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Calcitonin gene-related peptide (CGRP) antagonizing drugs represent a major advance in migraine treatment. However, up to 50% of patients do not benefit from monoclonal antibodies against CGRP or its receptor. Here, we test the hypothesis that a closely related peptide, pituitary adenylate cyclase-activating peptide (PACAP-38), works independently of CGRP and thus might represent a new, alternative drug target. To understand differences in CGRP- and PACAP-mediated migraine pain, we used mouse models of provoked migraine-like pain based upon multiple stimulations and subsequent measurement of tactile sensitivity response with von Frey filaments. Genetically modified mice lacking either functional CGRP receptors (Ramp1 knockout) or TRPA1 channels (Trpa1 knockout) were used together with CGRP-targeting antibodies and chemical inhibitors in wildtype mice (Ntotal = 299). Ex vivo myograph studies were used to measure dilatory responses to CGRP and PACAP-38 in mouse carotid arteries. PACAP-38 provoked significant hypersensitivity and dilated the carotid arteries independently of CGRP. In contrast, glyceryl trinitrate-induced hypersensitivity is dependent on CGRP. Contrary to previous results with the migraine-inducing substances glyceryl trinitrate, cilostazol, and levcromakalim, PACAP-38-induced hypersensitivity worked only partially through inhibition of ATP-sensitive potassium channels. Using multiple migraine-relevant models, these findings establish the PACAP-38 pathway as distinct from other migraine provoking pathways such as CGRP and glyceryl trinitrate. PACAP antagonism may therefore be a novel therapeutic target of particular interest in patients unresponsive to CGRP antagonizing drugs.
Learn More >Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca influx via PreNMDARs. Small conductance Ca-activated K (SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization.
Learn More >Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.
Learn More >Both opioids and nonsteroidal anti-inflammatory drugs (NSAIDS) produce deleterious side effects and fail to provide sustained relief in patients with chronic inflammatory pain. Peripheral neuroinflammation (PN) is critical for initiation and development of inflammatory pain. A better understanding of molecular mechanisms underlying PN would facilitate the discovery of new analgesic targets and the development of new therapeutics. Emerging evidence suggests that peripheral sensory neurons are not only responders to painful stimuli, but are also actively engaged in inflammation and immunity, whereas the intrinsic regulatory mechanism is poorly understood. Here we report the expression of proton-selective ion channel Hv1 in peripheral sensory neurons in rodents and humans, which was previously shown as selectively expressed in microglia in mammalian central nervous system. Neuronal Hv1 was up-regulated by PN or depolarizing stimulation, which in turn aggravates inflammation and nociception. Inhibiting neuronal Hv1 genetically or by a newly discovered selective inhibitor YHV98-4 reduced intracellular alkalization and ROS production in inflammatory pain, mitigated the imbalance in downstream SHP-1-pAKT signaling, and also diminished pro-inflammatory chemokine release to alleviate nociception and morphine-induced hyperalgesia and tolerance. Thus, our data reveal neuronal Hv1 as a novel target in analgesia strategy and managing opioids-related side effects.
Learn More >Mu opioid receptor (MOR) agonists are potent analgesics, but also cause sedation, respiratory depression, and addiction risk. The epithalamic lateral habenula (LHb) signals aversive states including pain, and here we found that it is a potent site for MOR-agonist analgesia-like responses in rats. Importantly, LHb MOR activation is not reinforcing in the absence of noxious input. The LHb receives excitatory inputs from multiple sites including the ventral tegmental area, lateral hypothalamus, entopeduncular nucleus, and the lateral preoptic area of the hypothalamus (LPO). Here we report that LHb-projecting glutamatergic LPO neurons are excited by noxious stimulation and are preferentially inhibited by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state that is relieved by LHb MOR activation, and optogenetic inhibition of LHb-projecting LPO neurons relieves the aversiveness of ongoing pain.
Learn More >Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens. However, signaling pathways downstream to these receptors in dorsal root ganglion (DRG) neurons are not yet understood. We found that Anoctamin 1 (ANO1), a Ca2+-activated chloride channel, is a transduction channel mediating Mrgprs-dependent itch signals. Genetic ablation of Ano1 in DRG neurons displayed a significant reduction in scratching behaviors in response to acute and chronic Mrgprs-dependent itch models and the epidermal hyperplasia induced by dry skin. In-vivo Ca2+ imaging and electrophysiological recording revealed that chloroquine and other agonists of Mrgpr receptors excited DRG neurons via ANO1. More importantly, the overexpression of Ano1 in DRG neurons of Ano1-deficient mice rescued the impaired itching observed in Ano1-deficient mice. These results demonstrate that ANO1 mediates the Mrgprs-dependent itch signaling in pruriceptors and provides clues to treating pathologic itch syndromes.
Learn More >Efficacy of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor/receptor activity modifying protein-1, CLR/RAMP1) implicates peripherally-released CGRP in migraine pain. However, the site and mechanism of CGRP-evoked peripheral pain remain unclear. By cell-selective RAMP1 gene deletion, we reveal that CGRP released from mouse cutaneous trigeminal fibers targets CLR/RAMP1 on surrounding Schwann cells to evoke periorbital mechanical allodynia. CLR/RAMP1 activation in human and mouse Schwann cells generates long-lasting signals from endosomes that evoke cAMP-dependent formation of NO. NO, by gating Schwann cell transient receptor potential ankyrin 1 (TRPA1), releases ROS, which in a feed-forward manner sustain allodynia via nociceptor TRPA1. When encapsulated into nanoparticles that release cargo in acidified endosomes, a CLR/RAMP1 antagonist provides superior inhibition of CGRP signaling and allodynia in mice. Our data suggest that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.
Learn More >Medication overuse headache significantly contributes to the chronification process and treatment refractoriness of migraine. Currently, abrupt discontinuation of the overused medication still represents the best management strategy for these patients, challenging public health system resources.
Learn More >Small nerve fibres are important when studying diabetic peripheral neuropathy (DPN) as they could be first affected. However, assessing their integrity and function adequately remains a major challenge. The aim of this study was to investigate the association between different degrees of DPN, the presence of neuropathic pain (NP), and the intensity of the axon-reflex flare response provoked by epidermal histamine.
Learn More >The role of the major estrogen estradiol (E2) on orofacial pain conditions remains controversial with studies reporting both a pronociceptive and antinociceptive role of E2. E2 modulation of peripheral serotonergic activity may be one mechanism underlying the female prevalence of orofacial pain disorders. We recently reported that female rats in proestrus and estrus exhibit greater serotonin (5HT)-evoked orofacial nocifensive behaviors compared to diestrus and males. Further coexpression of 5HT2A receptor mRNA in nociceptive trigeminal sensory neurons that express transient receptor potential vanilloid 1 ion channels (TRPV1) contribute to pain sensitization. E2 may exacerbate orofacial pain via 5HT-sensitive trigeminal nociceptors, but whether low or high E2 contributes to orofacial pain and by what mechanism remains unclear. We hypothesized that steady-state exposure to a proestrus level of E2 exacerbates 5HT-evoked orofacial nocifensive behaviors in female rats, we explored the transcriptome of E2-treated females, and we determined which E2 receptor contributes to sensitization of female trigeminal sensory neurons. We report that a diestrus level of E2 is protective against 5HT-evoked orofacial pain behaviors, which increase with increasing E2 concentrations, and E2 differentially alters several pain genes in the trigeminal ganglia. Further, E2 receptors co-expressed with 5HT2A and TRPV1 and enhanced capsaicin-evoked signaling in the trigeminal ganglia via ERα. Overall our data indicate that low, but not high, physiological levels of E2 protect against orofacial pain, and we provide evidence that ERα receptor activation, but not others, contribute to sensitization of nociceptive signaling in trigeminal sensory neurons.
Learn More >This study investigated the association between serological biomarkers at hospital admission with the development of long-term post-COVID pain symptoms in previously hospitalized COVID-19 survivors. A cohort study including patients hospitalised due to COVID-19 in one urban hospital of Madrid (Spain) during the first wave of the outbreak was conducted. Hospitalisation data, clinical data and eleven serological biomarkers were collected at hospital admission. Participants were scheduled for an individual telephone interview after hospital discharge for collecting data about post-COVID pain symptoms. A total of 412 (mean age: 62, SD: 15 years; 46.1% women) were assessed twice, a mean of 6.8 and 13.2 months after discharge. The prevalence of post-COVID pain symptoms was 42.7% (n=176) and 36.2% (n=149) at 6.8 and 13.2 months after hospital discharge. Patients reporting post-COVID pain exhibited a greater number of COVID-19 associated symptoms at hospital admission, more medical comorbidities, higher lymphocyte count, and lower glucose and creatine kinase (CK) levels (all, P<0.01) than those not reporting post-COVID pain. The multivariate analysis revealed that lower CK and glucose levels were significantly associated, but just explaining 6.9% of the variance of suffering post-COVID pain. In conclusion, the association between serological biomarkers associated with COVID-19 severity at hospital admission and the development of post-COVID pain is small. Other factors, e.g., higher number of COVID-19 onset symptoms (higher symptom load) could be more relevant for the development of post-COVID pain. As inflammatory biomarkers were not directly analyzed, they may have stronger predictive strengths for the development of post-COVID pain symptoms.
Learn More >As opioid prescribing has declined, it is unclear how the landscape of prescription pain treatment across the US has changed. We used nationally-representative data from the Medical Expenditure Health Survey, 2014-2018 to examine trends in prescriptions for opioid and non-opioid pain medications, including acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), gabapentinoids, and antidepressants among US adults with self-reported pain. Overall, from 2014-2018, the percentage of participants receiving a prescription for opioids declined, (38.8% vs. 32.8%), remained stable for NSAIDs (26.8% vs. 27.7%), and increased for acetaminophen (1.6% vs. 2.3%), antidepressants (9.6% vs. 12.0%) and gabapentinoids (13.2% vs. 19.0%). In this period, the adjusted odds of receiving an opioid prescription decreased (aOR=0.93, 95% CI=0.90-0.96), while the adjusted odds of receiving antidepressant, gabapentinoid and acetaminophen prescriptions increased (antidepressants: aOR=1.08, 95% CI=1.03-1.13 gabapentinoids: aOR=1.11, 95% CI=1.06-1.17; acetaminophen: aOR=1.10, 95% CI: 1.02-1.20). Secondary analyses stratifiying within the 2014-2016 and 2016-2018 periods revealed particular increases in prescriptions for gabapentinoids (aOR=1.13, 95% CI=1.05-1.21) and antidepressants (aOR=1.23, 95% CI=1.12-1.35) since 2016.
