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Pain is a subjective sensory experience that can, mostly, be reported but cannot be directly measured or quantified. Nevertheless, a suite of biomarkers related to mechanisms, neural activity, and susceptibility offer the possibility-especially when used in combination-to produce objective pain-related indicators with the specificity and sensitivity required for diagnosis and for evaluation of risk of developing pain and of analgesic efficacy. Such composite biomarkers will also provide improved understanding of pain pathophysiology.
Learn More >Therapeutic interventions for neuropathic pain (NP), such as the NMDA-antagonist ketamine, can vary widely in effectiveness; Here, we conducted a longitudinal functional MRI study to test the hypothesis that the pain relieving effect of ketamine is due to reversal of abnormalities in regional low frequency brain oscillations (LFOs) and abnormal cross-network functional connectivity (FC) of the dynamic pain connectome. We found that: 1) ketamine decreased regional LFOs in the posterior cingulate cortex (PCC) of the default mode network (DMN), 2) a machine learning algorithm demonstrated that treatment-induced brain changes could be used to make generalizable inferences about pain relief, 3) treatment responders exhibited a significant decrease in cross-network static FC between the PCC and regions of the sensorimotor (SM) and salience networks following treatment, 4) the degree of reduced cross-network FC was correlated with the amount of pain relief, and 5) ketamine treatment did not produce significant differences in static or dynamic FC within the ascending nociceptive- or descending antinociceptive pathway. These findings support the proposition that regional LFOs contribute to cross-network connectivity that underlie the effectiveness of ketamine to produce significant relief of neuropathic pain. Together with our recent findings that pre-treatment dynamic FC of the descending antinociceptive pathway can predict ketamine treatment outcomes, these new findings indicate that pain relief from ketamine arises from a combination of a strong and flexible pre-treatment FC of the descending antinocieptive pathway together with plasticity (reduction) of cross-network connectivity of the DMN with SM and salience networks.
Learn More >Presynaptic inhibition (PSI) of primary sensory neurons is implicated in controlling gain and acuity in sensory systems. Here, we define circuit mechanisms and functions of PSI of cutaneous somatosensory neuron inputs to the spinal cord. We observed that PSI can be evoked by different sensory neuron populations and mediated through at least two distinct dorsal horn circuit mechanisms. Low-threshold cutaneous afferents evoke a GABA-receptor-dependent form of PSI that inhibits similar afferent subtypes, whereas small-diameter afferents predominantly evoke an NMDA-receptor-dependent form of PSI that inhibits large-diameter fibers. Behaviorally, loss of either GABA receptors (GABARs) or NMDA receptors (NMDARs) in primary afferents leads to tactile hypersensitivity across skin types, and loss of GABARs, but not NMDARs, leads to impaired texture discrimination. Post-weaning age loss of either GABARs or NMDARs in somatosensory neurons causes systemic behavioral abnormalities, revealing critical roles of two distinct modes of PSI of somatosensory afferents in adolescence and throughout adulthood.
Learn More >We conducted a meta-analysis of controlled trials that used experimental models of acute pain and hyperalgesia to examine the analgesic effects of NMDA receptor (NMDAR) antagonists.
Learn More >Chronic pain affects 1 in 5 people and has been shown to disrupt attention. Here, we investigated whether pain disrupts everyday decision making. In Study 1, 1322 participants completed two tasks online: a shopping decisions task and a measure of decision outcomes over the previous 10 years. Participants who were in pain during the study made more errors on the shopping task than those who were pain-free. Participants with a recurrent pain condition reported more negative outcomes from their past decisions than those without recurrent pain. In Study 2, 44 healthy participants completed the shopping decisions task with and without experimentally-induced pain. Participants made more errors while in pain than while pain-free. We suggest that the disruptive effect of pain on attending translates into poorer decisions in more complex and ecologically valid contexts, that the effect is causal, and that the consequences are not only attentional, but financial.
Learn More >Based on previous clinic-based MRI studies showing regional differences in the cerebral cortex between those with and without headache, we hypothesized that headache sufferers have a decrease in volume, thickness or surface area in anterior cingulate cortex (ACC), prefrontal cortex (PFC), and insula. In addition, exploratory analyses on volume, thickness and surface area across the cerebral cortical mantle were performed. 1006 participants (50-66 years) from the general population were selected to an imaging study of the head at 1.5 T (HUNT-MRI). 283 individuals suffered from headache, 80 with migraine and 87 with tension-type headache, whereas 309 individuals did not suffer from headache and were used as controls. T1 weighted 3D scans of the brain were analysed with voxel-based morphometry and FreeSurfer. The association between cortical volume, thickness and surface area and questionnaire-based headache diagnoses was evaluated, taking into consideration evolution of headache and frequency of attacks. There were no significant differences in cortical volume, thickness or surface area between headache sufferers and non-sufferers in ACC, PFC or insula. Similarly, the exploratory analyses across the cortical mantle demonstrated no significant differences in volume, thickness or surface area between any of the headache groups and the non-sufferers. Maps of effect sizes showed small differences in the cortical measures between headache sufferers and non-sufferers. Hence, there are probably no or only very small differences in volume, thickness or surface area of the cerebral cortex between those with and without headache in the general population.
Learn More >Presynaptic N-methyl-D-aspartate receptors contribute to opioid tolerance and hyperalgesia as well as neuropathic painThe α2δ-1 protein subunit enhances presynaptic N-methyl-D-aspartate receptor activity WHAT THIS ARTICLE TELLS US THAT IS NEW: Using mouse and rat models, it was demonstrated that α2δ-1 is essential for the increase in presynaptic N-methyl-D-aspartate receptor activity seen during chronic morphine exposureInhibiting α2δ-1 activity using gabapentin or genetically deleting the gene coding for α2δ-1 results in diminished opioid tolerance and hyperalgesia BACKGROUND:: Chronic use of μ-opioid receptor agonists paradoxically causes both hyperalgesia and the loss of analgesic efficacy. Opioid treatment increases presynaptic N-methyl-D-aspartate receptor activity to potentiate nociceptive input to spinal dorsal horn neurons. However, the mechanism responsible for this opioid-induced activation of presynaptic N-methyl-D-aspartate receptors remains unclear. α2δ-1, formerly known as a calcium channel subunit, interacts with N-methyl-D-aspartate receptors and is primarily expressed at presynaptic terminals. This study tested the hypothesis that α2δ-1-bound N-methyl-D-aspartate receptors contribute to presynaptic N-methyl-D-aspartate receptor hyperactivity associated with opioid-induced hyperalgesia and analgesic tolerance.
Learn More >Post-traumatic injury pain is commonly treated with oral nonsteroidal anti-inflammatory drugs (NSAIDs). However, oral NSAIDs causes several adverse events, with topical formulations arising as an important alternative. Therefore, we aimed to evaluate the efficacy and safety of loxoprofen patch in the treatment of patients with post-traumatic pain. This phase III, randomized, double-blind, non-inferiority study enrolled Brazilian patients aged 18-65 years diagnosed with lower and upper limbs post-traumatic injury who were experiencing moderate or severe pain. Patients were assigned to active loxoprofen patch (LX-P) or to loxoprofen tablet (LX-T) and pain intensity was measured based on a Visual Analog Scale (VAS) score variation after seven days of treatment. Data on clinical symptoms, rescue medication use, and adverse events were also collected. VAS score variation was compared using a 10% non-inferiority margin. Two hundred and forty-two patients were randomly assigned to the LX-P (n=123) or to LX-T (n=119). The results showed a reduction in pain after seven days of treatment: -49.96 (n=118; SE 1.7) in the LX-P and -47.71 (n=117; SE 1.6) in the LX-T groups (difference of -2.25; 95% CI: -5.97 – 1.47; p=0.23). On the safety analysis, LX-T group presented twice as many patients with treatment-emergent adverse events as the LX-P group (30.8% and 14.2%, respectively). A sensitivity analysis demonstrated that rescue medication use has not affected the primary endpoint. This study showed that LX-P has a comparable efficacy to LX-T, but with a better safety profile, being a therapeutic option for the treatment of post-traumatic injury pain.
