded conflicting results. Alpha's basic psychometric properties in pain populations requires further study. The present study reports on the test-retest reliability and internal consistency of EEG alpha power in older adults with chronic knee pain.
Learn More >Chronic pain, particularly that following nerve injury, can occur in the absence of external stimuli. Although the ongoing pain is sometimes continuous, in many individuals the intensity of their pain fluctuates. Experimental animal studies have shown that the brainstem contains circuits that modulate nociceptive information at the primary afferent synapse and these circuits are involved in maintaining ongoing continuous neuropathic pain. However, it remains unknown if these circuits are involved in regulating fluctuations of ongoing neuropathic pain in humans.
Learn More >To determine what dose of melatonin is most effective for treating migraine acutely in children and adolescents.
Learn More >Low-value care is associated with harm among patients and with wasteful health care spending but has not been well characterized in the Veterans Health Administration.
Learn More >Overexpression of Ca3.2 T-type Ca channels in L4 dorsal root ganglion (DRG) participates in neuropathic pain after L5 spinal nerve cutting (L5SNC) in rats. The L5SNC-induced neuropathic pain also involves high mobility group box 1 (HMGB1), a damage-associated molecular pattern protein, and its target, the receptor for advanced glycation end-products (RAGE). We thus studied the molecular mechanisms for the L5SNC-induced Ca3.2 overexpression as well as neuropathic pain in rats by focusing on; 1) possible involvement of early growth response 1 (Egr-1), known to regulate transcriptional expression of Ca3.2, and ubiquitin-specific protease 5 (USP5) that protects Ca3.2 from proteasomal degradation, and 2) possible role of HMGB1/RAGE as an upstream signal. Protein levels of Ca3.2 as well as Egr-1 in L4 DRG significantly increased in the early (day 6) and persistent (day 14) phases of neuropathy after L5SNC, while USP5 protein in L4 DRG did not increase on day 6, but day 14. An anti-HMGB1-neutralizing antibody or a low molecular weight heparin, a RAGE antagonist, prevented the development of neuropathic pain and upregulation of Egr-1 and Ca3.2 in L4 DRG after L5SNC. L5SNC increased macrophages accumulating in the sciatic nerves, and the cytoplasm/nuclear ratio of immunoreactive HMGB1 in those macrophages. Our findings suggest that L5SNC-induced Ca3.2 overexpression in L4 DRG and neuropathic pain involves Egr-1 upregulation downstream of the macrophage-derived HMGB1/RAGE pathway, and that the delayed upregulation of USP5 might contribute to the persistent Ca3.2 overexpression and neuropathy.
Learn More >Objectives Chronic pain patients often suffer in multiple locations. In health care, examinations of bodily pain usually do not include questions about temporomandibular disorders (TMD); hence TMD symptoms and potential comorbidities are not regularly assessed. Therefore, the primary aim was to evaluate the prevalence of TMD in patients referred to a pain rehabilitation clinic, and the secondary aim was to evaluate possible factors associated with TMD symptoms. Methods Consecutive chronic pain patients referred to the Pain Rehabilitation Clinic at the Umeå University Hospital in Sweden were included. TMD symptoms were assessed using three valid screening questions – 3Q/TMD. Pain sites, emotional distress, kinesiophobia, and demographics were obtained from the Swedish Quality Registry for Pain Rehabilitation. Results In total, 188 (144 women) chronic pain patients (mean age 41.8 years) were included. Of these, 123 (96 women) answered affirmatively to at least one of the 3Q/TMD. The relative risk of TMD symptoms among the patients with chronic pain, in comparison to the general population, was 7.1 (95% CI 5.9-8.4). Age was the only independent variable associated with TMD among the patients (p = 0.018). Conclusions The prevalence of TMD symptoms was higher in a chronic pain population compared to the general population. The 3Q/TMD questionnaire could be a suitable screening tool at pain rehabilitation clinics to identify patients for further examination of involvement of pain in the trigeminal region. Our results reinforce the clinical importance of paying attention to concurrent widespread pain and local TMD symptoms.
Learn More >Placebo effects may occur when it is known that an inert substance is given (i.e., open-label placebo). It is not yet clear whether these effects are similar to concealed (i.e. closed-label) placebo effects for itch, or whether nocebo effects can be induced under open-label conditions.