Learn More >Burn injury-induced pain (BIP) is an extremely complicated condition usually resistant to analgesic drugs, while its pathogenesis remains unknown. Considerable attention has been attracted to elucidate the glial mechanisms in chronic pain. In this study, we initiatively used a mouse model of second-degree BIP to investigate the underlying non-neuronal mechanisms at the spinal cord level. Our behavioral results showed that hind-paw burn injury caused persistent allodynia and hyperalgesia for 2 weeks in mice. Further studies revealed that both microglia and astrocytes activated in a spatially- and temporally-dependent manner in spinal cord after burn injury. In addition, the phosphorylated p38 mitogen-activated protein kinase (MAPK)-mediated tumor necrosis factor (TNF) release in spinal microglia is essentially attributed to the early stage of BIP, while the c-Jun N-terminal kinase (JNK) MAPK-dependent chemokine CXCL1 expression is mainly involved in the maintenance of pain hypersensitivity. Most strikingly, burn injury-induced pain symptoms and the activation of astrocytes were significantly suppressed by TNF inhibitor Thalidomide. On the contrary, intrathecal injection of TNF caused apparent pain hypersensitivity, accompanied by the activation of astrocytes and the upregulation of CXCL1 via the JNK MAPK signaling pathway, indicating that TNF is the key cytokine in the interaction between microglia and astrocytes at the spinal level. Moreover, treatment with the CXCR2 receptor antagonist SB225002 to block the biological activities of CXCL1 significantly attenuated the mechanical allodynia and thermal hyperalgesia in this BIP model. Taken together, this study indicates that intervention of glial pathways provides a new perspective in the management of BIP.
Learn More >To describe the prevalence of frailty in a single-centre cohort of patients with polymyalgia rheumatica (PMR) and describe its association with health-related quality of life (HRQoL), cognition and sarcopenia.
Learn More >Clinically focused interventions for people living with pain, such as health professional education, clinical decision support systems, prescription drug monitoring programs, and multidisciplinary care to support opioid tapering, have all been promoted as important solutions to the North American opioid crisis. Yet none have so far delivered substantive beneficial opioid-related population health outcomes. In fact, while total opioid prescribing has leveled off or reduced in many jurisdictions, population-level harms from opioids have continued to increase dramatically. We attribute this failure partly to a poor recognition of the epistemic and ethical complexities at the interface of clinical and population health. We draw on a framework of knowledge networks in wicked problems to identify 3 strategies to help navigate these complexities: (1) designing and evaluating clinically focused interventions as complex interventions, (2) reformulating evidence to make population health dynamics apparent, and (3) appealing to the inseparability of facts and values to support decision-making in uncertainty. We advocate that applying these strategies will better equip clinically focused interventions as complements to structural and public health interventions to achieve the desired beneficial population health effects. (. 2022;112(S1):S56-S65. https://doi.org/10.2105/AJPH.2021.306500).
Learn More >Although electroacupuncture is widely used in chronic pain management, it is quite controversial due to its unclear mechanism. We hypothesised that EA alleviates pain by inhibiting degradation of the ecto-nucleotidase prostatic acid phosphatase (PAP) and facilitating ATP dephosphorylation in dorsal root ganglions (DRGs).
Learn More >Opioids are the most popular drugs for both acute and chronic pain management. The G protein-coupled mu-opioid receptor (MOR) is the therapeutic target for most clinically used opioids, including morphine. A mounting number of publications suggest a relationship between the MOR and possible cancer progression and recurrence extending to managing chronic cancer pain. In this study, we studied the possible link between opioid use and pancreatic cancer (PC) progression. We found increased MOR expression in murine and human PC cell lines, human PC-derived organoids, and in the undifferentiated or poorly differentiated areas of surgically resected PC tissues. Direct stimulation of MOR by morphine (MOR agonist) caused a significant dose-dependent increase in proliferation, invasion, and levels of stemness markers in PC cells. In a co-culture system, MOR stimulation of macrophages also resulted in increased proliferation of PC cells. MOR overexpression increased proliferation and cancer stemness, whereas knock-down of MOR followed opposite results in the PC cells. Morphine induced chemoresistance to conventional chemotherapeutic agents used for PC treatment. Overall, our results suggest that MOR is expressed in pancreatic cancer and may be involved in tumor progression and chemoresistance.
Learn More >Assessing mechanical pain thresholds from trigeminal, cervical, and distal pain-free areas during the four phases of a migraine cycle in patients with episodic migraine (EM).
Learn More >Sedentary lifestyle, chronic disease, or microgravity can cause muscle deconditioning that then has an impact on other physiological systems. An example is the nervous system, which is adversely affected by decreased physical activity resulting in increased incidence of neurological problems such as chronic pain. We sought to better understand how this might occur by conducting RNA sequencing experiments on muscle biopsies from human volunteers in a 5-week bed-rest study with an exercise intervention arm. We also used a computational method for examining ligand-receptor interactions between muscle and human dorsal root ganglion (DRG) neurons, the latter of which play a key role in nociception and are generators of signals responsible for chronic pain. We identified 1352 differentially expressed genes (DEGs) in bed rest subjects without an exercise intervention but only 132 DEGs in subjects with the intervention. Among 591 upregulated muscle genes in the no intervention arm, 26 of these were ligands that have receptors that are expressed by human DRG neurons. We detected a specific splice variant of one of these ligands, placental growth factor (PGF), in deconditioned muscle that binds to neuropilin 1, a receptor that is highly expressed in DRG neurons and known to promote neuropathic pain. We conclude that exercise intervention protects muscle from deconditioning transcriptomic changes, and prevents changes in the expression of ligands that might sensitize DRG neurons, or act on other cell types throughout the body. Our work creates a set of actionable hypotheses to better understand how deconditioned muscle may influence the function of sensory neurons that innervate the entire body.
Learn More >The anti-diabetic drug metformin has been shown to reduce pain hypersensitivity in preclinical models of chronic pain and in neuropathic pain in humans. Multiple intracellular pathways have been described as metformin targets. Among them, metformin is an activator of the adenosine 5'-monophosphate protein kinase (AMPK) that can in turn modulate the activity of the E3 ubiquitin ligase NEDD4-2 and thus posttranslational expression of voltage gated sodium channels (Nas). In this study, we found that the bulk of the effect of metformin on Na1.7 is dependent on NEDD4-2. In HEK cells, the expression of Na1.7 at the membrane fraction, obtained by a biotinylation approach, is only reduced by metformin when co-transfected with NEDD4-2. Similarly, in voltage clamp recordings, metformin significantly reduced Na1.7 current density when co-transfected with NEDD4-2. In mouse dorsal root ganglion (DRG) neurons, without changing the biophysical properties of Na1.7, metformin significantly decreased Na1.7 current densities, but not in Nedd4L knockout mice ( ). In addition, metformin induced a significant reduction in NEDD4-2 phosphorylation at the Serine 328 residue in DRG neurons, an inhibitory phosphorylation site of NEDD4-2. In current clamp recordings, metformin reduced the number of action potentials elicited by DRG neurons from , with a partial decrease also present in mice, suggesting that metformin can also change neuronal excitability in an NEDD4-2-independent manner. We suggest that NEDD4-2 is a player for the effect of metformin on the excitability of nociceptive neurons; this action may contribute to the relief of neuropathic pain.Metformin is a multi-target, anti-diabetic drug that has shown therapeutic potential to reduce neuropathic pain. The intracellular mechanisms leading to a reduction in hyperexcitability and pain hypersensitivity remain unclear. We found that metformin acts through the activity of the E3-ubiquitin ligase NEDD4-2 to reduce cell surface expression and currents of voltage gated sodium channels (Nas), especially the Na1.7 isoform. In current clamp experiments, metformin reduced the DRG neuron firing frequency, with a smaller effect in knockout mice ( ). On the other hand, NEDD4-2 is indispensable for the metformin effect on the rheobase and the resting membrane potential of DRG neurons. These results suggest that NEDD4-2 activity is a crucial actor, although not exclusive, to reduce the excitability of nociceptive neurons.
Learn More >The midbrain periaqueductal gray (PAG) is a key structure involved in the supraspinal modulation of pain. Previous studies have reported the association of gut inflammation-triggered chronic abdominal pain with structural and neuronal alterations within the PAG. However, whether PAG-executed visceral nociception processing and descending modulation are altered in gut pathology is not known. We used c-Fos immunohistochemistry and extracellular microelectrode recording in urethane-anesthetized male Wistar rats to evaluate the colitis-induced changes in visceral pain-related neuronal properties of the PAG and its descending outflow to visceral nociceptive neurons of the caudal ventrolateral medulla (CVLM). Analysis of c-Fos protein expression in inflamed animals has shown diminished activation of the lateral and ventrolateral PAG columns by noxious colorectal distension (CRD), although the nonstimulated c-Fos labeling in these PAG subdivisions was enhanced compared with that in controls. Microelectrode recording in the ventrolateral PAG revealed a colitis-elicited decrease in the proportion of CRD-excited neurons accompanied by an increase in the number of unresponsive cells and weakened reactions to the stimulation of CRD-inhibited PAG units. Colonic inflammation has also been found to cause a shift in the effects of ventrolateral PAG electrostimulation on CRD-excited CVLM neurons from being mostly inhibitory under normal conditions to excitatory in colitis. These findings identify impaired PAG functioning in ascending and descending visceral nociception control that may contribute to gut injury-associated visceral hyperalgesia. The data obtained can benefit a better understanding of the supraspinal mechanisms involved in the pathogenesis of postinflammatory chronic abdominal pain.
Learn More >P75 pan-neurotrophin receptor (p75NTR) is an important receptor for the role of neurotrophins in survival and death of neurons during development and after nerve injury. Our previous research found that the precursor of brain-derived neurotrophic factor (proBDNF) regulates pain as an inflammatory mediator. The current understanding of the role of proBDNF/p75NTR signaling pathway in inflammatory arthritis pain and rheumatoid arthritis (RA) is unclear. We recruited 20 RA patients, 20 healthy donors (HDs), and 10 osteoarthritis (OA) patients. Hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) of proBDNF and p75NTR in synovial membrane were performed and evaluated. We next examined the mRNA and protein expression of proBDNF/p75NTR signaling pathway in peripheral blood mononuclear cells (PBMCs) and synovial tissue. ELISA and flow cytometry were assessed between the blood of RA patients and HD. To induce RA, collagen-induced arthritis (CIA) were induced in mice. We found over-synovitis of RA synovial membrane compared to OA controls in histologic sections. P75NTR and sortilin mRNA, and proBDNF protein level were significantly increased in PBMCs of RA patients compared with the HD. Consistently, ELISA showed that p75NTR, sortilin, tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10) levels in the serum of RA patients were increased compared with HD and p75NTR, sortilin were positively correlated with Disease Activity Score in 28 joints (DAS28). In addition, using flow cytometry we showed that the increased levels of proBDNF and p75NTR characterized in CD4 and CD8 T cells of RA patients were subsequently reversed with methotrexate (MTX) treatment. Furthermore, we found pathological changes, inflammatory pain, upregulation of the mRNA and protein expression of proBDNF/p75NTR signaling pathway, and upregulation of inflammatory cytokines in spinal cord using a well-established CIA mouse model. We showed intravenous treatment of recombinant p75ECD-Fc that biologically blocked all inflammatory responses and relieved inflammatory pain of animals with CIA. Our findings showed the involvement of proBDNF/p75NTR pathway in the RA inflammatory response and how blocking it with p75ECD-Fc may be a promising therapeutic treatment for RA.