Learn More >While several studies have found that chronic pain is characterized by increased cross-network connectivity between salience, sensorimotor, and default mode (DMN) networks, a large sample-size investigation allowing a more reliable evaluation of somatotopic specificity and subgroup analyses with linkage to clinical pain intensity has been lacking. We enrolled healthy adults and a large cohort of patients (N=181) suffering from chronic low back pain (cLBP). To specifically link brain connectivity with clinical pain intensity, patients were scanned at baseline and after performing physical maneuvers that exacerbated pain. Compared to healthy adults, cLBP patients demonstrated increased connectivity between the functionally-localized back representation in primary somatosensory cortex (S1back) and both salience and DMN networks. Pain exacerbation maneuvers increased S1back connectivity to salience network regions, but decreased connectivity to DMN, with greater pain intensity increase associated with greater shifts in these connectivity patterns. Furthermore, only in cLBP patients reporting high pain catastrophizing, DMN connectivity was increased to a cardinal node of the salience network, anterior insula cortex, which was correlated with increased post-maneuver pain in this cLBP subgroup. Hence, increased information transfer between salience processing regions, particularly anterior insula, and DMN may be strongly influenced by pain catastrophizing. Increased information transfer between salience network and S1 likely plays an important role in shifting nociceptive afference away from self-referential processing, re-allocating attentional focus and affective coding of nociceptive afference from specific body areas. These results demonstrate S1 somatotopic specificity for cross-network connectivity in encoding clinical back pain, and moderating influence of catastrophizing for DMN/insula connectivity.
Learn More >Clinicians report reluctance to deliver opioid-tapering advice to patients with chronic pain, in part due to concerns that patients will be angry and dissatisfied. An experiment was conducted to examine chronic pain patients' emotional and attitudinal responses to simulated opioid-tapering advice. Patients scheduled for an initial assessment at a tertiary pain clinic and currently taking opioid medications for pain (N = 196) were randomly assigned to view video footage of a standardized patient receiving one of three forms of treatment advice: 1) stay on current medication, 2) change to a different pain medication, or 3) taper off pain medications and participate in a CBT-based pain self-management program. Participants reported how positive/enthusiastic, anxious/worried, and angry/irritable they felt in response to the simulated treatment advice, and how satisfied with and willing they would be to accept and follow the advice. Participants expressed more positive emotional and attitudinal responses to simulated opioid-tapering advice than to simulated opioid-maintenance advice. Furthermore, participants' responses to simulated opioid-tapering and opioid-change advice were not significantly different, suggesting that participants responded positively to the prospect of change in treatment strategy. Additional analyses revealed that participants with a longer history of chronic pain and opioid use responded less positively to simulated opioid-tapering advice. The results of this study contribute to our understanding of factors that may shape chronic pain patients' responses to opioid-tapering advice and suggest that patients may respond more positively to opioid tapering advice if it is presented together with an alternative treatment approach.
Learn More >Chronic or persistent pain is a growing global health problem. Effective management of pain emerging in childhood may prevent long-term health and vocational consequences. Internationally, paediatric pain services are a limited resource and, as such, must strive to improve equity, outcomes and value for money. The Paediatric electronic Persistent Pain Outcomes Collaboration (PaedePPOC) is a bi-national paediatric outcome measurement centre that aims to measure, benchmark, and improve children's specialist pain services in Australasia. This study documents the establishment of PaedePPOC and presents baseline and initial outcome data. Bi-national consensus meetings determined the measures. Governance structures, collection protocols, information technology, site-specific logistics and onsite training were achieved within 18 months. Children and parents complete baseline and progress questionnaires. Seven of ten Australasian services provided data to PaedePPOC, with 1432 patients enrolled to June 2018. At baseline, patients were 12.4±[3.0] years, 68% female, 93% Australian-born, and 5% Aboriginal and/or Torres Strait Islander people. Most had moderate-severe functional disability and impaired quality of life, with pain affecting school attendance and employment. Opioid-containing medicines were used often or daily by 16%. Patients completing outcome measures at treatment end reported clinically significant improvement in pain intensity (49% of patients), functional ability (59%) and quality of life (69%). The PaedePPOC initiative has been successfully integrated into children's pain services, yielding timely point-of-care information to support clinicians and families, and valuable bi-national and service data to inform quality improvement and future sector planning.
Learn More >Pain after surgery remains a major health problem, calling for optimized treatment regimens to maximize the efficacy of pharmacological interventions. In this randomized controlled trial, we tested in a routine surgical treatment setting whether postoperative pain can be reduced by a brief preoperative intervention, i.e., positive verbal suggestions in combination with sham acupuncture, designed to optimize treatment expectations. We hypothesized that the expectancy intervention as add-on to patient-controlled intravenous analgesia (PCIA) with morphine reduces patient-reported postoperative pain and improves satisfaction with analgesia.Ninety-six women undergoing breast cancer surgery were randomized at two stages: Prior to surgery, anesthesiologists delivered either positive or neutral verbal suggestions regarding the benefits of acupuncture needling on postoperative pain ("information condition"). Patients were then randomized to receive sham acupuncture or no sham-acupuncture during postoperative care ("sham acupuncture condition"). Average pain during the 24h observation period after surgery as primary and satisfaction with analgesia as secondary outcome were assessed with standardized measures, and analyzed with ANCOVA accounting for morphine dose, surgery-related and psychological parameters.Postoperative pain ratings were significantly reduced in patients who received positive treatment-related suggestions (F=4.45, p=0.038, main effect of information). Moreover, patients who received an intervention aimed at optimized treatment expectations reported significantly greater satisfaction with analgesia (F=4.89, p=0.030, interaction effect).Together, our proof-of-concept data support that optimizing treatment expectations via verbal suggestions may offer a promising approach to improve patient-reported outcomes. Future translational and clinical studies are needed to test such psychological strategies in different surgical interventions, patient groups, and pharmacological treatment regimens.
Learn More >Postoperative pain is highly debilitating and hinders recovery. Opioids are the main pain medication used for acute postoperative pain. Given the devastating opioid addiction and overdose epidemic across the US, non-opioid pain therapeutics are desperately needed. In order to develop novel, non-opioid therapies for the treatment of postoperative pain and identify the mechanisms underlying this pain, rodent models of incisional pain have been established. The protocol herein describes in detail how to create a mouse model of postoperative pain that was adapted from established protocols. This model of postoperative pain is frequently-used, highly reproducible, and results in peripheral and central nervous system alterations.
Learn More >Itch consists of both sensory and affective components. For chronic itch patients, the affective component of itch affects both quality of life (leading to psychological comorbidities) and disease prognosis (by promoting scratching of itchy skin). We found that acute itch stimuli such as histamine induced anxiety-like behavior and increased activity (c-Fos expression) in the amygdala in adult male C57BL/6 mice. Itch stimuli also increased activity in projection areas to the amygdala, suggesting that these regions form a circuit for affective itch processing. Electrophysiological characterization of histamine-responsive amygdala neurons showed that this population was active on a behaviorally relevant timescale and partially overlapped with pain signaling. Selective optogenetic activation of histamine-responsive amygdala neurons in adult male and female Fos:CreER;R26 mice using the Targeted Recombination in Active Populations system enhanced both scratching and anxiety-like behavior. These results highlight the importance of itch-responsive amygdala neurons in modulating itch-related affect and behavior.The sensation of itch includes an affective component that leads to stress and anxiety in chronic itch patients. We investigated the neuronal basis of affective itch in mice, with a focus on the amygdala, the key brain region for the generation of anxiety. A subpopulation of amygdala neurons responded to itch stimuli such as histamine. Optogenetic activation of histamine-responsive amygdala neurons affected both scratching and anxiety-like behavior. Therefore, this population appears to be important for mediating the affective component of itch.
