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Neuropathic pain caused by nerve injury or disease remains a major challenge for modern medicine worldwide. Most of the pathogenic mechanisms underlying neuropathic pain are centered on neuronal mechanisms. Accumulating evidence suggests that non-neuronal cells, especially glial cells, also play active roles in the initiation and resolution of pain. The preponderance of evidence has implicated central nervous system (CNS) glial cells, i.e., microglia and astrocytes, in the control of pain. The role of Schwann cells in neuropathic pain remains poorly understood. Schwann cells, which detect nerve injury and provide the first response, play a critical role in the development and maintenance of neuropathic pain. The cells respond to nerve injury by changing their phenotype, proliferating and interacting with nociceptive neurons by releasing glial mediators (growth factors, cytokines, chemokines, and biologically active small molecules). In addition, receptors expressed in active Schwann cells have the potential to regulate different pain conditions. In this review article, we will provide and discuss emerging evidence by integrating recent advances related to Schwann cells and neuropathic pain.
Learn More >High dose monotherapies or drug combinations are used to achieve sufficient analgesia for the treatment of severe chronic low back pain, before invasive therapy options are considered. In order to demonstrate an alternative for an empirical treatment approach, the authors' primary aim was to present an algorithm for the objective identification of treatment predictors. Additionally, the study identified baseline-characteristics in chronic low back pain patients prior to tapentadol PR treatment, as well as scrutinized those patients, either benefitting from a medium/high dose tapentadol PR monotherapy or a combination therapy (medium dose tapentadol PR + pregabalin). The statistical approach included data of a previously published randomized, double blind, phase 3b study which compared the effectiveness and safety of tapentadol PR vs. a combination of tapentadol PR and pregabalin. In total, 46 clinical parameters were included in the statistical prediction models which were applied separately either to 50 patients who already responded well during the titration period (i.e., medium dose tapentadol PR) or to 261 patients with in the comparative treatment period [i.e., monotherapy (high dose tapentadol PR) or combination therapy (medium dose tapentadol PR/pregabalin)]. The first statistical model identified three co-variables (NRS-3, PDQ, SQ) with predictive effects on patients responding well ("optimal responders") to a medium dose tapentadol PR titration. Those patients presented low baseline pain intensity scores, good sleep quality and high painDETECT scores. The second statistical model identified eight co-variables (PDQ, numbness, SF-12 MCS, SF-12 PCS, VAS, HADS-A, HADS-D, SQ) with predictive effects on patients responding to high dose tapentadol PR monotherapy vs. a combination therapy (tapentadol PR + pregabalin). The high dose tapentadol PR responders indicated high painDETECT scores, little numbness and a good mental health status. Whereas, the combination therapy (tapentadol PR + pregabalin) responders were characterized by severe sleep disturbances and little anxiety. The statistical analysis characterized chronic low back pain patients and identified factors contributing to a treatment response. Thus, this retrospective statistical algorithm represents an elegant method, which may contribute to future strategies toward a more individualized and improved mechanism based pain therapy.
Learn More >Voltage-gated sodium channel Nav1.9 is a threshold channel that regulates action potential firing. Nav1.9 is preferentially expressed in myenteric neurons, and small-diameter dorsal root ganglion (DRG) and trigeminal ganglion neurons including nociceptors. Recent studies have demonstrated a monogenic Mendelian link of Nav1.9 to human pain disorders. Gain-of-function variants in Nav1.9, which cause smaller depolarizations of RMP, have been identified in patients with familial episodic pain type 3 (FEPS3) and the more common pain disorder small fiber neuropathy. To explore the phenotypic spectrum of Nav1.9 channelopathy, here we report a new Nav1.9 mutation, N816K, in a child with early-onset episodic pain in both legs, episodic abdominal pain, and chronic constipation. Sequencing of further selected pain genes was normal. N816K alters a residue at the N-terminus of loop 2, proximal to the cytoplasmic terminus of transmembrane segment 6 in domain II. Voltage-clamp recordings demonstrate that Nav1.9-N816K significantly increases current density and hyperpolarizes voltage-dependence of activation by 10 mV, enabling a larger window current. Current-clamp recordings in DRG neurons shows that N816K channels depolarize RMP of small DRG neurons by 7 mV, reduce current threshold of firing an action potential and render DRG neurons hyperexcitable. Taken together these data demonstrate gain-of-function attributes of the newly described N816K mutation at the channel and cellular levels, which are consistent with a pain phenotype in the carrier of this mutation.
Learn More >An endemic increase in the number of deaths attributable to prescribed opioids is found in all developed countries. In 2016 in the USA, more than 46 people died each day from overdoses involving prescription opioids. European data show that the number of patients receiving strong opioids is increasing. In addition, there is an upsurge in hospitalisations for opioid intoxication, opioid abuse and deaths in some European countries. This class of analgesic is increasingly used in many rheumatological pathologies. Cohort studies, in various chronic non-cancer pain (CNCP) (osteoarthritis, chronic low back pain, rheumatoid arthritis, etc), show that between 2% and 8% of patients are treated with strong opioids. In order to help rheumatologists prescribe strong opioids under optimal conditions and to prevent the risk of death, abuse and misuse, recommendations have recently been published (in France in 2016, the recommendations of the French Society of Study and Treatment of Pain, in 2017, the European recommendations of the European Federation of IASP Chapters and the American Society of International Pain Physicians). They agree on the same general principles: opioids may be of interest in situations of CNCP, but their prescription must follow essential rules. It is necessary to make an accurate assessment of the pain and its origin, to formulate therapeutic objectives (pain, function and/or quality of life), to evaluate beforehand the risk of abuse and to get a specialised opinion beyond a certain dose or duration of prescription.