Learn More >Chronic primary low back pain may be associated with hyperalgesia in uninjured tissues and with decreased pain inhibition. Previous studies have shown that the amygdala is involved in pain regulation and chronic pain, that neuronal activity in the amygdala is altered in models of persistent pain, and that the central nucleus of the right amygdala plays an active role in widespread hypersensitivity to noxious stimuli.
Learn More >Chronic pain and its underlying biological mechanisms have been studied for many decades, with a myriad of molecules, receptors and cell types known to contribute to abnormal pain sensations. Besides an obvious role for neurons, immune cells like microglia, macrophages and T cells are also important drivers of persistent pain. While neuroinflammation has therefore been widely studied in pain research, there is one cell type that appears to be rather neglected in this context: the humble fibroblast. Fibroblasts may seem unassuming but actually play a major part in regulating immune cell function and driving chronic inflammation. Here, our aim was to determine the breadth and quality of research that implicates fibroblasts in chronic pain conditions and models.
Learn More >The spinal cord injury (SCI) patient population is overwhelmingly affected by neuropathic pain (NP), a secondary condition for which therapeutic options are limited and have a low degree of efficacy. The objective of this study was to identify novel deep brain stimulation (DBS) targets that may theoretically benefit those with NP in the SCI patient population. We hypothesize that localized changes in white matter identified in SCI subjects with NP compared to those without NP could be used to develop an evidence-based approach to DBS target identification.
Learn More >Chronic pain with its comorbidities, such as depression, insomnia, and social deprivation, is a major cause of disability and health-economic burden. Insufficient response to pain medication and potentially serious adverse effects have led the majority of chronic pain patients to seek relief from non-pharmacological remedies. Along with this trend, pain research has paid increasing interest in critical evaluation of various complementary treatments. Music-based treatments have emerged as an efficacious and safe means to enhance the management of acute and chronic pain. We review the current position of music-based interventions in the treatment of chronic pain and present explanations for the analgesic effects of music through modulation of the primary nociception and discuss the contribution of the mesolimbic dopaminergic system to the affective component of pain perception. We propose ways to translate the novel theoretical understanding into clinical practice in different health care settings, primary health care in particular, and discuss the preconditions of successful implementation. We argue that music interventions provide low-cost, easily applicable complementary pain treatments not requiring heavy utilization of health care resources. Finally, we provide research and quality improvement frameworks and make suggestions to cover the gaps of existing evidence. PERSPECTIVE: This article addresses the current evidence for analgesic effects of music interventions, discusses its neurobiological basis and evaluates potential use of music in treating chronic pain patients in different health care settings. We also propose directions for future research to cover shortages in the currently published data.
Learn More >Bone marrow lesions (BMLs) are associated with pain in osteoarthritis (OA), but histological scores for OA focus on cartilage pathology. We developed a new scoring system, the Osteoarthritis Bone Score (OABS), to characterise OA-related BMLs.
Learn More >Orexins or hypocretins are excitatory neuropeptides predominantly produced by neuronal clusters in the lateral hypothalamus. The orexinergic system's involvement in pain modulation makes it a candidate for pain control alternative to the opioid system. Moreover, orexin-1 and orexin -2 receptors (OX1r and OX2r, respectively) play a role in responsiveness to stressful stimuli. Some evidence indicates that the Cornu Ammonis 1 (CA1) region of the hippocampus potentially participates in the modulation of both pain and stress. In quest of better understanding the interaction between orexin receptors and stress-induced analgesia (SIA), The present study examined the involvement of OX1r and OX2r within the CA1 in response to acute pain after exposure to forced swim stress (FSS) for a 6-min period. Adult male Wistar rats received different doses of OX1r antagonist (SB334867; 1, 3, 10, and 30 nmol), OX2r antagonist (TCS OX2 29; 3, 10, 30 and 100 nmol), or vehicle (0.5µl DMSO) through an implanted cannula. After that, animals individually experienced acute pain by performing the tail-flick test. Results indicated that FSS produces antinociceptive responses in the tail-flick test. Blockade of both orexin receptors within the CA1 region attenuated the analgesic effect of FSS. The antinociceptive effect of swim stress was prevented by lower doses of SB334867 than TCS OX2 29. These findings show that the orexinergic system might be partially involved in the SIA via the OX1 and OX2 receptors in the hippocampal CA1 region.
Learn More >A treat-to-target strategy, in which strictly defined treatment targets facilitate decision making in clinical practice, is advocated as an optimised management approach for some chronic disorders. The aim of the STARDUST trial was to assess whether a treat-to-target strategy with early endoscopy, regular biomarker and clinical symptom monitoring, and dose intensification for persistent inflammatory activity, was more successful in achieving endoscopic improvement at week 48 than a clinically driven maintenance strategy in patients with moderate-to-severe active Crohn's disease receiving ustekinumab.
Learn More >Musculoskeletal pain is a global health concern and work-related psychosocial stress might be a potential contributing factor. This cross-sectional study investigates whether job stress is associated with chronic and widespread musculoskeletal pain in 2,051 Brazilian active civil servants included in the ELSA-Brasil MSK cohort. Job stress was assessed using the Effort-Reward Imbalance (ERI) questionnaire. Associations between ERI domains, categorized into tertiles, and chronic musculoskeletal pain (CMP) at any site and per number of affected sites (0, 1-2, ≥3-multisite pain) and body regions (0, 1-2, 3-generalized pain), were investigated using binary and multinomial logistic regression, adjusted for sociodemographic, occupational and health covariates. The prevalence of CMP at any site, multisite and generalized was 52.9%, 18.2% and 9.5%, respectively. Following adjustments, the lower the reward and the greater the overcommitment, the higher the odds of CMP at any site. The ERI domains were more strongly associated with multisite and generalized CMP than with CMP at any site. Multisite CMP was associated with lower reward, and with greater effort, overcommitment, and effort-reward imbalance ratio. CMP according to body regions, especially generalized pain, was also associated with ERI domains effort (OR=2.06; 95%CI=1.33-3.21), overcommitment (OR=3.44; 95%CI=2.20-5.39), and effort-reward imbalance ratio (OR= 2.06; 95%CI=1.30-3.27). Results reveal an association between job stress not only with CMP at any site, but notably with the pain spread to other body sites/regions. Our findings suggest that lowering stress at work and discouraging overcommitment may help reduce the CMP burden including reduction of CMP spread from one sites/regions of the body to another.
Learn More >This study examined the efficacy of Internet-delivered cognitive and behavioural interventions for adults with chronic pain, and explored the role of clinical and study characteristics as moderators of treatment effects. PubMed, Embase, PsycINFO, and CENTRAL and CINAHL were searched to identify randomised controlled trials published up to October 2021. A meta-analysis of 36 studies (5778 participants) was conducted, which found small effect sizes for interference/disability (Hedges' g = 0.28; 95% CI 0.21, 0.35), depression (g = 0.43; 95% CI 0.33, 0.54), anxiety (g = 0.32; 95% CI 0.24, 0.40), pain intensity (g = 0.27; 95% CI 0.21, 0.33), self-efficacy (g = 0.39; 95% CI 0.27, 0.52) and pain catastrophizing (g = 0.31; 95% CI 0.22, 0.39). Moderator analyses found interventions which involved clinician guidance had significantly greater effect sizes for interference/disability (g = 0.38), anxiety (g = 0.39), and pain intensity (g = 0.33) compared to those without (g = 0.16, g = 0.18; g = 0.20, respectively). Studies using an inactive control had greater effects for depression (g = 0.46) compared to active control trials (g = 0.22). No differences were found between treatments based on traditional Cognitive Behaviour Therapy versus Acceptance and Commitment Therapy. Sample size, study year, and overall risk of bias (Cochrane rating) did not consistently moderate treatment effects. Overall, the results support the use of internet-delivered cognitive and behavioural interventions as efficacious and suggest guided interventions are associated with greater clinical gains for several key pain management outcomes.Prospectively registered on OSF Registries (citation: osf.io/cvq3j/).
Learn More >Higher body mass and obesity are associated with bodily pain, and rates of chronic pain increase among older adults. Most past studies are cross-sectional, precluding determination of the temporal relationship between body mass and pain. A longitudinal study of body mass and pain among middle-aged adults found that higher body mass index (BMI) led to greater lower back pain. No longitudinal study of BMI and pain has been conducted among adults over age 70. This study utilized dual-change-score models (DCSMs) to determine the directional relationship between BMI and bodily pain in a sample of middle-aged and older adults. Participants (n=1889) from the Swedish Twin Registry (baseline age range 40-93 years) completed at least one nurse assessment of BMI and self-report ratings of pain interference and joint pain. Pain interference was not associated with BMI, but joint pain was analyzed in univariate and bivariate models, with DCSMs modeling the relationship of BMI and joint pain across age, both independently and as part of bivariate relationships. Results indicated a reciprocal relationship between BMI and joint pain, but joint pain generally led to changes in BMI. In addition, the relationship changed with age: until approximately age 80, increasing joint pain contributed to higher BMI, but after that time increasing joint pain contributed to lower BMI. Also, sex differences in the relationship between BMI and pain appeared after age 70. Thus, joint pain contributes to changes in BMI among middle-aged and older adults, but the relationship may change by age and sex.
Learn More >Stress has been shown to affect brain activity and exert potent and complex modulatory effects on pain. Several behavioral tests have shown that acute stress produces hyperalgesia, depending on the stress conditions. In the present study, we investigated the effects of single restraint stress on the tactile threshold and anxiety sensitivity in mice. Mice were evaluated for the tactile threshold using von Frey filaments and for anxiety sensitivity using the elevated plus maze (EPM) test. Tactile thresholds were lowered by both 2 and 4 hour of restraint stress, but anxiety-like behaviors were observed only after 4 hour of restraint stress in the EPM test. In addition, we found that alfaxalone, which is a positive allosteric modulator of the γ-aminobutyric acid (GABA) receptor, prevented restraint stress-induced hyperalgesia-like and anxiety-like behaviors. These results indicate that GABAergic function appears to be critical in the regulation of physical stress-induced hyperalgesia and anxiety.