Learn More >Mutations within the SCN11A gene which encodes the voltage-gated sodium channel Na1.9 mainly expressed in small fiber sensory neurons have been associated with neuropathic disorders; however, suitable medications have not been fully investigated. To develop drug therapies against Na1.9-related neuropathic pain, we aimed to establish a novel model using mice carrying the Scn11a p.R222S mutation initially identified in patients with familial episodic limb pain that is characterized by paroxysmal pain induced by fatigue or bad weather conditions. We investigated the influence of cold exposure (4 °C, overnight) on the behavioral and biochemical phenotypes of Scn11a p.R222S mutant (R222S) and wild type C57BL/6N (WT) mice. We also tested the effects of acetaminophen (125, 250 mg/kg, perorally, p.o.) and traditional Japanese medicine, goshajinkigan (0.5 or 1.0 g/kg, p.o.), which are analgesic drugs prescribed to patients with neuropathic pain, in this model of cold-induced mechanical allodynia in R222S mice.Cold-exposed R222S mice exhibited enhanced mechanical allodynia and thermal hypersensitivity compared with WT mice. The decrease of the mechanical withdrawal threshold in R222S mice was reversible 24 h after housing at room temperature. There was no significant change in the levels of interleukin-1β, interleukin-6, tumor necrosis factor-α, or interferon-γ in the plasma or spinal cords of WT and R222S mice after cold exposure. Both acetaminophen (250 mg/kg) and goshajinkigan (1.0 g/kg) significantly attenuated mechanical allodynia in R222S mice. The model of cold-induced mechanical allodynia in mice with the Scn11a p.R222S mutation is novel and useful for evaluating analgesic drugs for intractable neuropathies related to Na1.9.
Learn More >Patients with classic trigeminal neuralgia (CTN) have abnormalities in white matter integrity of the corpus callosum (CC). However, in CTN patients, it is unclear whether the CC substructure region is affected to varying degrees.
Learn More >Gap junctions play a pivotal role in contributing to the formation of astroglial networks and in chronic pain. However, the mechanisms underlying the dysfunction of astroglial gap junctions in chronic pain have not been fully elucidated.
Learn More >Tolerance and hyperalgesia associated with chronic exposure to morphine are major limitations in the clinical management of chronic pain. At a cellular level, neuronal signaling can in part account for these undesired side effects, but unknown mechanisms mediated by central nervous system glial cells are likely also involved. Here we applied data-independent acquisition mass spectrometry to perform a deep proteome and phosphoproteome analysis of how human astrocytes responds to opioid stimulation. We unveil time- and dose-dependent effects induced by morphine and its major active metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide that converging on activation of mitogen-activated protein kinase and mammalian target of rapamycin signaling pathways. We also find that especially longer exposure to M3G leads to significant dysregulation of biological pathways linked to extracellular matrix organization, antigen presentation, cell adhesion, and glutamate homeostasis, which are crucial for neuron- and leukocyte-astrocyte interactions.
Learn More >To estimate all-cause and overdose crude mortality rates and standardized mortality ratios among people prescribed opioids for chronic noncancer pain and risk of overdose death in this population relative to people with similar clinical profiles but not prescribed opioids.
Learn More >The increased use of opioids to treat pain has led to a dramatic increase in opioid abuse. Our previous data indicate that pain may facilitate the development of opioid abuse by increasing the magnitude and duration of opioid withdrawal. The present study tested the hypothesis that social housing would facilitate recovery of activity depressed by pain and opioid withdrawal. Male Sprague Dawley rats were housed either in pairs or alone and then moved to a cage with a running wheel for 6 hrs daily to assess pain- and opioid withdrawal-induced depression of wheel running. Rats were implanted with two morphine (75 mg each) or placebo pellets to induce opioid dependence and were simultaneously injected with Complete Freund's Adjuvant or saline into the right hind paw to induce persistent inflammatory pain. Hind paw inflammation depressed wheel running whether rats were implanted with a morphine or placebo pellet. Pair-housed rats showed greater recovery of wheel running than individually housed rats. Spontaneous morphine withdrawal precipitated by removal of the morphine pellets caused a reduction in wheel running that was greater in rats with hind paw inflammation compared to pain free rats. Social housing facilitated recovery from withdrawal in rats with hind paw inflammation, but slowed recovery in pain free rats. These data suggest that social housing facilitates recovery by reducing pain both before and during opioid withdrawal. Our findings are consistent with previous studies showing that social buffering reduces pain-evoked responses.
Learn More >A growing body of research highlights the pervasive harms of adverse childhood experiences (ACEs) on health throughout the life-course. However, findings from prior reviews and recent longitudinal studies investigating the association between types of ACEs and persistent pain have yielded inconsistent findings in the strength and direction of associations. The purpose of this review is to appraise and summarize evidence on the relationship between ACEs and persistent pain and disability outcomes in adulthood. The specific aims are (1) to determine whether there is a relationship between exposure to ACE and persistent pain and disability in adults and (2) to determine whether unique and cumulative ACEs exposures (number and type) increase the risk of developing persistent pain and disability in adulthood.