Learn More >Therapeutic virtual reality (VR) has emerged as an effective, drug-free tool for pain management, but there is a lack of randomized, controlled data evaluating its effectiveness in hospitalized patients. We sought to measure the impact of on-demand VR versus "health and wellness" television programming for pain in hospitalized patients.
Learn More >Exercise can be used as a treatment for depressive symptoms in the general population. However, little is known as to whether exercise has mental health benefits for adults experiencing chronic low back pain (CLBP). The aim of this study was to examine the feasibility of two intervention protocols commonly used in clinical practice for treating chronic low back pain, but with differing exercise dose, on depressive symptoms.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) with associated chronic pain is a common and disabling condition. Current treatments for neuropathic pain in CIPN are largely ineffective, with unfavorable side-effects. The capsaicin 8% patch (capsaicin 179 mg patch) is approved for the treatment of neuropathic pain: a single topical cutaneous application can produce effective pain relief for up to 12 weeks. We assessed the therapeutic potential of capsaicin 8% patch in patients with painful CIPN, and its mechanism of action.
Learn More >Acid-sensing ion channels (ASICs) are important acid sensors involved in neural modulation in the central nervous system and pain-associated tissue acidosis in the peripheral system. Among ASIC subtypes, ASIC1b is the most selectively expressed in peripheral sensory neurons. However, the role of ASIC1b is still elusive in terms of its functions and expression profile. In this study, we probed the role of ASIC1b in acid-induced muscle pain in -knockout () and transgenic ( ) mice. We tested the effect of ASIC1b knockout in a mouse model of fibromyalgia induced by dual intramuscular acid injections. In this model, a unilateral acid injection to the gastrocnemius muscle induced transient bilateral hyperalgesia in wild-type () but not mice; a second acid injection, spaced 1 or 5 days apart, to the same muscle induced chronic hyperalgesia lasting for 4 weeks in mice, but the duration of hyperalgesia was significantly shortened in mice. Mambalgin-1, an ASIC1b-containing channel inhibitor that was mixed with acid saline at the first injection, dose-dependently blocked the acid-induced transient and chronic hyperalgesia in mice. In contrast, psalmotoxin 1 (PcTx1), an ASIC1a-selective antagonist, had no effect on acid-induced transient or chronic hyperalgesia. We used whole-cell patch clamp recording to study the properties of acid-induced currents in ASIC1b-expressing dorsal root ganglia (DRG) neurons from -TdTomato reporter mice. Medium- to large-sized ASIC1b-expressing DRG neurons mainly exhibited an amiloride-sensitive ASIC-like biphasic current () in response to acid stimulation, whereas small- to medium-sized ASIC1b-expressing DRG neurons predominantly exhibited an amiloride-insensitive sustained current. Specifically, mambalgin-1 selectively inhibited the in most ASIC1b-expressing DRG neurons. However, PcTx1 or APETx2 (an ASIC3-selective antagonist) had only a mild inhibitory effect on in about half of the ASIC1b-expressing DRG neurons. hybridization revealed that ASIC1b-positive DRG neurons co-expressed highly with ASIC1a and ASIC2a mRNA and partially with ASIC3 and ASIC2b. Thus, ASIC1b might form a wide variety of heteromeric channels. ASIC1b-containing heteromeric channels might be promising targets for the therapeutic treatment of acid-induced chronic muscle pain.
Learn More >Whiplash injury is a common consequence of motor vehicle crashes (MVC), yet it is also one of the most poorly understood. While more than 50% of those injured should expect to rapidly recover, others are not as fortunate with approximately 25% of those exposed to and injured in an MVC transitioning from acute to chronic pain and disability. The purpose of this prospective study was to determine if the severity and direction of collisions involving participants enrolled in a longitudinal study of recovery from whiplash are able to differentiate between different recovery groups based on the neck disability index (NDI) percentage scores at 3-months, and if these crash specific parameters are associated with known risk factors for recovery. Here, we examined objective collision data, repair invoices, and characteristics of the crash for 37 acutely injured participants consented and enrolled at their emergency department visit and further assessed at three time points; < 1 week, 2-weeks, and 3-months post MVC. Collision data were used to reconstruct and estimate the severity of the crash and determine if they aligned with the heterogeneity of whiplash injury recovery. Wilcoxon rank sum tests were used to determine if % scores on the Neck Disability Index (NDI) at 3-months post MVC were associated with the following variables: sex, head turned at time of impact, seatbelt use, whether or not airbags deployed, if the vehicle was struck while stopped or while turning, or the principle direction of force (PDOF). Spearman's correlation coefficients were used to determine if NDI at 3-months post MVC was associated with age, Body Mass Index, pain-related disability at baseline, signs of post-traumatic distress, intrusion/hyperarousal, negative affect, pain intensity, estimated speed change from the impact, and damage estimates (in US$). There was a significant positive association between self-reported neck disability at 3-months post MVC, post-traumatic distress, negative affect and uncontrolled pain. There was no direct effect of participant characteristics, arousal, intrusion/hyperarousal sub-score, damage, PDOF, speed change, or other crash characteristics. Established crash parameters were not associated with the heterogeneity of whiplash injury recovery in a small sample of injured participants.
Learn More >Frequencies of single nucleotide polymorphisms (SNPs) from pain related candidate genes are available for individuals with sickle cell disease (SCD). One of those genes, the arginine vasopressin receptor 1A gene (AVPR1A) and one of its SNPs, rs10877969, has been associated with pain and disability in other pain populations. In patients with SCD, clinical factors such as pain and stress have been associated with increased health care utilization, but it is not known if the presence of the AVPR1A SNP plays a role in this observation. The study purpose was to explore the relationships between rs10877969 and self-reported pain, stress, and acute care utilization events among individuals with SCD.
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