Learn More >Early onset of action has become recognized as an important efficacy feature of preventive migraine treatment, which can help overcome adherence issues commonly associated with older medications. Preventive treatments that target the calcitonin gene-related peptide (CGRP) or the CGRP receptor have been previously shown to provide early onset of action.
Learn More >Migraines is likely to play a protective role in the risk of breast cancer. Some studies have shown that there is an inverse relationship between migraine and breast cancer, and some studies have not found an association; therefore, results from previous studies have been inconclusive and we conducted a meta-analysis to evaluate association between migraine and breast cancer.
Learn More >To examine the association of body mass index (BMI) with pain in people with hand osteoarthritis, and explore whether this association, if causal, is mediated by systemic inflammatory biomarkers.
Learn More >To evaluate the efficacy and safety of opioids for analgesic therapy for people with osteoarthritis.
Learn More >The purpose of this study was to investigate if vessel-wall magnetic resonance imaging (VW-MRI) could differentiate among primary headaches disorders, such as migraine and cluster headache (CH), and detect the presence of neurogenic inflammation.
Learn More >Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology with aberrant immunological responses leading to inflammation, swelling and pain of the joints. CD8 T cells have been known to be one of the major immune modulators in the progression of RA and the presence of toll-like receptors (TLRs) on these cells further accentuate their role in RA. Herein, we report an increased expression of TLR7 in the endosomes of CD8 T cells of RA patients correlating with disease severity. The stimulation of TLR7 with Imiquimod (IMQ) in these CD8 T cells drives the signalling cascade via NFkB and pERK activation and hence an increase in the mRNA transcripts of signature cytokines and cytolytic enzymes. However, a parallel synthesis of Tristetraprolin (TTP), an mRNA destabilizing protein prevents the translation of the mRNA transcripts, leading to a rapid degeneration of the target mRNA. We thus report that a direct TLR7 ligation by its agonist increases cytokine transcript signature but not an equivalent protein surge.
Learn More >The purpose of this study was to examine changes in the functional impact of migraine following treatment with erenumab, as measured by the Migraine Functional Impact Questionnaire (MFIQ).
Learn More >Opioids, and numerous centrally active drugs, are metabolized by cytochrome P450 2D (CYP2D). There are sex and estrous cycle differences in brain oxycodone analgesia. Here we investigated the mechanism examining the selective role of CYP2D in the brain on sex, estrous cycle, and hormonal regulation. Propranolol, CYP2D-specific mechanism-based inhibitor, or vehicle was delivered into cerebral ventricles 24 hours before administering oxycodone (or oxymorphone, negative control) orally to male and female (in estrus and diestrus) rats. Ovariectomized and sham-operated females received no treatment, estradiol, progesterone or vehicle. Analgesia was measured using tail-flick latency, and brain drug and metabolite concentrations were measured by microdialysis. Data were analyzed by two-way or mixed ANOVA. Following propranolol (versus vehicle) inhibition and oral oxycodone, there were greater increases in brain oxycodone concentrations and analgesia, and greater decreases in brain oxymorphone/oxycodone ratios (an in vivo phenotype of CYP2D in brain) in males and females in estrus, compared to females in diestrus; with no impact on plasma drug concentrations. There was no impact of propranolol pre-treatment, sex, or cycle after oral oxymorphone (non-CYP2D substrate) on brain oxymorphone concentrations or analgesia. There was no impact of propranolol pre-treatment following ovariectomy on brain oxycodone concentrations or analgesia, which was restored in ovariectomized females following estradiol, but not progesterone, treatment. Sex, cycle, and estradiol regulation of CYP2D in brain in turn altered brain oxycodone concentration and response, which may contribute to the large inter-individual variation in response to the numerous centrally acting CYP2D substrate drugs, including opioids.
Learn More >Chronic pain is associated with anhedonia and decreased motivation. These behavioral alterations have been linked to alterations in the limbic brain and could explain the increased risk for obesity in pain patients. The mechanism of these behavioral changes and how they set in in relation to the development of chronic pain remain however poorly understood. Here we asked how eating behavior was affected in low-back pain patients before and after they transitioned to chronic pain, compared to patients whose pain subsided. Additionally, we assessed how the hedonic perception of fat-rich food, which is altered in chronic pain patients, related to the properties of the nucleus accumbens in this patients' population. We hypothesized that the accumbens would be directly implicated in the hedonic processing of fat-rich food in pain patients because of its well-established role in hedonic feeding and fat ingestion, and its emerging role in chronic pain. Accordingly, we used behavioral assays and structural brain imaging to test sub-acute back pain patients (SBP) and healthy control subjects at baseline and at approximately one-year follow-up. We also studied a sample of chronic low-back pain patients (CLBP) at one time point only. We found that SBP patients who recovered at follow-up (SBPr) and CLBP patients showed disrupted eating behaviors. In contrast, SBP patients who persisted in having pain at follow-up (SBPp) showed intact eating behavior. From a neurological standpoint, only SBPp and CLBP patients showed a strong and direct relationship between hedonic perception of fat-rich food and nucleus accumbens volume. This suggests that accumbens alterations observed in SBPp patients in previous works might protect them from hedonic eating disruptions during the early course of the illness. We conclude that disrupted eating behavior specifically sets in after pain chronification and is accompanied by structural changes in the nucleus accumbens.
Learn More >In a recently published genome-wide association study (GWAS) chronic back pain was associated with three loci; and . This GWAS was based on a heterogeneous sample of back pain disorders, and it is unknown whether these loci are of clinical relevance for low back pain (LBP) with persistent radiculopathy. Thus, we examine if LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy is associated with the selected single nucleotide polymorphisms (SNPs); rs34616559, rs7833174 and rs4384683. In this prospective cohort study, subjects admitted to a secondary health care institution due to an acute episode of LBP with radiculopathy, reported back pain, leg pain, and Oswestry Disability Index (ODI), were genotyped and followed up at 12 months ( = 338). Kruskal-Wallis H test showed no association between the SNPs and back pain, leg pain or ODI. In conclusion, LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy, is not associated with the selected SNPs; rs34616559, rs7833174 and rs4384683. This absent or weak association suggests that the SNPs previously associated with chronic back pain are not useful as prognostic biomarkers for LBP with persistent radiculopathy.
Learn More >Pain, either nociceptive or neuropathic (NP), is a common symptom in Charcot-Marie-Tooth (CMT) disease.
Learn More >Psychobiological temperament and cognitive-evaluative character link to coping with chronic pain. The aim was to study possible independent role of temperament and character dimensions both in chronic and experimental pain in chronic post-surgical pain patients. This is a substudy of a previously published larger cohort of patients with intercostobrachial nerve injury after breast cancer surgery.
Learn More >Ion channels play a pivotal role in anesthesia, including general and regional anesthesia. Two main classes of general anesthetics (GAs) are inhalational anesthetics, such as isoflurane, sevoflurane, and nitrous oxide; injectable anesthetics, such as propofol, etomidate, and ketamine. Besides hypnotic agents, muscle relaxants for immobility and opioids for analgesia are needed to achieve balanced anesthesia. Although our understanding of anesthesia is far from complete, recent studies have revealed the molecular interactions between anesthetic drugs and ion channels, particularly, the ligand-gated ion channels (LGICs). Ionotropic GABA receptors (GABARs), the main mediators of the inhibitory signals in the central nervous system (CNS), are the key to hypnosis by general anesthetics. Ionotropic cholinergic receptors (nAChRs), expressed at the neuromuscular junction and the nervous system, are the molecular targets of muscle relaxants. GABARs and nAChRs belong to the same family of pentameric LGICs. With a completely different architecture, ionotropic glutamate receptors (iGluRs) carry the excitatory signals in the CNS and are targeted by inhalational anesthetics and ketamine. Another distinct family of ion channels, two-pore-domain K (K2P) channels, can be activated by inhalational anesthetics and cause neuron hyperpolarization. In this chapter, we will discuss the recent advance in understanding the molecular mechanisms underlying anesthesia through the molecular structures of these ion channels.
Learn More >Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel that is intensively expressed in the peripheral nerve system and involved in a variety of physiological and pathophysiological processes in mammals. Its activity is of great significance in transmitting pain or itch signals from peripheral sensory neurons to the central nervous system. The alteration or hypersensitivity of TRPV1 channel is well evidenced under various pathological conditions. Moreover, accumulative studies have revealed that TRPV1-expressing (TRPV1) sensory neurons mediate the neuroimmune crosstalk by releasing neuropeptides to innervated tissues as well as immune cells. In the central projection, TRPV1 terminals synapse with the secondary neurons for the transmission of pain and itch signalling. The intense involvement of TRPV1 and TRPV1 neurons in pain and itch makes it a potential pharmaceutical target. Over decades, the basis of TRPV1 channel structure, the nature of its activity, and its modulation in pathological processes have been broadly studied and well documented. Herein, we highlight the role of TRPV1 and its associated neurons in sensing pain and itch. The fundamental understandings of TRPV1-involved nociception, pruriception, neurogenic inflammation, and cell-specific modulation will help bring out more effective strategies of TRPV1 modulation in treating pain- and itch-related diseases.
Learn More >The goal of this study was to analyze the reasons for delayed diagnosis of Guillain-Barre syndrome (GBS).
Learn More >Therapeutic monoclonal antibodies against the calcitonin gene-related peptide (CGRP) receptor or its ligand have changed the landscape of treatment options for migraine. Erenumab is the first and only fully human monoclonal antibody designed to target and block the CGRP receptor. It is approved by the Food and Drug Administration for preventive treatment of migraine in adults. The recommended dose of erenumab is 70 mg monthly, with guidance that some patients may benefit from the 140 mg monthly dose. There is a need for information to guide clinical practice on the comparative efficacy and safety of these two dosing options.
Learn More >To examine the clusters of chronic conditions present in people with osteoarthritis and the associated risk factors and health outcomes.
Learn More >To determine the efficacy of psychological interventions in studies of adults with migraine, in reducing pain, and functional and psychosocial difficulties.
Learn More >To evaluate the evidence regarding acute migraine treatment optimization to prevent the progression of episodic migraine to chronic migraine. This review also provides a summary of evidence-based acute migraine treatments and how to tailor a regimen based on an individual patient's needs.