Learn More >Neurons exhibit a limited ability of repair. Given that mechanical forces affect neuronal outgrowth, it is important to investigate whether mechanosensitive ion channels may regulate axon regeneration. Here, we show that DmPiezo, a Ca-permeable non-selective cation channel, functions as an intrinsic inhibitor for axon regeneration in Drosophila. DmPiezo activation during axon regeneration induces local Ca transients at the growth cone, leading to activation of nitric oxide synthase and the downstream cGMP kinase Foraging or PKG to restrict axon regrowth. Loss of DmPiezo enhances axon regeneration of sensory neurons in the peripheral and CNS. Conditional knockout of its mammalian homolog Piezo1 in vivo accelerates regeneration, while its pharmacological activation in vitro modestly reduces regeneration, suggesting the role of Piezo in inhibiting regeneration may be evolutionarily conserved. These findings provide a precedent for the involvement of mechanosensitive channels in axon regeneration and add a potential target for modulating nervous system repair.
Learn More >Persistent post-surgical pain is defined as pain localized to the area of surgery of at least 2-month duration and is unfortunately a common complication after breast cancer surgery. While there is insufficient evidence to support any preventative strategy, prior literature suggests possible efficacy of intravenous lidocaine and perioperative pregabalin in preventing persistent pain after surgery. To determine feasibility of conducting a larger definitive trial, we conducted a multicenter 2-by-2 factorial randomized placebo-controlled pilot trial of 100 female patients undergoing breast cancer surgery. Patients were randomized to receive an intraoperative lidocaine infusion (1.5 mg/kg bolus followed by 2 mg/kg/hr) or placebo and perioperative pregabalin (300 mg preoperatively, 75 mg twice daily for nine days) or placebo. All feasibility criteria were surpassed; recruitment of 100 patients within 42-weeks, follow-up rate of 100%, and study-drug compliance of ≥80%. At 3-months, 53% of patients reported persistent neuropathic pain. While there was no interaction between lidocaine and pregabalin, lidocaine reduced the development of persistent neuropathic pain (43.1% vs 63.3%; RR 0.68, 95% CI 0.47-1.0). Pregabalin did not reduce persistent pain (60% vs 46%; RR 1.3, 95% CI 0.90 to 1.90) and neither pregabalin nor lidocaine impacted acute postoperative pain, opioid consumption, pain interference, or quality of life. Our pilot trial successfully demonstrated feasibility and provided promising data for conducting further trials of intraoperative lidocaine infusions in breast cancer surgeries. Clinical trial number: NCT02240199 Perspectives: This article reports the findings of a pilot randomized controlled trial evaluating the effects of perioperative pregabalin and intraoperative lidocaine infusions in patients undergoing breast cancer surgery. This trial demonstrated feasibility of conducting a larger trial and provided promising data that these interventions may reduce the development of persistent pain.
Learn More >Chronic musculoskeletal pain (CMP) is an urgent global public health concern. Pain neuroscience education (PNE) is an intervention used in the management of CMP aiming to reconceptualise an individual's understanding of their pain as less threatening. This mixed-methods review undertook a segregated synthesis of quantitative and qualitative studies to investigate the clinical effectiveness, and patients' experience of, PNE for people with CMP. Electronic databases were searched for studies published between 01/01/2002 and 14/06/2018. Twelve randomised controlled trials (n = 755) that reported pain, disability and psychosocial outcomes and four qualitative studies (n = 50) that explored patients experience of PNE were included. The meta-analysed pooled treatment effects for PNE vs control had low clinical relevance in the short-term for pain (-3.20/100; 95%CI -6.66 to 0.27) and disability (-4.10/100; 95%CI -7.89 to -0.32) and the medium-term for pain (-4.22/100; 95%CI -16.44 to 8.01) and disability (-8.23/100; 95%CI -15.61 to -0.84). The treatment effect of PNE for kinesiophobia was clinically relevant in the short-term (-13.55/100; 95%CI -25.89 to -1.21) and for pain catastrophising in the medium-term (-5.26; 95%CI -10.59 to 0.08). Meta-synthesis of 23 qualitative findings resulted in the identification of two synthesized findings that identified several key components important for enhancing the patient experience of PNE such as allowing the patient to tell their own story. These components can enhance pain reconceptualisation, which appears to be an important process to facilitate patients' ability to cope with their condition. The protocol was published on PROSPERO (CRD42017068436). PERSPECTIVE: We outline the effectiveness of PNE for the management of pain, disability and psychosocial outcomes in adults with CMP. Key components that can enhance the patient experience of PNE such as allowing the patient to tell their own story are also presented. These components may enhance pain reconceptualisation.
Learn More >Sexual assault (SA) is associated with increased risk for chronic pain, but the mechanisms for this relationship are poorly understood. To explore whether disrupted descending inhibition is involved, this study used a conditioned pain modulation (CPM) task to study inhibition of pain and the nociceptive flexion reflex (NFR; a correlate of spinal nociception) in 32 pain-free SA survivors. This group was compared to 32 pain-free, trauma-exposed persons without SA (no-SA group) and a group of 40 pain-free persons who reported no trauma exposure (no-TE). CPM was assessed from painful electric stimulations (test stimulus) delivered to the ankle before, during, and after participants submerged their hand in painful 10°C water (conditioning stimulus). Pain ratings and NFR were assessed in response to test stimuli. All groups demonstrated significant inhibition of pain during CPM. However, only the no-TE group demonstrated significant inhibition of NFR. The no-SA group showed no inhibition of NFR, whereas the SA group showed significant facilitation of NFR. These findings suggest that trauma exposure may impair inhibitory cerebrospinal circuits, but that SA may specifically promote facilitation of spinal nociception. Perspective: This study suggests trauma exposure disrupts cerebrospinal inhibition of spinal nociception but that exposure to sexual assault further promotes chronic pain risk by facilitating spinal nociception. This help may help elucidate the pain risk mechanisms in trauma survivors.
Learn More >Research on chronic pain has traditionally focused on how direct pain experiences lead to maladaptive thoughts, feelings, and actions which set the stage for, and maintain, pain-related disability. Yet the capacity for language (and more specifically verbal instructions or rules) to put people into indirect contact with pain has never been systematically investigated. In this paper we introduce a novel theoretical perspective on verbal processes and discuss how the study of verbal rules may increase our understanding of both maladaptive and adaptive functioning in chronic pain. Several useful characteristics of verbal rules and rule-following in the context of chronic pain are outlined. Future research directions and implications for clinical practice are then discussed. Perspective: This focus article argues that by studying verbal rules and rule-following we will gain a better understanding of (mal)adaptive functioning in the context of chronic pain. Future research directions are outlined and suggestions for improving clinical practice are considered.
Learn More >To estimate the national burden of school absenteeism associated with pain among 6-17 year old children in the United States.
Learn More >Potential harmful stimuli like heat, mechanical pressure or chemicals are detected by specialized cutaneous nerve fiber endings of nociceptor neurons in a process called nociception. Acute stimulation results in immediate protective reflexes and pain sensation as a normal, physiological behavior. However, ongoing (chronic) pain is a severe pathophysiological condition with diverse pathogeneses that is clinically challenging because of limited therapeutic options. Therefore, an urgent need exists for new potent and specific analgesics without afflicting adverse effects. Recently, TRPM3, a member of the superfamily of transient receptor potential (TRP) ion channels, has been shown to be expressed in nociceptors and to be involved in the detection of noxious heat (acute pain) as well as inflammatory hyperalgesia (acute and chronic pain). Current results in TRPM3 research indicate that this ion channel might not only be part of yet unraveled mechanisms underlying chronic pain but also has the potential to become a clinically relevant pharmacological target of future analgesic strategies. The aim of this review is to summarize and present the basic features of TRPM3 proteins and channels, to highlight recent findings and developments and to provide an outlook on emerging directions of TRPM3 research in the field of chronic pain.