Learn More >Exercise has been shown to significantly improve pain and function in individuals with fibromyalgia. Research into the effectiveness of exercise is often based on standardised exercise programmes that are chosen by the investigating clinical research team. However, such programmes may not necessarily be appealing to the participating patients. Furthermore, in addition to being taught exercises, patients with chronic conditions like fibromyalgia also need to learn to manage their condition themselves and so be actively involved in their treatment. The primary aim of this study is to compare the effects of two, 6-month physical activity programs on quality of life in patients with fibromyalgia. One group followed a patient-led, fibromyalgia-orientated programme (experimental) whilst the control group followed a standard, general exercise programme.
Learn More >Migraine can negatively impact patient functioning and quality of life. Here, we report the effects of galcanezumab (GMB), a humanized monoclonal antibody that binds to calcitonin gene-related peptide, on patient-reported outcome (PRO) measures in migraine.
Learn More >Chronic pain is a growing problem in the military, and the methods by which we have to perform epidemiologic surveillance are insufficient. It represents both a public health and military readiness concern, as those who suffer from it experience adverse impacts on work productivity, physiological health, and quality of life.
Learn More >To investigate changes in analgesic use before and after supervised exercise therapy and patient education in patients with knee or hip osteoarthritis (OA).
Learn More >Exposure to a traumatic event is common among US adults, yet only a small fraction develops post-traumatic stress disorder (PTSD). Higher pain after a traumatic injury has been associated with higher PTSD symptomology and thus may be a risk factor. However, few studies have examined how pain during the period immediately after a trauma, referred to as the acute post trauma period, relates to later to PTSD outcomes.
Learn More >To examine stressor elevations among older adults with pain, and gender and race disparities in the dual burdens of late-life pain and stressors.
Learn More >This study was designed to investigate painless and painful subsets of pediatric restless legs syndrome (RLS) for genetic influence and for associations with iron deficiency and common pediatric pain disorders.
Learn More >The aim of this investigation was to evaluate the effects of local anaesthesia on nerve growth factor (NGF) induced masseter hyperalgesia. Healthy participants randomly received an injection into the right masseter muscle of either isotonic saline (IS) given as a single injection (n = 15) or an injection of NGF (n = 30) followed by a second injection of lidocaine (NGF + lidocaine; n = 15) or IS (NGF + IS; n = 15) in the same muscle 48 h later. Mechanical sensitivity scores of the right and left masseter, referred sensations and jaw pain intensity and jaw function were assessed at baseline, 48 h after the first injection, 5 min after the second injection and 72 h after the first injection. NGF caused significant jaw pain evoked by chewing at 48 and 72 h after the first injection when compared to the IS group, but without significant differences between the NGF + lidocaine and NGF + IS groups. However, the mechanical sensitivity of the right masseter 5 min after the second injection in the NGF + lidocaine group was significantly lower than the second injection in the NGF + IS and was similar to the IS group. There were no significant differences for the referred sensations. Local anaesthetics may provide relevant information regarding the contribution of peripheral mechanisms in the maintenance of persistent musculoskeletal pain.
Learn More >In response to a declared statewide public health emergency due to opioid-related overdose deaths, the Arizona Department of Health Services guided the creation of a modern, statewide, evidence-based curriculum on pain and addiction that would be relevant for all health care provider types.
Learn More >The aim of this study was to investigate the association between temporomandibular disorder (TMD) and migraine through a longitudinal follow-up study using population data from a national health screening cohort.
Learn More >Pain is a complex syndrome that is difficult to treat. The increasing numbers of patients living with chronic diseases has led to increasing pain management needs and the rise of opioid use disorder as a major, and potentially lethal, public health concern. Treatment of chronic pain with prescription opioids alone is not always successful, and a multi-disciplinary approach is paramount to address the needs of patients at risk of developing or suffering from OUD. Interventional radiologists trained to perform minimally invasive procedures with negligible downtime and post procedure pain can help stem the tide of opioid related deaths and disability. This article reviews a wide range of minimally invasive procedures, including vertebral augmentation, sacroplasty, thermal ablation of osseous metastasis, nerve blocks, and gonadal vein embolization, that interventional radiologists are now using successfully to treat chronic pain. The evidence to support use of such procedures is highlighted. This article also briefly discusses emerging techniques, such as arterial embolization and ablation for knee and shoulder osteoarthritis, that have not yet been fully tested though exhibit strong potential in chronic pain management. By reducing opioid use in patients suffering from chronic pain, these minimally invasive procedures can potentially prevent escalation to OUD.