Learn More >Adverse childhood experiences (ACEs) are cross-sectionally associated with headache, including migraine, in pediatric populations.
Learn More >To explore a protection motivation theory screening tool for predicting rehabilitation adherence.
Learn More >Thalamocortical dysfunction is thought to underlie the pathophysiology of chronic pain revealed by electroencephalographic studies. The thalamus serves as a primary relay center to transmit sensory information and motor impulses via dense connections with the somatosensory and motor cortex. In this study, diffusion tensor imaging (probabilistic tractography) and resting-state functional magnetic resonance imaging (functional connectivity) were used to characterize the anatomical and functional integrity of the thalamo-sensorimotor pathway in chronic low back pain (cLBP). Fifty-four patients with cLBP and 54 healthy controls were included. The results suggested significantly increased anatomical connectivity of the left thalamo-motor pathway characterized by probabilistic tractography in patients with cLBP. Moreover, there was significantly increased resting-state functional connectivity (rsFC) of bilateral thalamo-motor/somatosensory pathways in patients with cLBP as compared to healthy controls. We also detected a significant positive correlation between pain intensity during the MRI scan and rsFC of the right thalamo-somatosensory pathway in cLBP. Our findings highlight the involvement of the thalamo-sensorimotor circuit in the pathophysiology of cLBP.
Learn More >Total joint arthroplasties are among the most common elective procedures in the United States, and they are associated with postoperative pain. Gabapentin enacarbil is a prodrug with an extended-release formulation that has been proposed for multimodal postoperative analgesia, but the drug's efficacy for major arthroplasties remains unclear.
Learn More >High-frequency (10-kHz) spinal cord stimulation (SCS) continues to be an emerging therapy in chronic pain management. The same complications that plagued earlier SCS systems may affect newer stimulation technologies, although there is limited data on the type of complications and surgical management of these complications.
Learn More >Toll-like receptors (TLR) have been proposed as a site of action that alters opioid pharmacodynamics. However, a comprehensive assessment of acute opioid antinociception, tolerance and withdrawal behaviours in genetic null mutant strains with altered innate immune signalling has not been performed. Nor has the impact of genetic deletion of TLR2/4 on high-affinity opioid receptor binding. Here we show that diminished TLR signalling potentiates acute morphine antinociception equally in male and female mice. However, only male TIR8 null mutant mice showed reduced morphine analgesia. Analgesic tolerance was prevented in TLR2 and TLR4 null mutants, but not MyD88 animals. Withdrawal behaviours were only protected in TLR2 mice. In silico docking simulations revealed opioid ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. There was no binding of [H](-)-naloxone or [H]diprenorphine to TLR4 in the concentrations explored. These data confirm that opioids have high efficacy activity at innate immune pattern recognition binding sites but do not bind to TLR4 and identify critical pathway and sex-specific effects of the complex innate immune signalling contributions to opioid pharmacodynamics. These data further support the behavioural importance of the TLR-opioid interaction but fail to demonstrate direct evidence for high-affinity binding of the TLR4 signalling complex to ligands.
Learn More >Anodal transcranial direct current stimulation (tDCS) of primary motor cortex (M1) and cathodal of the primary sensory cortex (S1) have previously shown to modulate the sensory thresholds when administered with the reference electrode located over the contralateral supraorbital area (SO). Combining the two stimulation paradigms into one with simultaneous stimulation of the two brain areas (M1 + S1 – tDCS) may result in a synergistic effect inducing a prominent neuromodulation, noticeable in the pain thresholds. The aim of this study is to assess the efficacy of the novel M1 + S1 – tDCS montage compared to sham-stimulation in modulating the pain thresholds in healthy adults.
Learn More >Vocacapsaicin is a novel prodrug of trans-capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) being developed as a nonopioid, long-lasting, site-specific treatment for postsurgical pain management. The objective of these studies was to examine the safety and tolerability of vocacapsaicin in an osteotomy model in two animal species and to evaluate bone healing parameters. Rats undergoing unilateral femoral osteotomy received a single perioperative administration (by instillation) of vocacapsaicin (vehicle, 0.15, 0.3, and 0.6 mg/kg). Rabbits undergoing unilateral ulnar osteotomy received a single perioperative administration (by infiltration and instillation) of vocacapsaicin (vehicle, 0.256 and 0.52 mg) alone or in combination with 0.5% ropivacaine. Clinical signs, body weights, food consumption, radiography, histopathologic examinations, ex vivo bone mineral density measurements (rats only), and biomechanical testing were evaluated at 4 and 8 weeks in rats and at 2 and 10 weeks in rabbits. Plasma samples were also collected in rabbits. There were no vocacapsaicin-related effects on mortality, clinical observations, body weight, or food consumption in either species. Systemic exposure to vocacapsaicin and its metabolites, including capsaicin, was transient. In rats, vocacapsaicin was devoid of deleterious effects on bone healing parameters, and there was a trend for enhanced bone healing in rats treated with the mid-dose. In rabbits, vocacapsaicin administered alone or in combination with ropivacaine did not adversely affect bone healing parameters. In conclusion, a single perioperative administration of vocacapsaicin in unilateral osteotomy models was well tolerated, locally and systemically, supporting its continued development as a novel, nonopioid treatment for postsurgical pain management.
Learn More >Endometriosis is a chronic neuroinflammatory pain condition affecting ~180 million women worldwide. Surgical removal or hormonal suppression of endometriosis lesions only relieves pain symptoms in some women and symptomatic relapse following treatment is common. Identifying factors that contribute to pain is key to developing new therapies. We collected peritoneal fluid samples and clinical data from a cohort of women receiving diagnostic laparoscopy for suspected endometriosis ( = 52). Peritoneal fluid immune cells were analysed by flow cytometry and data compared with pain scores determined using the pain domain of the Endometriosis Health Profile Questionnaire (EHP-30) in order to investigate the association between peritoneal immune cells and pain symptoms. Pain scores were not different between women with or without endometriosis, nor did they differ according to disease stage; consistent with a poor association between disease presentation and pain symptoms. However, linear regression and correlation analysis demonstrated that peritoneal macrophage abundance correlated with the severity of pelvic pain. CD14 peritoneal macrophages negatively correlated with pain scores whereas CD14 peritoneal macrophages were positively correlated, independent of diagnostic outcome at laparoscopy. Stratification by pain subtype, rather than endometriosis diagnosis, resulted in the most robust correlation between pain and macrophage adundance. Pain score strongly correlated with CD14 ( = 0.007) and CD14 ( = 0.008) macrophages in patients with non-menstrual pain and also in patients who reported dysmennorhea (CD14 = 0.021, CD14 = 0.019) or dysparunia (CD14 = 0.027, CD14 = 0.031). These results provide new insight into the association between peritoneal macrophages and pelvic pain which may aid the identification of future therapeutic targets.
Learn More >Chronic pain arising from peripheral nerve injuries represents a significant clinical challenge because even the most efficacious anticonvulsant drug treatments are limited by their side effects profile. We investigated pain behavior, changes in axonal signal conduction and excitability of trigeminal neurons, and expression of voltage-gated sodium channels (NaVs) in the infraorbital nerve and trigeminal ganglion (TG) after infraorbital nerve entrapment (IoNE). Compared to Sham, IoNE rats had increased A- and C-fiber compound action potentials (CAPs) and Aδ component of A-CAP area from fibers innervating the vibrissal pad. After IoNE, A- and C-fiber CAPs were more sensitive to blockade by tetrodotoxin (TTX), and those fibers that were TTX-resistant were more sensitive to blockade by the NaV1.8 selective blocker, A-803467. Although NaV1.7 blocker, ICA-121431 alone, did not affect Aδ-fiber signal propagation, cumulative application with A-803467 and 4,9-anhydro-TTX significantly reduced the Aδ-fiber CAP in IoNE rats. In patch clamp recordings from small- and medium-sized TG neurons, IoNE resulted in reduced action potential (AP) depolarizing current threshold, hyperpolarized AP voltage threshold, increased AP duration, and a more depolarized membrane potential. While the transcripts of most NaVs were reduced in the ipsilateral TG after IoNE, NaV1.3, NaV1.7, and NaV1.8 mRNAs, and NaV1.8 protein, were significantly increased in the nerve. Altogether, our data suggest that axonal redistribution of NaV1.8, and to a lesser extent NaV1.3, and NaV1.7 contributes to enhanced nociceptive signal propagation in peripheral nerve after IoNE.
Learn More >Non-operative management of trapeziometacarpal osteoarthritis (TMOA) demonstrates only short-term symptomatic alleviation, and no approved disease modifying drugs exist to treat this condition. A key issue in these patients is that radiographic disease severity can be discordant with patient reported pain, illustrating the need to identify molecular mediators of disease. This study characterizes the biochemical profile of TMOA patients to elucidate molecular mechanisms driving TMOA progression.
Learn More >Diffusion spectrum imaging (DSI) was used to quantitatively study the changes in the trigeminal cistern segment in patients with trigeminal neuralgia (TN) and to further explore the value of acquiring DSI data from patients with TN.
Learn More >Chemotherapy-induced peripheral neurotoxicity is a common dose-limiting side effect of several cancer chemotherapeutic agents, and no effective therapies exist. Here we constructed a systems pharmacology model of intracellular signaling in peripheral neurons to identify novel drug targets for preventing peripheral neuropathy associated with proteasome inhibitors. Model predictions suggested the combinatorial inhibition of TNFα, NMDA receptors, and reactive oxygen species should prevent proteasome inhibitor-induced neuronal apoptosis. Dexanabinol, an inhibitor of all three targets, partially restored bortezomib-induced reduction of proximal action potential amplitude and distal nerve conduction velocity and prevented bortezomib-induced mechanical allodynia and thermal hyperalgesia in rats, including a partial recovery of intraepidermal nerve fiber density. Dexanabinol failed to restore bortezomib-induced decreases in electrophysiological endpoints in rats, and it did not compromise bortezomib anti-cancer effects in U266 multiple myeloma cells and a murine xenograft model. Owing to its favorable safety profile in humans and preclinical efficacy, dexanabinol might represent a treatment option for bortezomib-induced neuropathic pain.