Learn More >Reports in the literature have conflicting findings about an association between dry eye disease (DED) and migraine headaches.
Learn More >Low back pain is associated with degeneration of the intervertebral disc, but specific mechanisms of pain generation in this pathology remain unknown. Sensory afferent nerve fiber growth into the intervertebral disc after injury-induced inflammation may contribute to discogenic pain. We describe a clinically relevant behavioral phenotype in a rodent model of chronic intervertebral disc degeneration which provides a means to map sensory neuron changes to a single affected lumbar intervertebral disc. Unilateral disc puncture of one lumbar intervertebral disc revealed a bilateral behavioral phenotype characterized by gait changes and decreased activity. Moreover, neurons extracted from the dorsal root ganglia in animals with intervertebral disc injury demonstrated altered TRPV1 activation in vitro independent of exogenous NGF administration. Finally, neuronal nuclear hypertrophy and elevated expression of p75NTR provide evidence of active adaptation of innervating sensory neurons in chronic intervertebral disc degeneration. Therefore, this model and findings provide the template for future studies to establish specific mechanisms of nociceptive pain in chronic intervertebral disc degeneration.
Learn More >To investigate the functional connectivity of the hypothalamus in chronic migraine compared to interictal episodic migraine in order to improve our understanding of migraine chronification.
Learn More >Offset analgesia (OA) studies have found that small decreases in the intensity of a tonic noxious heat stimulus yield a disproportionately large amount of pain relief. In the classic OA paradigm, the decrease in stimulus intensity is preceded by an increase of equal size from an initial noxious level. While the majority of researchers believe this temporal sequence of two changes is important for eliciting OA, it has also been suggested that the temporal contrast mechanism underlying OA may enhance detection of simple, isolated decreases in noxious heat. To test whether decreases in noxious heat intensity, by themselves, are perceived better than increases of comparable sizes, we used an adaptive two-interval alternative forced choice task to find perceptual thresholds for increases and decreases in radiant and contact heat. Decreases in noxious heat were more difficult to perceive than increases of comparable sizes from the same initial temperature of 45°C. In contrast, decreases and increases were perceived equally well within a common range of noxious temperatures (i.e., when increases started from 45°C and decreases started from 47°C). In another task, participants rated the pain intensity of heat stimuli that randomly and unpredictably increased, decreased or remained constant. Ratings of unpredictable stimulus decreases also showed no evidence of perceptual enhancement. Our results demonstrate that there is no temporal contrast enhancement of simple, isolated decreases in noxious heat intensity. Combined with previous OA findings, they suggest that long-lasting noxious stimuli that follow an increase-decrease pattern may be important for eliciting the OA effect.
Learn More >1) To assess the feasibility of research methods to test a self-management intervention aimed at preventing acute to chronic pain transition in patients with major lower extremity trauma (iPACT-E-Trauma) and 2) to evaluate its potential effects at three and six months postinjury. Design. A pilot randomized controlled trial (RCT) with two parallel groups.
Learn More >Acute postoperative pain is associated with the development of persistent postsurgical pain, but it is unclear which aspect is most estimable.
Learn More >Neuropathic pain represents a primary detrimental outcome of spinal cord injury. A major challenge facing effective management is a lack of surrogate measures to examine the physiology and anatomy of neuropathic pain. To this end, we investigated the relationship between psychophysical responses to tonic heat stimulation and neuropathic pain rating after traumatic spinal cord injury. Subjects provided a continuous rating to 2 min of tonic heat at admission to rehabilitation and again at discharge. Adaptation, temporal summation of pain, and modulation profile (i.e., the relationship between adaptation and temporal summation of pain) were extracted from tonic heat curves for each subject. There was no association between any of the tonic heat outcomes and neuropathic pain severity at admission. The degree of adaptation, the degree of temporal summation of pain, and the modulation profile did not change significantly from admission to discharge. However, changes in modulation profiles between admission and discharge were significantly correlated with changes in neuropathic pain severity ( = 0.027; = 0.323). The modulation profile may represent an effective measure to track changes in neuropathic pain severity from early to later stages of spinal cord injury.
Learn More >Pain in sickle cell disease (SCD) is severe, variable, and inadequately comprehended. The β2-adrenergic receptor () is critical in mediating neurotransmitter response in the sympathetic nervous system. In this association study, we examined 16 single nucleotide polymorphisms (SNPs) covering 5'-UTR and coding regions of for pain variability in SCD. Subjects recorded their non-crisis, baseline pain experience on a computerized tool from which we obtained chronic pain measurement score- composite pain index (CPI). Regression models yielded significant associations between chronic pain and seven SNPs. Non-synonymous SNP rs1042713 A allele (Arg16) caused a 5.73-fold decrease in CPI ( = 0.002). Allele A of rs12654778 and T of rs17778257 reduced CPI by a fold of 4.52 ( = 0.019), and 4.39 ( = 0.032), respectively. Whereas, in the 5' UTR, allele C of rs1042711, G of rs11168070, C of rs11959427, and C of rs1801704 increased CPI by a fold of 10.86 ( = 0.00049), 5.99 ( = 0.016), 5.69 ( = 0.023), and 5.26 ( = 0.031), respectively. Together, these SNPs accounted for 2-15% of CPI variance after adjusting for covariates. Moreover, these SNPs were in high linkage disequilibrium (LD) showing three LD blocks in our cohort. A 10-marker haplotype increased CPI by 11.5-fold ( = 0.000407). Thus, polymorphisms might contribute to chronic pain severity and heterogeneity in SCD.
Learn More >The headache phase of migraine could in selected cases potentially be treated by surgical decompression of one or more "trigger sites," located at frontal, temporal, nasal, and occipital sites. This systematic review with subsequent meta-analysis aims at critically evaluating the currently available evidence for the surgical treatment of migraine headache and to determine the effect size of this treatment in a specific patient population. This study was conducted following the PRISMA guidelines. An online database search was performed. Inclusion was based on studies published between 2000 and March 2018, containing a diagnosis of migraine in compliance with the classification of the International Headache Society. The treatment must consist of one or more surgical procedures involving the extracranial nerves and/or arteries with outcome data available at minimum 6 months. Eight hundred and forty-seven records were identified after duplicates were removed, 44 full text articles were assessed and 14 records were selected for inclusion. A total number of 627 patients were included in the analysis. A proportion of 0.38 of patients (random effects model, 95% CI [0.30-0.46]) experienced elimination of migraine headaches at 6-12 months follow-up. Using data from three randomized controlled trials, the calculated odds ratio for 90-100% elimination of migraine headaches is 21.46 (random effects model, 95% CI [5.64-81.58]) for patients receiving migraine surgery compared to sham or no surgery. Migraine surgery leads to elimination of migraine headaches in 38% of the migraine patients included in this review. However, more elaborate randomized trials are needed with transparent reporting of patient selection, medication use, and surgical procedures and implementing detailed and longer follow-up times.
Learn More >In joint initiatives, the European Headache Federation and Lifting The Burden have described a model of structured headache services (with their basis in primary care), defined service quality in this context, and developed practical methods for its evaluation.Here, in a continuation of the service quality evaluation programme, we set out ten suggested role- and performance-defining standards for specialized headache centres operating as an integral component of these services. Verifiable criteria for evaluation accompany each standard. The purposes are five-fold: (i) to inspire and promote, or stimulate the establishment of, specialized headache centres as centres of excellence; (ii) to define the role of such centres within optimally structured and organized national headache services; (iii) to set out criteria by which such centres may be recognized as exemplary in their fulfilment of this role; (iv) to provide the basis for, and to initiate and motivate, collaboration and networking between such centres both nationally and internationally; (v) ultimately to improve the delivery and quality of health care for headache.