Learn More >Persistent post-surgical pain is common among patients undergoing surgery, is detrimental to patients' quality of life, and can precipitate long-term opioid use. The purpose of this randomized controlled trial is to assess the effects of a behavioral intervention offered prior to surgery for patients at risk for poor post-surgical outcomes, including persistent pain and impaired functioning.
Learn More >Peripheral nerve injury is associated with spinal microgliosis which plays a pivotal role in the development of neuropathic pain behavior. Several agents of primary afferent origin causing the microglial reaction have been identified, but the type(s) of primary afferents that release these mediators are still unclear. In this study, specific labeling of C-fiber spinal afferents by lectin histochemistry and selective chemodenervation by capsaicin were applied to identify the type(s) of primary afferents involved in the microglial response. Comparative quantitative morphometric evaluation of the microglial reaction in central projection territories of intact and injured peripheral nerves in the superficial (laminae I and II) and deep (laminae III and IV) spinal dorsal horn revealed a significant, about three-fold increase in microglial density after transection of the sciatic or the saphenous nerve. Prior perineural treatment of these nerves with capsaicin, resulting in a selective defunctionalization of C-fiber afferent fibers failed to affect spinal microgliosis. Similarly, peripheral nerve injury-induced increase in microglial density was unaffected in rats treated neonatally with capsaicin known to result in a near-total loss of C-fiber dorsal root fibers. Perineural treatment with capsaicin per se did not evoke a significant increase in microglial density. These observations indicate that injury-induced spinal microgliosis may be attributed to phenotypic changes in injured myelinated primary afferent neurons, whereas the contribution of C-fiber primary sensory neurons to this neuroimmune response is negligible. Spinal myelinated primary afferents may play a hitherto unrecognized role in regulation of neuroimmune and perisynaptic microenvironments of the spinal dorsal horn.
Learn More >Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which promotes the activation of astrocytes, is known to be synthesized in microglia. However, it is unclear whether microglia-astrocyte communication via C1q is involved in orofacial neuropathic pain. Here, we analyzed microglia-astrocyte communication in a rat model with infraorbital nerve injury (IONI). The orofacial mechanical hypersensitivity induced by IONI was significantly attenuated by preemptive treatment with minocycline. Immunohistochemical analyses revealed that minocycline inhibited the increase in c-Fos immune-reactive (IR) cells and the fluorescence intensity of both Iba1 and glial fibrillary acidic protein (GFAP) in the Vc following IONI. Intracisternal administration of C1q caused orofacial mechanical hypersensitivity and an increase in the number of c-Fos-IR cells and fluorescence intensity of GFAP. C1q-induced orofacial mechanical hypersensitivity was completely abrogated by intracisternal administration of fluorocitrate. The present findings suggest that the enhancement in the excitability of Vc nociceptive neurons is produced by astrocytic activation via the signaling of C1q released from activated microglia in the Vc following IONI, resulting in persistent orofacial neuropathic pain.
Learn More >In this observational study, using the Global Burden of Disease and Risk Factors Study, we aimed to (i) report the magnitude of health loss due to non-communicable neurological disorders in the USA in 2017 by sex, age, years and States and (ii) to identify non-communicable neurological disorders attributable environmental, metabolic and behavioural risk factors. We provide estimates of the burden of non-communicable neurological disorders by reporting disability-adjusted life-years and their trends from 1990 to 2017 by age and sex in the USA. The non-communicable neurological disorders include migraines, tension-type headaches, multiple sclerosis, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, motor neuron diseases and other neurological disorders. In 2017, the global burdens of non-communicable neurological disorders were 1444.41 per 100 000, compared to the USA burden of 1574.0. Migraine was the leading age-standardized disability-adjusted life-years 704.7 per 100 000, with Alzheimer's disease and other dementias (41.8.7), and epilepsy (123.8) taking the second and third places, respectively. Between 1990 and 2017, the age-standardized disability-adjusted life-years rates for aggregate non-communicable neurological disorders relative to all cause increased by 3.42%. More specifically, this value for motor neuron diseases, Parkinson's disease and multiple sclerosis increase by 20.9%, 4.0%, 2.47%, 3.0% and 1.65%, respectively. In 2017, the age-standardized disability-adjusted life-years rates for the aggregate non-communicable neurological disorders was significantly higher in females than the males (1843.5 versus 1297.3 per 100 000), respectively. The age-standardized disability-adjusted life-years rates for migraine were the largest in both females (968.8) and males were (432.5) compared to other individual non-communicable neurological disorders. In the same year, the leading non-communicable neurological disorders age-standardized disability-adjusted life-years rates among children ≤9 was epilepsy (216.4 per 100 000). Among the adults aged 35-60 years, it was migraine (5792.0 per 100 000), and among the aged 65 and above was Alzheimer's disease and other dementias (78 800.1 per 100 000). High body mass index, smoking, high fasting plasma glaucous and alcohol use were the attributable age-standardized disability-adjusted life-years risks for aggregate and individual non-communicable neurological disorders. Despite efforts to decrease the burden of non-communicable neurological disorders in the USA, they continue to burden the health of the population. Children are most vulnerable to epilepsy-related health burden, adolescents and young adults to migraine, and elderly to Alzheimer's disease and other dementias and epilepsy. In all, the most vulnerable populations to non-communicable neurological disorders are females, young adults and the elderly.