Learn More >Fibromyalgia (FM) is characterised by chronic, continuous, widespread pain, often associated with a sense of fatigue, non-restorative sleep and physical exhaustion. Due to the nature of this condition and the absence of other neurological issues potentially able to induce disorders in body representations per se, it represents a perfect model since it provides an opportunity to study the relationship between pain and the bodily self. Corporeal illusions were investigated in 60 participants with or without a diagnosis of FM by means of an devised interview. In addition, motor imagery was investigated and illusions relating to body part movements and changes in body size, feelings of alienness, and sensations of body parts not belonging to one's own body (disownership and somatoparaphrenic-like sensations) were found. Crucially, these symptoms do not correlate with any of the clinical measures of pain or functional deficits. The results showed that motor imagery was also impaired, and the severity of the deficits found correlated with the functional impairment of the participant. This indicates that disorders in body representations and motor imagery are part of the clinical expression of FM. However, while motor imagery seems to be linked to reduced autonomy and functional deficits, bodily illusions are independent and potentially represent a concurrent symptom.
Learn More >5-Lipoxygenase (5-LO) is the key enzyme in the formation of pro-inflammatory leukotrienes (LT) which play an important role in a number of inflammatory diseases. Accordingly, 5-LO inhibitors are frequently used to study the role of 5-LO and LT in models of inflammation and cancer. Interestingly, the therapeutic efficacy of these inhibitors is highly variable. Here we show that the frequently used 5-LO inhibitors AA-861, BWA4C, C06, CJ-13,610 and the FDA approved compound zileuton as well as the pan-LO inhibitor nordihydroguaiaretic acid interfere with prostaglandin E (PGE) release into the supernatants of cytokine-stimulated (TNFα/IL-1β) HeLa cervix carcinoma, A549 lung cancer as well as HCA-7 colon carcinoma cells with similar potencies compared to their LT inhibitory activities (IC values ranging from 0.1-9.1 µM). In addition, AA-861, BWA4C, CJ-13,610 and zileuton concentration-dependently inhibited bacterial lipopolysaccharide triggered prostaglandin (PG) release into human whole blood. Western Blot analysis revealed that inhibition of expression of enzymes involved in PG synthesis was not part of the underlying mechanism. Also, liberation of arachidonic acid which is the substrate for PG synthesis as well as PGH and PGE formation were not impaired by the compounds. However, accumulation of intracellular PGE was found in the inhibitor treated HeLa cells suggesting inhibition of PG export as major mechanism. Further, experiments showed that the PG exporter ATP-binding cassette transporter multidrug resistance protein 4 (MRP-4) is targeted by the inhibitors and may be involved in the 5-LO inhibitor-mediated PGE inhibition. In conclusion, the pharmacological effects of a number of 5-LO inhibitors are compound-specific and involve the potent inhibition of PGE export. Results from experimental models on the role of 5-LO in inflammation and pain using 5-LO inhibitors may be misleading and their use as pharmacological tools in experimental models has to be revisited. In addition, 5-LO inhibitors may serve as new scaffolds for the development of potent prostaglandin export inhibitors.
Learn More >Since PA-8 (5-(4-(Allyloxy)-3-methoxyphenyl)-2-amino-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione) was recently identified as a novel small-molecule antagonist of the pituitary adenylate cyclase-activating polypeptide (PACAP) type I (PAC1) receptor, a series of pyrido[2,3-d]pyrimidine derivatives have been designed, synthesized and subsequently evaluated for antagonistic activity on the PAC1 receptor. In this study, we synthesized 21 derivatives based on the PA-8 structure. Among them, the compound 2o (2-Amino-5-(3-trifluoromethoxy-phenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione) showed more potent antagonistic activities than PA-8. Intrathecal (i.t.) injection of 2o blocked the induction of PACAP-induced aversive behaviors and mechanical allodynia in mice, and the effects were more potent than those of PA-8. A single i.t. injection of 2o also inhibited spinal nerve ligation (SNL)-induced mechanical allodynia. Repeated intraperitoneal administration of 2o gradually reduced the SNL-induced mechanical allodynia, and this effect appeared earlier than for PA-8. In addition, 2o exhibited a favorable ADME and pharmacokinetics profiles. These results suggest that 2o may become an analgesic for the treatment of neuropathic pain.
Learn More >Some osteoarthritis (OA) patients experience inadequate pain relief from analgesics like acetaminophen and nonsteroidal anti-inflammatory drugs. This could be the result of experienced non-nociceptive centralized pain. Placebo-controlled randomized trials (RCT) have proven the effectiveness of duloxetine for OA and several chronic pain conditions where central sensitization (CS) is one of the key underlying pain mechanisms.
Learn More >Migraine has complex pathophysiological characteristics and episodic attacks. To decipher the cyclic neurophysiological features of migraine attacks, in this study, we compared neuronal excitability in the brainstem and primary somatosensory (S1) region between migraine phases for 30 consecutive days in two patients with episodic migraine.
Learn More >Migraine is a risk factor for ischemic stroke, but the mechanisms of stroke associated with migraine are debated. The aim of this study was to investigate the association between migraine and large artery atherosclerosis (LAA) in young adults with ischemic stroke.
Learn More >Burning mouth syndrome is a chronic condition, which is characterised by a burning sensation or pain in the mucosa of the oral cavity. Treatment options include antidepressants, antipsychotics, anticonvulsants, analgesics, hormone replacement therapies and more recently photobiomodulation. This study aims to perform a systematic review with meta-analysis in order to determine the effect of photobiomodulation on pain relief and the oral health-related quality of life associated with this condition. A bibliographical search of the Pubmed, Embase, Web of Science and Scopus databases was conducted. Only randomised clinical trials were included. Pain and quality of life were calculated as mean difference and pooled at different treatment points (baseline = T0 and final time point = Tf) and laser modality. From a total of 103 records, 7 articles were retrieved for inclusion. PBM group had a greater decrease in pain than control group at Tf with a mean difference = - 2.536 (IC 95% - 3.662 to - 1.410; I = 85.33%, p < 0.001). An improvement in oral health-related quality of life was observed in both groups, although this was more significant in the photobiomodulation group mean difference = - 5.148 (IC 95% - 8.576 to - 1.719; I = 84.91%, p = 0.003). For the red laser, a greater improvement than infrared was observed, in pain, mean difference = - 2.498 (IC 95% - 3.942 to - 1.053; I = 79.93%, p < 0.001), and in quality of life, mean difference = - 8.144 (IC 95% - 12.082 to - 4.206; I = 64.22%, p = 0.027). Photobiomodulation, in particular, red laser protocols, resulted in improvement in pain and in quality of life of burning mouth syndrome patients.
Learn More >Rheumatoid arthritis (RA) is a common systemic inflammatory autoimmune disease that severely affects the life quality of patients. Current therapeutics in clinic mainly focus on alleviating the development of RA or relieving the pain of patients. The emerging biological disease-modifying antirheumatic drugs (DMARDs) require long-term treatment to achieve the expected efficacy. With the development of bionanotechnology, nucleic acids fulfill characters as therapeutics or nanocarriers and can therefore be alternatives to combat RA. This review summarizes the therapeutic RNAs developed through RNA interference (RNAi), nucleic acid aptamers, DNA nanostructures-based drug delivery systems, and nucleic acid vaccines for the applications in RA therapy and diagnosis. Furthermore, prospects of nucleic acids for RA therapy are intensively discussed as well.
Learn More >Cilostazol is an antiplatelet agent with vasodilating, endothelial function restoration, and anti-inflammatory effects. This study aims to investigate the efficacy of oral cilostazol for preventing the development of diabetic peripheral neuropathy (DPN). Ninety adult male Sprague-Dawley rats were divided into five groups: 1) naïve (control); 2) diabetic (DM); 3) DM receiving 10 mg/kg cilostazol (cilo-10); 4) DM receiving 30 mg/kg cilostazol (cilo-30); and 5) DM receiving 100 mg/kg cilostazol (cilo-100). Hindpaw responses to thermal and mechanical stimuli were measured. Activation of microglia and astrocytes in the spinal dorsal horn (SDH) and expression of NaVs in the dorsal root ganglia (DRG) were examined with Western blots and immunofluorescence. DM rats displayed decreased withdrawal thresholds to mechanical stimuli (mechanical allodynia) and blunted responses to thermal stimuli. In addition, the expression of microglia increased, but astrocytes were reduced in the SDH. Upregulation of Nav -1.1, 1.2, -1.3, -1.6, and -1.7 and downregulation of Nav-1.8 were observed in the DRG. The DM rats receiving cilostazol all returned DM-induced decrease in withdrawal threshold to mechanical stimuli and attenuated neuropathic pain. Additionally, all cilostazol treatments suppressed the level of activated microglial cells and ameliorated the DM-induced decline in astrocyte expression levels in the SDH. However, only the rats treated with cilo-100 demonstrated significant improvements to the aberrant NaV expression in the DRG. Oral cilostazol can blunt the responses of mechanical allodynia and has the potential to treat diabetic neuropathy by attenuating NaV and glial cell dysregulation.
Learn More >A randomized controlled trial of a new type of Physiotherapy informed by Acceptance and Commitment Therapy (PACT), found that it improved functioning in people with chronic low back pain compared to usual physiotherapy care. Fidelity evaluation is necessary to understand trial processes and outcomes. This study evaluated PACT treatment fidelity including delivery, receipt, and enactment.
Learn More >Characteristics of persistent post-traumatic headache (PTH) in young individuals are poorly known leading to diagnostic problems and diverse management. We aimed to describe headache phenotypes and self-reported management strategies in young individuals with PTH following mild traumatic brain injury (mTBI). A comprehensive structured questionnaire was used to evaluate headache phenotypes/characteristics and management strategies to relieve headache in 107, 15-30-year-old individuals with PTH. Around 4 months post-injury, migraine-like headache in combination with tension-type like headache (40%) was the most commonly encountered headache phenotype followed by migraine-like headache (36%). Around 50% reported aura-like symptoms before/during the headache attack. Medication-overuse headache was diagnosed in 10%. Stress, sleep disturbances, and bright lights were the most common trigger factors. More than 80% reported that their headache was worsened by work-related activity and alleviated by rest/lying down. Simple analgesics were commonly used (88%) whereas prophylactic drugs were rarely used (5%). Bedrest and physiotherapy were also commonly used as management strategies by 56% and 34% of the participants, respectively. In conclusion, most young individuals with PTH after mTBI presented with combined migraine-like and tension-type-like headache followed by migraine-like headache, only. Preventive headache medication was rarely used, while simple analgesics and bedrest were commonly used for short-term headache relief.
Learn More >This review was designated to evaluate the efficacy of parenteral ketorolac in treating acute migraine headache.
Learn More >Conditioned pain modulation (CPM) is a psychophysical parameter that is used to reflect the efficacy of endogenous pain inhibition. CPM reliability is important for research and potential clinical applications. The aim of this systematic review and meta-analysis was to evaluate the reliability of CPM tests in healthy individuals and chronic pain patients.
Learn More >Black patients in the USA are disproportionately affected by chronic pain, yet there are few interventions that address these disparities.