Learn More >Prognosis of medically treated trigeminal neuralgia patients is assumed to be poor, but the evidence is lacking. Thus, prospective real-life studies of medical management of trigeminal neuralgia are warranted.
Learn More >Pain and depression are highly prevalent symptoms in cancer patients. They tend to occur simultaneously and affect each other and share biological pathways and neurotransmitters. In this study, we investigated the roles of microglia in the hippocampus in the comorbidity of bone cancer pain and depressive-like behaviors in an animal model of bone cancer pain.
Learn More >Phantom limb pain (PLP) is a disabling and intractable sensation arising in about 80% of patients after amputation. The aim of this study was to evaluate the possibility to modulate nociceptive processing and pain perception with cerebellar transcranial direct current stimulation (ctDCS) in patients suffering from painful and non-painful phantom limb sensations. Fourteen upper limb amputees underwent ctDCS (anodal or sham, 2.0 mA, 20 min per day, 5 days a week). Clinical scores and electrophysiological parameters were assessed before tDCS, at the end of the 5-day treatment, 2 and 4 weeks later. Laser-evoked potentials (LEPs) were obtained from the stump using a Nd:YAP laser by pulses with short duration (5 ms) and small diameter spots (5 mm). Changes in visual analogue scores (VAS) were evaluated (chronic pain, paroxysmal pain, stump pain, phantom movements, phantom sensations). Anodal polarization significantly dampened LEP amplitudes (N1, p = 0.021 and N2/P2, p = 0.0034), whereas sham intervention left them unchanged. Anodal ctDCS significantly reduced paroxysmal pain (p < 0.0001), non-painful phantom limb sensations (p < 0.0001) and phantom limb movements (p = 0.0003), whereas phantom limb and stump pain did not change compared to the sham condition. Anodal ctDCS significantly improves both paroxysmal pain and non-painful phantom limb sensations, which are likely induced by maladaptive changes in the sensorimotor network and posterior parietal cortex respectively.
Learn More >The goal of the review was to highlight recent advances in our understanding of descending pain-modulating systems and how these contribute to persistent pain states, with an emphasis on the current state of knowledge around "bottom-up" (sensory) and "top-down" (higher structures mediating cognitive and emotional processing) influences on pain-modulating circuits.
Learn More >Tissue injuries such as surgery and trauma are usually accompanied by simultaneous development of acute pain, which typically resolves along with tissue healing. However, in many cases, acute pain does not resolve despite proper tissue repair; rather, it transitions to chronic pain. In this study, we examined whether proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondria biogenesis, is implicated in pain chronification after burn injury in mice.
Learn More >Many Osteoarthritis (OA) patients report with clinical features to their pain that cannot be explained by purely peripheral mechanisms. Yet, the analgesic agents available that tackle centrally driven chronic pain often provide only partial pain relief, or have dose-limiting side effects. We explored a combination therapy of the centrally acting analgesic agents tapentadol and pregabalin, to investigate if they could be used in combination to provide superior analgesia.
Learn More >To describe long-term treatment patterns in migraine patients initiating prophylactic therapy and to evaluate acute medication use and adverse events associated with opioids.
Learn More >Cluster headache is by many regarded as a males' disorder that is often accompanied by an unhealthy lifestyle. We aimed to study the influence of sex and lifestyle factors on clinical presentation, the diagnostic process and management.
Learn More >The transient receptor potential ankyrin A 1 (TRPA1) channel and calcitonin gene-related peptide (CGRP) are targets for migraine prophylaxis. This study aimed to understand their mechanisms in migraine by investigating the role of TRPA1 in cortical spreading depression (CSD) in vivo and exploring how reactive oxygen species (ROS)/TRPA1/CGRP interplay in regulating cortical susceptibility to CSD.
Learn More >To review the pharmacology, efficacy, and safety of the calcitonin gene-related peptide (CGRP) inhibitor erenumab for migraine preventive therapy.
Learn More >People with sensory overresponsiveness (SOR) perceive nonpainful stimuli as noxious and demonstrate hyperalgesia and lingering sensation to laboratory pain stimuli. Electroencephalography (EEG) of cortical activity at rest is widely used to explore endophenotypes but has not yet been tested in people with SOR. Therefore, we investigated the characteristics of resting-state EEG in participants with SOR.
Learn More >It has been known for decades that classical conditioning influences pain perception. However, the precise relationship between conditioning and pain remains unclear. In addition, the clinical implications of their relationship are vastly underappreciated. Thus, we aim to (a) examine how conditioning increases or decreases pain sensitivity, (b) assess how conditioning contributes to the development and maintenance of chronic pain, and (c) explore strategies to utilize conditioning to optimize pain treatment.
Learn More >Analgesics and sedative hypnotics in clinical use often give rise to significant side effects, particularly respiratory depression. For emergency use, specific antagonists are currently administered to counteract respiratory depression. However, antagonists are often short-lasting and eliminate drug generated analgesia. To resolve this issue, novel positive AMPA modulators, LCX001, was tested to alleviate respiratory depression triggered by different drugs. The acetic acid writhing and hot-plate test were conducted to evaluate analgesic effect of LCX001. Binding assay, whole-cell recording, live cell imaging, and Ca imaging were used to clarify mechanism and impact of LCX001 on respiratory protection. Results showed that LCX001 effectively rescued and prevented opioid (fentanyl and TH-030418), propofol, and pentobarbital-induced respiratory depression by strengthening respiratory frequency and minute ventilation. The acetic acid writhing test and hot-plate test revealed potent anti-nociceptive efficacy of LCX001, in contrast to other typical ampakines that did not affect analgesia. Furthermore, LCX001 potentiated [H]AMPA and L-glutamate binding affinity to AMPA receptors, and facilitated glutamate-evoked inward currents in HEK293 cells stably expressing GluA2(R). LCX001 had a typical positive modulatory impact on AMPAR-mediated function. Importantly, application of LCX001 generated a significant increase in GluA2(R) surface expression, and restrained opioid-induced abnormal intracellular Ca load, which might participate in breathing modulation. Our study improves therapeutic interventions for the treatment of drug induced respiratory depression, and increases understanding of potential mechanism of AMPA receptor modulators.
Learn More >Sedation and somnolence remain serious adverse effects of the existing analgesics (e.g., pregabalin, duloxetine) for neuropathic pain. The available evidence indicates that serotonin (5-HT), noradrenaline (NE), and dopamine (DA) play important roles in modulating the descending inhibitory pain pathway and sleep-wake cycle. The aim of this work was to test the hypothesis that LPM580098, a novel triple reuptake inhibitor (TRI) of 5-HT, NE, and DA, has analgesic effect, and does not induce significant adverse effects associated with central inhibition, such as sedation and somnolence. The analgesic activity of LPM580098 was assessed on formalin test and spinal nerve ligation (SNL)-induced neuropathic pain model. Locomotor activity, pentobarbital sodium-induced sleeping and rota-rod tests were also conducted. binding and uptake assays, and Western blotting were performed to examine the potential mechanisms. LPM580098 suppressed the nocifensive behaviors during phase II of the formalin test in mice. In SNL rats, LPM580098 (16 mg kg) inhibited mechanical allodynia, thermal hyperalgesia and hyperexcitation of wide-dynamic range (WDR) neurons, in which the effect of LPM580098 was similar to pregabalin (30 mg kg). However, pregabalin altered the spontaneous locomotion, affected pentobarbital sodium-induced sleep, and showed a trend to perform motor dysfunction, which were not induced by LPM580098. Mechanistically, LPM580098 inhibited the uptake of 5-HT, NE, and DA, improved pain-induced changes of the synaptic functional plasticity and structural plasticity possibly via downregulating the NR2B/CaMKIIα/GluR1 and Rac1/RhoA signaling pathways. Our results suggest that LPM580098, a novel TRI, is effective in attenuating neuropathic pain without producing unwanted sedation and somnolence associated with central nervous system (CNS) depressants.