Learn More >Calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypetide-38 (PACAP-38) have relevant roles in migraine pathophysiology. Their serum levels have been proposed as biomarkers for migraine. Our aim was to assess their diagnostic value in real clinical practice in a cohort of chronic migraine (CM), episodic migraine (EM) and healthy controls (HC). We recruited subjects with CM, EM and HC at two medical centers. Blood samples were drawn under fasting conditions in the interictal period, immediately centrifuged and stored at – 80 ºC. Serum levels were determined by ELISA. Neuropeptide levels, the effect of preventatives, correlations with clinical and demographic variables, and their diagnostic value were studied among clinical categories. 296 age- and sex-matched subjects (101 CM, 98 EM and 97 HC) were included. All three neuropeptide serum levels were higher in CM [median and IQ for CGRP = 18.023 pg/ml (14.4-24.7); VIP = 121.732 pg/ml (48.72-186.72) and PACAP = 204.931 pg/ml (101.08-597.64)] vs EM [CGRP = 14.659 pg/ml (10.29-17.45); VIP = 75.603 pg/ml (28.722-107.10); and PACAP = 94.992 pg/ml (65.77-128.48)] and vs HC [CGRP = 13.988 pg/ml (10.095-17.87); VIP = 84.685 pg/ml (35.32-99.79), and PACAP = 103.142 pg/ml (59.42-123.97)]. Using multinomial modeling, only VIP (OR 1.011, 95% CI 1.003-1.018, p = 0.005) and PACAP (OR 1.003, 95% CI 1.001-1.005, p = 0.002) increased the risk for CM, but not for EM. CGRP did not predict CM or EM. This model could correctly classify only 62/101 (61.38%) of CM, 75/98 (76.53%) of EM, and 5/97 (4.12%) of HC [globally 147/296 (49.8%)]. Individually, PACAP performed the best for classifying clinical categories [global accuracy 150/296 (50.67%)]. In CM, neuropeptide levels were higher in those OnaBT-treated than in no-treated patients. Although interictal serum CGRP and VIP were higher in CM than both EM or HC, their utility to discriminate migraine categories was low. Contrary to other studies, PACAP serum levels were also higher in CM than in EM or HC and had more discriminative capability to distinguish CM from EM and HC. Further investigation is needed for determination technique standardization.
Learn More >In osteoarthritis (OA), pain is the dominant clinical symptom, yet the therapeutic approaches remain inadequate. The knowledge of the nociceptive mechanisms in OA, which will allow to develop effective therapies for OA pain, is of utmost need. In this study, we investigated the nociceptive mechanisms involved in post-traumatic OA pain, using the destabilization of the medial meniscus (DMM) mouse model. Our results revealed the development of peripheral pain sensitization, reflected by augmented mechanical allodynia. Along with the development of pain behaviour, we observed an increase in the expression of calcitonin gene-related peptide (CGRP) in both the sensory nerve fibers of the periosteum and the dorsal root ganglia. Interestingly, we also observed that other nociceptive mechanisms commonly described in non-traumatic OA phenotypes, such as infiltration of the synovium by immune cells, neuropathic mechanisms and also central sensitization were not present. Overall, our results suggest that CGRP in the sensory nervous system is underlying the peripheral sensitization observed after traumatic knee injury in the DMM model, highlighting the CGRP as a putative therapeutic target to treat pain in post-traumatic OA. Moreover, our findings suggest that the nociceptive mechanisms involved in driving pain in post-traumatic OA are considerably different from those in non-traumatic OA.
Learn More >