Learn More >The combination of Transcranial Direct Current Stimulation (tDCS) with peripheral stimulation may optimize their effects and bring positive results in treatment of people with chronic pain.
Learn More >We reviewed the literature that explored the use of central and peripheral neuromodulation techniques for chronic daily headache (CDH) treatment.
Learn More >Nerve trauma-induced toll-like receptor 7 (TLR7) expression level increases in primary sensory neurons in injured dorsal root ganglion (DRG) avails to neuropathic pain, but the reason is still unknown. In the current study, we showed that unilateral lumbar 4 (L4) spinal nerve ligation (SNL) upregulated CCAAT/enhancer-binding protein-β (C/EBPβ) expression in ipsilateral L4 DRG. Preventing this elevation attenuated the SNL-induced upregulation of TLR7 in the ipsilateral L4 DRG and inhibited cold/thermal hyperalgesia and mechanical allodynia. In injected DRG, mimicking nerve trauma-induced C/EBPβ upregulation increased TLR7 levels, augmented responses to cold/thermal/mechanical stimuli, and caused ipsilateral spontaneous pain with no SNL. Mechanistically, SNL upregulated binding of increased C/EBPβ to Tlr7 promoter in ipsilateral L4 DRG. Accorded that C/EBPβ could trigger the activation of Tlr7 promoter and co-expressed with Tlr7 mRNA in individual DRG neurons, our findings strongly suggest the role of C/EBPβ in nerve trauma-mediated TLR7 upregulation in injured primary sensory neurons.
Learn More >To evaluate pain control in patients with joint and muscle pain in temporomandibular disorder (TMD) diagnosis treated with oral non-steroidal anti-inflammatory drugs (NSAIDs).
Learn More >Osteoarthritis (OA) is a chronic degenerative joint disease and a leading cause of disability worldwide. Pain is the main symptom, yet no current treatment can halt disease progression or effectively provide symptomatic relief. Numerous animal models have been described for studying OA and some for the associated OA pain. This review aims to update on current models used for studying OA pain, focusing on mice and rats. These models include surgical, chemical, mechanical, and spontaneous OA models. The impact of sex and age will also be addressed in the context of OA modelling. Although no single animal model has been shown ideal for studying OA pain, increased efforts to phenotype OA will likely impact the choice of models for pre-clinical and basic research studies.
Learn More >This narrative review examines stem cell therapy and its effect on opioid therapy in neuropathic pain.
Learn More >K (KCNK) potassium channels form "background" or "leak" currents that have critical roles in cell excitability control in the brain, cardiovascular system, and somatosensory neurons. Similar to many ion channel families, studies of Ks have been limited by poor pharmacology. Of six K subfamilies, the thermo- and mechanosensitive TREK subfamily comprising K2.1 (TREK-1), K4.1 (TRAAK), and K10.1 (TREK-2) are the first to have structures determined for each subfamily member. These structural studies have revealed key architectural features that underlie K function and have uncovered sites residing at every level of the channel structure with respect to the membrane where small molecules or lipids can control channel function. This polysite pharmacology within a relatively small (~70 kDa) ion channel comprises four structurally defined modulator binding sites that occur above (Keystone inhibitor site), at the level of (K modulator pocket), and below (Fenestration and Modulatory lipid sites) the C-type selectivity filter gate that is at the heart of K function. Uncovering this rich structural landscape provides the framework for understanding and developing subtype-selective modulators to probe K function that may provide leads for drugs for anesthesia, pain, arrhythmia, ischemia, and migraine.
Learn More >Post-traumatic headache is a common sequela of injury to the head and/or neck. Here, we review the current approach to pharmacologic management of post-traumatic headache and explore the therapeutic promise of targeting calcitonin gene-related peptide signaling to address unmet treatment needs.
Learn More >Endometriosis, affecting 5-10% of reproductive-age women, is a common contributor to dysmenorrhea and chronic pelvic pain. Diagnosis requires laparoscopic tissue biopsy, but careful pelvic examination, and/or imaging with either ultrasound or MRI, may identify patients who should receive empiric first-line therapy. The presence of dyschezia, particularly with cyclical exacerbation, should raise suspicion for bowel or rectovaginal septum involvement, and a greater need for surgical management. Treatment of dysmenorrhea includes hormonal suppression of the menstrual cycle, and/or analgesics; more severe cases with strong pain and disability may require earlier surgical intervention to excise disease while preserving fertility desires.
Learn More >Painful and bothersome anorectal syndromes can be a diagnostic and therapeutic challenge for clinicians because structural and functional abnormalities may often coexist and require a multidisciplinary approach to management. Although it is often difficult to attribute all of a patient's anorectal symptoms to a singular disorder with definitive intervention and cure, improving quality of life, treating coexistent conditions such as functional constipation and/or defecation disorders, addressing psychological comorbidities if present, and confirming there is no evidence of inflammatory or malignant conditions are top priorities.
Learn More >The goal of the present study was to comparatively analyze Social Cognition skills in a pediatric population diagnosed with Migraine or Epilepsy, compared to Typically Developing children (TD). The secondary aim was to relate Social Cognition skills with other migraine- or epilepsy-related variables and with executive and cognitive functions.
Learn More >Chronic spinal pain is one the most common musculoskeletal disorders. Previous studies have observed microscopic structural changes in the spinal extensor muscles in people with chronic spinal pain. This systematic review synthesizes and analyses all the existing evidence of muscle microscopic changes in people with chronic spinal pain.
Learn More >It is a common practice to control efficacy of pharmacological treatment with a placebo group. However, placebo itself may affect subjective and even objective results. The purpose of this study was to evaluate the placebo effect on symptoms of CP/CPPS to improve future clinical trials.
Learn More >Chronic pain management therapies have expanded quickly over the past decade. In particular, the use of laser therapy and ultrasound in the management of chronic pain has risen in recent years. Understanding the uses of these types of therapies can better equip chronic pain specialists for managing complicated chronic pain syndromes. The purpose of this review was to summarize the current literature regarding laser radiation and ultrasound therapy used for managing chronic pain syndromes.
Learn More >Negative Mood Regulation Expectancies (NMRE) describe the expectancies of an individual regarding his or her ability to regulate or reduce negative mood states by certain cognitive or behavioral strategies. NMRE are closely associated with the actual emotion regulation and potentially buffer the negative psychological and physical health consequences of stress. In the context of chronic pain, stress plays a central role, as long-term stress can have additional negative consequences regarding pain and its progression. The present study thus investigated the relationship of NMRE with treatment outcome, and more importantly, its buffering role in the association between stress and treatment outcome.
Learn More >To examine research on the impact of spinal cord stimulation (SCS) on the reduction of preimplantation opioid dose and what preimplantation opioid dose is associated with a reduction or discontinuation of opioid use post-implantation.
Learn More >Management of neuropathic cancer pain (NCP) refractory to regular opioids remains an important challenge. The efficacy of pregabalin for NCP except chemotherapy-induced peripheral neuropathy (CIPN) has already been confirmed in two randomised controlled trials (RCTs) compared with placebo. Duloxetine offers the potential of analgesia in opioid refractory NCP. However, there are no RCT of duloxetine for the management of opioid-refractory NCP as a first line treatment. Both classes of drugs have the potential to reduce NCP, but there has been no head-to-head comparison for the efficacy and safety, especially given differing side effect profiles.
Learn More >In the PROMISE-1 (Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-1) and PROMISE-2 (Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-2) clinical trials, eptinezumab 100 mg and 300 mg met the primary efficacy end point, significantly reducing mean monthly migraine days across weeks 1 to 12. Clinical efficacy was also shown across key secondary end points. However, to determine if clinical efficacy varies across subgroups, it is necessary to determine efficacy in patients with different sociodemographic features and headache characteristics. These post hoc analyses of patients in PROMISE-1 and PROMISE-2 evaluated the impact of intrinsic factors on the efficacy and safety of eptinezumab in subgroups defined according to baseline demographic and migraine disease characteristics.
Learn More >PROMISE-1 and PROMISE-2 evaluated the preventive efficacy, tolerability, and safety of eptinezumab, a calcitonin gene-related peptide-targeted monoclonal antibody, in adults with episodic (EM) and chronic migraine (CM), finding significant reductions in migraine frequency. This post hoc analysis compared patient-reported outcomes (PROs), health-related quality of life (HRQoL) and acute medication use in patients with a ≥ 75% migraine responder rate (MRR) after treatment with eptinezumab to patients with a ≥ 50- < 75% MRR.
Learn More >Demonstrating therapeutic value from the patient perspective is important in patient-centered migraine management. The objective of this study was to investigate the impact of eptinezumab, a preventive migraine treatment, on patient-reported headache impact, acute medication optimization, and perception of disease change when initiated during a migraine attack.
Learn More >Dimethyl sulfoxide (DMSO) is a highly reactive by-product of paper production in the form of an odorless, colorless liquid that has been studied since the 1860s. Initially it was utilized as a solvent, but more recently it is being investigated for therapeutic applications. Owing to its versatility, the use of DMSO has been proposed in many different medical fields for a variety of applications, with possibly the widest use being in the field of dermatology. The clinical interest in the use of DMSO for dermatology conditions stems from this solution's efficacy as a vehicle to deliver pharmacological agents across the stratum corneum and its ability to penetrate biological membranes. Currently there is only one FDA approval for the use of DMSO, and it is not in the dermatologic field but rather for interstitial cystitis. Outside of the FDA scope of usage, DMSO is used frequently to treat osteoarthritis in humans and animals, as well as other chronic pain conditions. This suggests the possible utility of DMSO being applicable to other inflammatory conditions such as pruritus. Further research is necessary to explore the promising utilization opportunities of DMSO in dermatology.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of cancer treatment with no effective preventative strategy or definitive treatment. To synthesize empiric literature from randomized controlled trials (RCTs) of pharmacological and nonpharmacological management of CIPN. Articles published between January 1, 2010, and February 28, 2021, were identified using keywords searching Medline, PubMed, CINAHL, Web of Science, Cochrane Library, and Embase. RCTs that recruited individuals who were post-chemotherapy and experienced persistent CIPN symptoms. Three independent reviewers screened a total of 2023 abstracts. After screening, full-text review, and quality appraisal, 22 articles were included in this review. Data related to study design, participant characteristics, interventions, controls, outcome measures, and relevant findings were extracted from full texts. Descriptive quantitative summaries were calculated and narrative analysis was performed. Of the 22 studies, 4 investigated pharmacologic treatments, 2 compared acupuncture to pharmacologic treatments, and 16 studies examined nonpharmacologic treatments. Pharmacologic studies reported mixed results with evidence of participant response varying by history of chemotherapeutic agent. Acupuncture, exercise/physical therapy, and neurofeedback appear to be effective treatments for CIPN. Evidence regarding biophysical agents and cognitive-behavioral therapy is equivocal. Scrambler therapy is not supported. Studies included in this review share several limitations, including widely variable outcome measures, small and demographically homogenous samples, and nonstandardized treatment protocols. This scoping review summarized the current body of high-quality RCTs investigating treatment for CIPN. The majority of studies in this review reports benefits of pharmacologic and nonpharmacologic interventions, although management may require a multipronged approach and should be tailored to the individual. Clinical implications are proposed and suggestions made for future research include implementation of standardized intervention protocols, use of outcome measures representative of the spectrum of CIPN symptoms, and stratification by the chemotherapeutic agent.