Learn More >The association between chronic pain, depression and anxiety has gained particular attention due to high rates of comorbidity. Recent data demonstrated that the mesolimbic reward circuitry is involved in the pathology of chronic pain. Interestingly, the mesolimbic reward circuit participates both in pain perception and in pain relief. The endocannabinoid system (ECS) has emerged as a highly relevant player involved in both pain perception and reward processing. Targeting ECS could become a novel treatment strategy for chronic pain patients. However, little is known about the underlying mechanisms of action of cannabinoids at the intersection of neurochemical changes in reward circuits and chronic pain. Because understanding the benefits and risks of cannabinoids is paramount, the aim of this review is to evaluate the state-of-art knowledge about the involvement of the ECS in dopamine signalling within the reward circuits affected by chronic pain.
Learn More >MaR1 is a specialized pro-resolving lipid mediator with anti-inflammatory and analgesic activities. In this study, we addressed the modulation of peripheral and spinal cord cells by MaR1 in inflammatory pain context.
Learn More >N-3 fatty acids, including docosahexaenoic acid (DHA), have a beneficial effect in both pain and psychiatric disorders. In fact, we previously reported that stress-induced pain prolongation might be mediated through the suppression of the G-protein coupled-receptor 40/free fatty acid receptor 1 (GPR40/FFAR1), which is activated by DHA and long-chain fatty acids. However, the involvement of GPR40/FFAR1 ligands in the development of stress-induced chronic pain has not yet been described. In this study, we investigated the role of DHA in stress-evoked pain chronicity using diet-induced n-3 fatty acid deficient mice. The n-3 fatty acid deficient mice showed exacerbation of anxiety-like behavior after repeated exposure to social defeat stress. The intact n-3 fatty acid deficient mice showed a decrease in paw threshold values. On the other hand, paw withdrawal thresholds of defeated but not non-stressed, n-3 fatty acid deficient mice continued until day 49 after paw surgery. We evaluated changes in phosphatidylcholine composition in the brains of repeat stress-evoked chronic pain model mice which were not on n-3 fatty acid deficiency diets On day 7 after paw surgery, phosphatidylcholines with DHA and other long-chain fatty acids were found to have decreased in the brains of stressed mice. Moreover, stress-induced persistent mechanical allodynia was improved by oral DHA supplementation. These results indicated that chronic stress may directly affect brain lipid composition; the related changes could be involved in chronic pain development. Our findings suggested that n-3 fatty acids, particularly DHA, are useful as a potential therapeutic target for stress-evoked chronic pain.
Learn More >To examine dorsal root ganglia and proximal nerve segments in patients carrying the Fabry-related GLA-gene variant p.D313Y in comparison to patients with classical Fabry mutations and healthy controls by morphometric and functional magnetic resonance neurography.
Learn More >A relationship between sleep and pain is well established. A better understanding of the mechanisms that link sleep and pain intensity is urgently needed to optimise pain management interventions. The objective of this systematic review was to identify, synthesise and critically appraise studies that have investigated putative mediators on the path between sleep and pain intensity.
Learn More >Pain affects over 70% of individuals with inflammatory bowel disease (IBD), with abdominal and musculoskeletal pain representing the most common complaints. Musculoskeletal pain in IBD is reported to be associated with multiple clinical features, however the scope and nature of pain is not well understood. Primary aims were to identify subgroups of musculoskeletal pain in individuals with IBD based on clinical features of pain, and assess how these subgroups differ in aspects of demographics, comorbidity, and IBD characteristics.
Learn More >The reason why some individuals develop chronic symptoms, whiplash-associated disorder, following whiplash trauma is poorly understood. We explored whether precollision pain-related diagnoses, medically unexplained symptoms, and psychiatric diagnoses are related to whiplash-associated disorder.
Learn More >Some patients with irritable bowel syndrome (IBS) have visceral hypersensitivity, which contributes to their abdominal pain. miRNA-29 was detected to be significantly upregulated in colonic tissues of patients with IBS. However, it is unknown whether miRNA-29a is involved in the visceral hypersensitivity pathogenesis of IBS. This study aimed to investigate whether miRNA-29a participates in visceral hypersensitivity in IBS. We investigated miRNA-29a in intestinal biopsies collected during endoscopy of patients with IBS (n = 10) and healthy volunteers (control) (n = 10). In addition, a water avoidance stress (WAS)-induced visceral hypersensitivity IBS mouse model was established. The abdominal withdrawal reflex (AWR) scores of mice in response to colorectal distention were used to assess visceral sensitivity. Reverse transcription quantitative-polymerase chain reaction (RT-qPCR) was used to measure miRNA-29a levels. Immunofluorescence, RT-qPCR and western blot were used to measure 5-HT receptor (HTR7) levels. Bioinformatic analysis and luciferase reporter assays were used to detect the direct relationship between miRNA-29a and HTR7. Finally, alterations in the levels of HTR7 and miRNA-29a were measured in the human intestinal epithelial cell line NCM460 after transfection with miRNA-29a inhibitor or mimic. Intestinal tissues from patients with IBS and WAS-induced IBS mice had increased levels of miRNA-29a, but reduced levels of HTR7. MiRNA-29a knockout resulted in overexpression of HTR7 and attenuated visceral hyperalgesia in WAS-induced IBS mice. HTR7 was a direct target of miRNA-29a. Based on analyses of intestinal tissue samples from patients with IBS and WAS-induced miRNA-29a mice, miRNA-29a plays a role in the visceral hyperalgesia pathogenesis of IBS, probably through regulating HTR7 expression.
Learn More >Pain management is complex regardless of whether the pain is acute or chronic in nature or non-cancer or cancer related. In addition, relatively few pain pharmacotherapy options with adequate efficacy and safety data currently exist. Consequently, interest in the role of NMDA receptor antagonists as a pharmacological pain management strategy has surfaced. This narrative review provides an overview of the NMDA receptor and elaborates on the pharmacotherapeutic profile and pain management literature findings for the following NMDA receptor antagonists: ketamine, memantine, dextromethorphan, and magnesium. The literature on this topic is characterized by small studies, many of which exhibit methodological flaws. To date, ketamine is the most studied NMDA receptor antagonist for both acute and chronic pain management. Although further research about NMDA receptor antagonists for analgesia is needed and the optimal dosage/administration regimens for these drugs have yet to be determined, ketamine appears to hold the most promise and may be of particular value in the perioperative pain management realm.
Learn More >Chemokines are important regulators of immune, inflammatory, and neuronal responses in peripheral and central pain pathway. The aim of this study was to investigate whether chemokine (C-X-C motif) ligand 13 (CXCL13) and its receptor (C-X-C chemokine receptor type 5, CXCR5) involve in the development of bone cancer pain (BCP) and the regulation of morphine analgesia in rats. The change of pain behaviors in BCP rats were measured by testing paw withdrawal threshold (PWT). The levels of CXCL13, CXCR5 and signal pathway proteins (p-p38, p-ERK and p-AKT etc) in the spinal cord were measured via western blots. The expression of CXCL13 and CXCR5 in spinal cord were increased in BCP rats. The BCP rats showed decrease of PWTs, which was relieved by CXCR5i. Intrathecally injection of murine recombinant CXCL13 (mrCXCL13) decreased the PWTs of BCP rats and opposed morphine-induced analgesia in BCP rats. In BCP rats, the signal pathway proteins (p38, ERK and AKT) in the spinal cord were activated. CXCL13 and morphine had contrary effect on the phosphorylation of these proteins. MrCXCL13 directly increased the levels of p-p38, p-ERK and p-AKT in BCP rats. However, morphine decreased the levels of these proteins in BCP rats. While blocking the activation of p-p38, p-ERK and p-AKT, morphine analgesia was enhanced. These results suggest CXCL13 participated in bone cancer pain and opposed morphine analgesia via p38, ERK and AKT pathways. It may be a target to enhance pain management in cancer pain patients.