Learn More >Accurate assessment of the risk of opioid abuse and misuse in people with noncancer chronic pain is crucial for their prevention. This study aimed to provide preliminary evidence of the diagnostic and predictive capacity of the Spanish versions of the Opioid Risk Tool (ORT) and the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R).
Learn More >Transient receptor potential vanilloid 4 (TRPV4) is a non-selective mechanosensitive ion channel expressed by various macrophage populations. Recent reports have characterized the role of TRPV4 in shaping the activity and phenotype of macrophages to influence the innate immune response to pathogen exposure and inflammation. TRPV4 has been studied extensively in the context of inflammation and inflammatory pain. Although TRPV4 activity has been generally described as pro-inflammatory, emerging evidence suggests a more complex role where this channel may also contribute to anti-inflammatory activities. However, detailed understanding of how TRPV4 may influence the initiation, maintenance, and resolution of inflammatory disease remains limited. This review highlights recent insights into the cellular processes through which TRPV4 contributes to pathological conditions and immune processes, with a focus on macrophage biology. The potential use of high-throughput and omics methods as an unbiased approach for studying the functional outcomes of TRPV4 activation is also discussed.
Learn More >Knee osteoarthritis (KOA) is a debilitating disease characterized by chronic pain, stiffness, and decreased mobility. Intra-articular injectable therapies show good clinical efficacy in improving symptoms; however, these therapies and their comparators (intra-articular saline) have been associated with a large underlying placebo effect. We aimed to describe the existing evidence on the challenges, hypotheses, and potential solutions to mitigate the intra-articular placebo effect in clinical trials in KOA. A targeted literature review was conducted by searching Embase, MEDLINE®, and CENTRAL using predefined study selection criteria. All eligible studies identified were extracted for relevant data, and results were narratively summarized. Forty-three studies were included following screening. Challenges associated with the intra-articular placebo effect included its ability to mask the comparative efficacy of active treatments in trials ( = 7 studies), long-lasting effects (up to 6 months; = 3), and substantial variation of placebo effect sizes across populations ( = 3). Hypotheses for the mechanism of the placebo effect included aspiration of synovial fluid during administration ( = 6) and dilution of inflammatory mediators ( = 2). Factors affecting the placebo effect size were more invasive routes of administration (e.g., injection oral; = 4) and patient expectations ( = 2). Proposed solutions included the suggestion for readers to weigh the relevance of clinical trial evidence against the presence of large underlying placebo effects ( = 9), discontinuation of intra-articular saline as an appropriate placebo ( = 5), and inclusion of 'no treatment' or sham injection as a control ( = 4). The intra-articular placebo effect is a well-documented occurrence in KOA clinical trials, and it is suggested that it be accounted for when designing randomized controlled trials. Awareness and understanding of the intra-articular placebo effect in KOA are required for fair interpretation of clinical trial evidence.
Learn More >Motor cortex stimulation (MCS) was introduced in 1985 and has been tested extensively for different types of peripheral and central neuropathic pain syndromes (eg, central poststroke pain, phantom limb pain, trigeminal neuropathic pain, migraines, etc). The motor cortex can be stimulated through different routes, including subdural, epidural, and transcranial.
Learn More >Meniere disease (MD) is a rare set of conditions associated with the accumulation of endolymph in the cochlear duct and the vestibular labyrinth with a decrease of endocochlear potential. It is considered a chronic inflammatory disorder of the inner ear with a multifactorial origin. The clinical syndrome includes several groups of patients with a core phenotype: sensorineural hearing loss, episodes of vertigo, and tinnitus with a non-predictable course. Genetic factors and the innate immune response seem to play a central role in the pathophysiology of the condition. Autoimmune MD should be diagnosed if a patient fulfills the diagnostic criteria for MD and one of the following autoimmune disorders: autoimmune thyroid disease, psoriasis, autoimmune arthritis, ankylosing spondylitis, or systemic lupus erythematosus. We summarize the evidence to support autoimmune MD as an endophenotype in bilateral MD associated with the allelic variant rs4947296 and nuclear factor-kappa B (NF-κB)-mediated inflammation, the role of cytokines (particularly interleukin-1β and tumor necrosis factor-α) in defining a subset of patients with autoinflammation, and the potential role of cytokines as biomarkers to distinguish between patients with MD and vestibular migraine. Finally, we also introduce a list of potential drugs that could regulate the immune response in MD with potential for repurposing in clinical trials.
Learn More >Scalp dysesthesia is an abnormal sensation of the scalp in the absence of cutaneous disease. It is characterized by a burning and/or itching sensation and can be related to a variety of neurogenic or psychogenic causes. This condition is extremely bothersome and is also common- especially amongst the geriatric population, in women, in patients with diabetes mellitus and patients with psychiatric history. However, despite its prevalence in many populations, there is limited data about its causes and characteristics. Given its limited cutaneous manifestations it is also easily misdiagnosed and an underrecognized cause of scalp pruritus in the dermatological community. Therefore, education on scalp dysesthesia is paramount to helping physicians identify and provide appropriate treatment for these patients. This review focuses predominately on the neurogenic causes (with a brief review of psychogenic itch) of scalp dysesthesia and the therapeutics that have been found to be effective for this condition. Neurogenic causes of scalp dysesthesia occur with damage to the central or peripheral pathways of itch sensation, resulting in modification and heightened sensitivity of nerves that result in abnormal sensations in the absence of or out of proportion to external stimuli. A comprehensive review of etiologies is provided here, ranging from lesions to the central nervous system caused by cervical spine disease, trigeminal trophic syndrome, tumor, stroke, and multiple sclerosis, to small fiber neuropathies caused by diabetes, brow lifts, keloid and burn scarring. Recently, there have also been reports of scalp dysesthesias associated with post-infectious COVID-19. Treatment options tailored towards disease severity and different causes of disease will also be discussed. By elucidating the different mechanisms and therapeutic treatments of scalp dysesthesia, we hope to provide clinicians with the tools to identify and treat this condition as well as encourage further research into its etiologies and therapeutics.
Learn More >G protein coupled receptor kinase 2 (GRK2) has been demonstrated to play a crucial role in the development of chronic pain. Acupuncture is an alternative therapy widely used for pain management. In this study, we investigated the role of spinal neuronal GRK2 in electroacupuncture (EA) analgesia.
Learn More >Opioid use disorder (OUD) has become a significant public health issue worldwide. Methadone and buprenorphine are the most common medications used for treating OUD. These drugs have the potential to assist many patients in managing their opioid dependence and withdrawal but they are currently misused and associated with certain compliance issues, side effects, and risk of relapse. As an opioid-like herbal supplement, Mitragyna speciosa Korth or kratom has received increased attention for managing chronic pain and opioid withdrawal symptoms. Nevertheless, the use of kratom as a self-treatment medication for opioid dependence continues to be controversial due to concerns raised about its effectiveness, safety, and abuse liability. The main active alkaloid constituent of the plant, mitragynine, has been shown to act as a partial mu-opioid agonist. Given this pharmacology, studies have been focusing on this psychoactive compound to examine its potential therapeutic values as medication-assisted therapy (MAT). This review aims to provide a current preclinical overview of mitragynine as a prospective novel option for MAT and summarise the recent developments in determining if the plant's active alkaloid could provide an alternative to opioids in the treatment of OUD.
Learn More >Opioids are an important therapeutic option for severe resistant chronic pain but, in the absence of proper oversight, their use has risks. The level of prescription opioid misuse/abuse differs among countries, due to differences in healthcare systems and pain management approaches. However, evaluating the true dimension of prescription opioid misuse/abuse is complicated by statistical reporting which often does not differentiate between prescription and illicit opioid use, or between prescription opioid use by patients and nonpatients, highlighting a need for greater uniformity. Parallel efforts to educate patients and the general public about opioid risks, facilitate appropriate analgesic prescribing and identify alternative formulations or options to use instead of or with opioids, may contribute to optimizing prescription opioid use for pain management.
Learn More >Improved understanding of vestibulodynia pathophysiology is required to develop appropriately targeted treatments. Established features include vulvovaginal hyperinnervation, increased nociceptive signalling and hypersensitivity. Emerging evidence indicates macrophage-neuron signalling contributes to chronic pain pathophysiology. Macrophages are broadly classified as M1 or M2, demonstrating pro-nociceptive or anti-nociceptive effects respectively. This study investigates the impact of clodronate liposomes, a macrophage depleting agent, on nociceptive signalling in a mouse model of vestibulodynia.
Learn More >More than 30% of cancer patients experience neuropathic pain. Opioids, as standard pain-relief agents, cannot achieve satisfactory outcomes to treat neuropathic cancer pain due to drug resistance and side effects. Meanwhile, gabapentin, a third-generation anticonvulsant drug, has great potential in providing relief for neuropathic cancer pain. However, there is currently no sufficient evidence to support the efficacy of a combination of gabapentin and opioids in ameliorating neuropathic cancer pain. Hence, the aim of the present study was to explore the analgesic efficacy of gabapentin combined with opioids in treating neuropathic cancer pain.
Learn More >Intra-articular injections of hyaluronic acid (HA), the United States Food and Drug Administration approved treatment and widely utilized to delay or reserve the progression of the osteoarthritis (OA) involves. However, this treatment has shown controversial results through various clinical practice guidelines and meta-analysis evaluations, warrants more advanced researches on its safety and effectiveness.
Learn More >Knee osteoarthritis is a common disease in the elderly. Patients suffer from long-term chronic pain and reduced life quality. Acupuncture has been proven to be an effective treatment for KOA. However, the neural mechanism of acupuncture is unclear, so far. Periaqueductal gray (PAG) and raphe nuclei (RPN) are essential structures associated with chronic pain in human brains. This study aims to investigate functional connectivity (FC) changes of PAG and RPN in KOA to interpret the neural mechanism of acupuncture.
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