Learn More >Despite the high incidence of neuropathic pain, its mechanism remains unclear. Oxytocin (OXT) is an established endogenous polypeptide produced in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus. OXT, which is synthesized by OXT neurons in the SON and the magnocellular part of the PVN (mPVN), is delivered into the posterior pituitary (PP), then released into the systemic blood circulation. Meanwhile, OXT-containing neurosecretory cells in the parvocellular part of the PVN (pPVN) are directly projected to the spinal cord and are associated with sensory modulation. In this study, the OXT system in the hypothalamo-neurohypophysial and hypothalamo-spinal pathway was surveyed using a rat neuropathic pain model induced by partial sciatic nerve ligation (PSL). In the present study, we used transgenic rats expressing an OXT-monomeric red fluorescent protein 1 (mRFP1) fusion gene. In a neuropathic pain model, mechanical allodynia was observed, and glial cell activation was also confirmed via immunohistochemistry. In this neuropathic pain model, a significant increase in the OXT- mRFP1 expression was observed in the PP, the SON, mPVN, and pPVN. Furthermore, OXT-mRFP1 granules with positive fluorescent reaction were remarkably increased in laminae I and II of the ipsilateral dorsal horn. Although the plasma concentrations of OXT did not significantly change, a significant increase of the mRNA levels of OXT and mRFP1 in the SON, mPVN, and pPVN were observed. These results suggest that neuropathic pain induced by PSL upregulates hypothalamic OXT synthesis and transportation to the OXTergic axon terminals in the PP and spinal cord.
Learn More >Disrupted sleep is associated with a reciprocal influence on headaches and is one of the contributing factors in the process of chronicity. The goal of the present study was to investigate the influence of sleep on headaches using animal rapid eye movement (REM) sleep deprivation and supradural capsaicin infusion models.
Learn More >Non-invasive neuromodulation therapies for migraine and cluster headache are a practical and safe alternative to pharmacologics. Comparisons of these therapies are difficult because of the heterogeneity in study designs. In this systematic review of clinical trials, the scientific rigour and clinical relevance of the available data were assessed to inform clinical decisions about non-invasive neuromodulation. PubMed, Cochrane Library and ClinicalTrials.gov databases and the WHO's International Clinical Trials Registry Platform were searched for relevant clinical studies of non-invasive neuromodulation devices for migraine and cluster headache (1 January 1990 to 31 January 2018), and 71 were identified. This analysis compared study designs using recommendations of the International Headache Society for pharmacological clinical trials, the only available guidelines for migraine and cluster headache. Non-invasive vagus nerve stimulation (nVNS), single-transcranial magnetic stimulation and external trigeminal nerve stimulation (all with regulatory clearance) were well studied compared with the other devices, for which studies frequently lacked proper blinding, sham controls and sufficient population sizes. nVNS studies demonstrated the most consistent adherence to available guidelines. Studies of all neuromodulation devices should strive to achieve the same high level of scientific rigour to allow for proper comparison across devices. Device-specific guidelines for migraine and cluster headache will be soon available, but adherence to current guidelines for pharmacological trials will remain a key consideration for investigators and clinicians.
Learn More >Disruptions of lumbar intervertebral discs may lead to severe discogenic low back pain (LBP). Severe pain has a deleterious effect on physical function and quality of life. Spinal cord stimulation (SCS) is a robust treatment for many neuropathic pain conditions. New innovations may be well-suited to treat neuropathic chronic LBP, including discogenic pain. The aim of this prospective study was to determine the effect of dorsal root ganglion (DRG) stimulation for a well-selected group of patients with discogenic LBP with no history of previous back surgeries.
Learn More >Compromised Na/K-ATPase function is associated with the occurrence of spreading depolarization (SD). Mutations in ATP1A2, the gene encoding the α2 isoform of the Na/K-ATPase, were identified in patients with familial hemiplegic migraine type 2 (FHM2), a Mendelian model disease for SD. This suggests a distinct role for the α2 isoform in modulating SD susceptibility and raises questions about underlying mechanisms including the roles of other Na/K-ATPase α isoforms. Here, we investigated the effects of genetic ablation and pharmacological inhibition of α1, α2, and α3 on SD using heterozygous knock-out mice. We found that only α2 heterozygous mice displayed higher SD susceptibility when challenged with prolonged extracellular high potassium concentration ([K]), a pronounced post SD oligemia and higher SD speed in-vivo. By contrast, under physiological [K], α2 heterozygous mice showed similar SD susceptibility compared to wild-type littermates. Deficiency of α3 resulted in increased resistance against electrically induced SD in-vivo, whereas α1 deficiency did not affect SD. The results support important roles of the α2 isoform in SD. Moreover, they suggest that specific experimental conditions can be necessary to reveal an inherent SD phenotype by driving a (meta-) stable system into decompensation, reminiscent of the episodic nature of SDs in various diseases.
Learn More >Temporomandibular joint (TMJ) osteoarthritis (OA) is a degenerative disease of the joint that can produce persistent orofacial pain as well as functional and structural changes to its bone, cartilage, and ligaments. Despite advances in the clinical utility and reliability of the Diagnostic Criteria for Temporomandibular Disorders, clinical tools inadequately predict which patients will develop chronic TMJ pain and degeneration, limiting clinical management. The challenges of managing and treating TMJ OA are due, in part, to a limited understanding of the mechanisms contributing to the development and maintenance of TMJ pain. OA is initiated by multiple factors, including injury, aging, abnormal joint mechanics, and atypical joint shape, which can produce microtrauma, remodeling of joint tissues, and synovial inflammation. TMJ microtrauma and remodeling can increase expression of cytokines, chemokines, and catabolic factors that damage synovial tissues and can activate free nerve endings in the joint. Although studies have separately investigated inflammation-driven orofacial pain, acute activity of the trigeminal nerve, or TMJ tissue degeneration and/or damage, the temporal mechanistic factors leading to chronic TMJ pain are undefined. Limited understanding of the interaction between degeneration, intra-articular chemical factors, and pain has further restricted the development of targeted, disease-modifying drugs to help patients avoid long-term pain and invasive procedures, like TMJ replacement. A range of animal models captures features of intra-articular inflammation, joint overloading, and tissue damage. Although those models traditionally measure peripheral sensitivity as a surrogate for pain, recent studies recognize the brain's role in integrating, modulating, and interpreting nociceptive inputs in the TMJ, particularly in light of psychosocial influences on TMJ pain. The articular and neural contributors to TMJ pain, imaging modalities with clinical potential to identify TMJ OA early, and future directions for clinical management of TMJ OA are reviewed in the context of evidence in the field.
Learn More >Chronic musculoskeletal pain affects a substantial portion of adults visiting the emergency department (ED). Current treatment is limited in scope and does not effectively reduce musculoskeletal pain in patients. The study will evaluate the use of duloxetine, a serotonin-norepinephrine reuptake inhibitor Food and Drug Administration approved for the treatment of chronic pain, as a promising option in its prevention. The proposed study may present a well-tolerated and effective non-opioid treatment for patients with acute musculoskeletal pain that may also be effective in preventing the transition to persistent or chronic musculoskeletal pain.
Learn More >The aim of the present study was to further elucidate the role of JAK2/STAT3-CAV-1-NR2B on painful diabetic neuropathy.
Learn More >To assess the characteristics of breakthrough cancer pain (BTcP) in patients with abdominal cancer pain, and the eventual factors associated with its presentation.
Learn More >Previous studies have reported that certain bacteria exert visceral antinociceptive activity in visceral pain and may also help to relieve neuropathic and inflammatory pain.
Learn More >Selective N-methyl-d-aspartate receptor subunit 2B (NR2B) antagonists show potential as analgesic drugs, and do not cause side effects associated with non-selective N-methyl-d-aspartate (NMDA) antagonists. Using a scaffold-hopping approach, we previously identified isoxazole derivative 4 as a potent selective NR2B antagonist. In this study, further scaffold hopping of isoxazole derivative 4 and optimization of its pharmacokinetic profile led to the discovery of the orally bioavailable compound 6v. In a rat study of analgesia, 6v demonstrated analgesic effects against neuropathic pain.
Learn More >The advent of anti-CGRP medications is an example of translational research made real. Pioneering research by Drs. Lars Edvinsson and Peter Goadsby has yielded the monoclonal antibody therapeutics and will likely also result in the gepants. The availability of MABs represents a watershed moment in the treatment of migraine. These medications have specificity, as they were designed for primary migraine prevention. They work across a group of wide therapeutic targets, episodic migraine, chronic migraine, medication-overuse headache, and episodic cluster headache. They separate from placebo within 1 week, and often show clinical effects within a month or less. They have tolerability similar to placebo. There has been no significant or worrisome safety signal thus far in their use. They manifest unprecedented responder rates at ≥ 75% and even 100%. They lower all acute medication use and can convert patients from chronic migraine to episodic migraine and from acute medication overuse to non-overuse. They work in patients who have already had lack of success with at least 2-4 previous preventive medications. Pent-up demand for designer, well-tolerated, and effective migraine preventive medication in the USA has resulted in more than 100,000 individual patients prescribed erenumab from May to December of 2018, and the numbers continue to increase. The preventive treatment of migraine in the USA has shifted dramatically, and is likely to do so in the rest of the world as well.
Learn More >Fibromyalgia is a complex chronic pain syndrome that can have debilitating consequences for affected patients. When compared to the general population, patients with fibromyalgia experience lowered mechanical and thermal pain thresholds, altered temporal summation of painful stimuli, and higher than normal pain ratings for known noxious stimuli.
Learn More >The International Classification of Headache Disorders provides an extensive framework to classify headaches. Physiotherapy is indicated if neuromusculoskeletal dysfunctions are involved in the pathophysiology. Maladaptive postures seem a dominant trigger in tension-type and cervicogenic headache. Yet, outcomes following physiotherapy vary. The absence of protocol studies to identify determinants concerning the role of spinal posture in headache might explain such variability. Hence, multi-dimensional profiling of patients with headache based on interactions between spinal posture, psychosocial and lifestyle factors might be essential. Therefore, the aim of this paper was to perform a comprehensive review to find support for the paradigm of spinal posture triggering episodic headache based on a multi-dimensional view on tension-type and cervicogenic headache including modern pain neuroscience.
Learn More >Pain is highly prevalent in patients with Parkinson's disease (PD), but underlying pathophysiological mechanisms are largely unclear. Alterations in somatosensory processing might contribute to sensory abnormalities in PD.
Learn More >Migraine is the most common cause of primary headache in children leading to a decrease in the quality of life. During the last decade, pain catastrophizing construct became a major focus of interest in the study and treatment of pain. To evaluate pain catastrophizing in episodic and chronic migraine children and adolescents selected in a tertiary headache Center.To test whether the children's pain catastrophizing might be associated (a) with the frequency of attacks and disability (b) with psychopathological aspects (c) with allodynia and total tenderness score as symptom of central sensitization.To test the best discriminating clinical variables and scores between episodic and chronic migraine, including pain catastrophizing. We conducted a cross sectional observational study on consecutive pediatric patients affected by migraine. We selected 190 headache patients who met the diagnostic criteria for Migraine without aura, Migraine with aura and Chronic migraine. We submitted all children to the Child version of the Pain Catastrophizing Scale (PCS-C), and to the disability scale for migraine (PedMIDAS), general quality of life estimated by children (PedsQL) and parents (PedsQL-P), anxiety and depression (SAFA-A; SAFA-D) scales. We also evaluated headache frequency and the presence and severity of allodynia and pericranial tenderness. No difference was detected in Total Pain Catastrophizing score (PCS-C) between chronic and episodic migraine groups (ANOVA = 0.59, = 0.70); the PedMIDAS, the PedsQL-P for physical functioning and the Total Tenderness Score were discriminant variables between episodic and chronic migraine. The PCS-C was not correlated with migraine related disability as expressed by Ped MIDAS, but it was significantly correlated with general low quality of life, allodynia, pericranial tenderness, anxiety, and depression. Pain catastrophizing seems a mental characteristic of a clinical phenotype with psychopathological traits and enhanced expression of central sensitization symptoms. This clinical profile causes general decline in quality of life in the child judgment, with a probable parents' underestimation. In childhood age, it would not be a feature of chronic migraine, but the possibility that it could predict this evolution is consistent and worthy of further prospective evaluation.
Learn More >Approximately 400 000 Americans and 36 000 Canadians undergo cardiac surgery annually, and up to 56% will develop chronic postsurgical pain (CPSP). The primary aim of this study is to explore the association of pain-related beliefs and gender-based pain expectations on the development of CPSP. Secondary goals are to: (A) explore risk factors for poor functional status and patient-level cost of illness from a societal perspective up to 12 months following cardiac surgery; and (B) determine the impact of CPSP on quality-adjusted life years (QALYs) borne by cardiac surgery, in addition to the incremental cost for one additional QALY gained, among those who develop CPSP compared with those who do not.
Learn More >The role of neurotransmitters and neuromodulators in the pathogenesis of cluster headache: a review.
The pathogenesis underlying cluster headache remains an unresolved issue. Although both the autonomic system and the hypothalamus play a central role, the modality of their involvement remains largely unknown. It is, also, unknown why the duration of the pain attacks is so brief and why their onset and termination are abrupt and extremely painful. This review summarizes the evidence to date accumulated in favor of a possible role of anomalies in the metabolism of tyrosine, tryptophan, and arginine in these unresolved issues.
Learn More >Clinical evidence indicates that positive allosteric modulators (PAMs) of GABA receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABA receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABA receptors associated with α2/3 subunits, KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole), has demonstrated anxiolytic, anticonvulsant, and antinociceptive effects in rodents with reduced motoric side effects. The present study evaluated the potential of KRM-II-81 as a novel analgesic. Oral administration of KRM-II-81 attenuated formalin-induced flinching; in contrast, diazepam was not active. KRM-II-81 attenuated nociceptive-associated behaviors engendered by chronic spinal nerve ligation (L5/L6). Diazepam decreased locomotion of rats at the dose tested in the formalin assay (10 mg/kg) whereas KRM-II-81 produced small decreases that were not dose-dependent (10-100 mg/kg). Plasma and brain levels of KRM-II-81 were used to demonstrate selectivity for α2/3- over α1-associated GABA receptors and to define the degree of engagement of these receptors. Plasma and brain concentrations of KRM-II-81 were positively-associated with analgesic efficacy. GABA currents from isolated rat dorsal-root ganglion cultures were potentiated by KRM-II-81 with an ED of 32 nM. Measures of respiratory depression were reduced by alprazolam whereas KRM-II-81 was either inactive or produced effects with lower potency and efficacy. These findings add to the growing body of data supporting the idea that α2/3-selective GABA receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABA receptor PAMs offer an additional inroad into the management of pain.
Learn More >Stratified care is an up-to-date treatment approach suggested for patients with back pain in several guidelines. A comprehensively studied stratification instrument is the STarT Back Tool (SBT). It was developed to stratify patients with back pain into three subgroups, according to their risk of persistent disabling symptoms. The primary aim was to analyse the disability differences in patients with back pain 12 months after inclusion according to the subgroups determined at baseline using the German version of the SBT (STarT-G). Moreover, the potential to improve prognosis for disability by adding further predictor variables, an analysis for differences in pain intensity according to the STarT-Classification, and discriminative ability were investigated.
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