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Painful neuropathy is a frequent complication in diabetes. Proopiomelanocortin (POMC) is an endogenous opioid precursor peptide, which plays a protective role against pain. Here, we report dysfunctional POMC-mediated antinociception in sensory neurons in diabetes. In streptozotocin-induced diabetic mice the Pomc promoter is repressed due to increased binding of NF-kB p50 subunit, leading to a loss in basal POMC level in peripheral nerves. Decreased POMC levels are also observed in peripheral nervous system tissue from diabetic patients. The antinociceptive pathway mediated by POMC is further impaired due to lysosomal degradation of μ-opioid receptor (MOR). Importantly, the neuropathic phenotype of the diabetic mice is rescued upon viral overexpression of POMC and MOR in the sensory ganglia. This study identifies an antinociceptive mechanism in the sensory ganglia that paves a way for a potential therapy for diabetic neuropathic pain.
Learn More >Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Herein, we identify that a large proportion of patients with AD harbor allergen-specific immunoglobulin E (IgE) and exhibit a propensity for acute itch flares. In mice, while allergen-provoked acute itch is mediated by the mast cell-histamine axis in steady state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene (LT) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a basophil-neuronal circuit that may underlie a variety of neuroimmune processes.
Learn More >TRPA1 is a promising target for the development of novel treatments for chronic pain. In this issue of Neuron, Liu et al. (2021) report a novel non-covalent TRPA1-biased agonist, GNE551, revealing a unique binding pocket by cryo-EM and activation properties that pave a path toward new avenues in the treatment of chronic pain.
Learn More >Trigeminal neuropathic pain is the most debilitating pain disorder but current treatments including opiates are not effective. A common symptom of trigeminal neuropathic pain is cold allyodynia/hyperalgesia or cold hypersensitivity in orofacial area, a region where exposure to cooling temperatures are inevitable in daily life. Mechanisms underlying trigeminal neuropathic pain manifested with cold hypersensitivity are not fully understood. In this study, we investigated trigeminal neuropathic pain in male rats following infraorbital nerve chronic constrictive injury (ION-CCI). Assessed by the orofacial operant behavioral test, ION-CCI animals displayed orofacial cold hypersensitivity. The cold hypersensitivity was associated with the hyperexcitability of small-sized trigeminal ganglion (TG) neurons that innervated orofacial regions. Furthermore, ION-CCI resulted in a reduction of A-type voltage-gated K currents (IA currents) in these TG neurons. We further showed that these small-sized TG neurons expressed Kv4.3 voltage-gated K channels, and Kv4.3 expression in these cells was significantly down-regulated following ION-CCI. Pharmacological inhibition of Kv4.3 channels with phrixotoxin-2 inhibited IA-currents in these TG neurons and induced orofacial cold hypersensitivity. On the other hand, pharmacological potentiation of Kv4.3 channels amplified IA currents in these TG neurons and alleviated orofacial cold hypersensitivity in ION-CCI rats. Collectively, Kv4.3 down-regulation in nociceptive trigeminal afferent fibers may contribute to peripheral cold hypersensitivity following trigeminal nerve injury, and Kv4.3 activators may be clinically useful to alleviate trigeminal neuropathic pain. Trigeminal neuropathic pain, the most debilitating pain disorder, is often triggered and exacerbated by cooling temperatures. Here we created infraorbital nerve chronic constrictive injury (ION-CCI) in rats, an animal model of trigeminal neuropathic pain to show that dysfunction of Kv4.3 voltage-gated K channels in nociceptive-like trigeminal ganglion neurons underlies the trigeminal neuropathic pain manifested with cold hypersensitivity in orofacial regions. Furthermore, we demonstrate that pharmacological potentiation of Kv4.3 channels can alleviate orofacial cold hypersensitivity in ION-CCI rats. Our results may have clinical implications in trigeminal neuropathic pain in human patients, and Kv4.3 channels may be an effective therapeutic target for this devastating pain disorder.
Learn More >Spinal cord stimulation (SCS) is an interventional non-pharmacologic treatment used for chronic pain and other indications. Methods for evaluating the safety and efficacy of SCS have evolved from uncontrolled and retrospective studies to prospective randomized controlled trials (RCTs). While randomization overcomes certain types of bias, additional challenges to the validity of RCTs of SCS include blinding, choice of control groups, non-specific effects of treatment variables (e.g., paresthesia, device programming and recharging, psychological support, and rehabilitative techniques), and safety considerations. In order to address these challenges, three professional societies (IMMPACT, ION, INS) convened a meeting to develop consensus recommendations on the design, conduct, analysis, and interpretation of RCTs of SCS for chronic pain. This paper summarizes the results of this meeting. Highlights of our recommendations include disclosing all funding source and potential conflicts; incorporating mechanistic objectives when possible; avoiding non-inferiority designs without internal demonstration of assay sensitivity; achieving and documenting double-blinding whenever possible; documenting investigator and site experience; keeping all information provided to patients balanced with respect to expectation of benefit; disclosing all information provided to patients, including verbal scripts; using placebo/sham controls when possible; capturing a complete set of outcome assessments; accounting for ancillary pharmacologic and non-pharmacologic treatments in a clear manner; providing a complete description of intended and actual programming interactions; making a prospective ascertainment of SCS-specific safety outcomes; training patients and researchers on appropriate expectations, outcome assessments, and other key aspects of study performance; and providing transparent and complete reporting of results according to applicable reporting guidelines.
Learn More >The current study used data from a clinical trial to identify variables that are associated with and/or mediate the beneficial effects of four psychological chronic pain treatments: one teaching patients self-hypnosis to reduce pain intensity (HYP), one teaching self-hypnosis to change thoughts about pain (hypnotic cognitive therapy, or HYP-CT), one teaching cognitive restructuring skills to change thoughts about pain (cognitive therapy, or CT), and one providing education about pain (ED; included as an active control condition). Of 17 possible mechanism variables examined, and with alpha not corrected for multiple comparisons, significant between-group differences were observed for three. Two of these (changes in beliefs about control over pain and number of days of skill practice) were supported as mediators of the beneficial effects of HYP, CT, or HYP-CT, relative to ED. Six mechanism variables evidenced significant pre- to post-treatment changes in the sample as a whole, without showing significant between-group differences. Pre- to post-treatment changes in all six were associated with improvements in pain interference, pain intensity, or both. In addition, participant ratings of therapeutic alliance at post-treatment were associated significantly with improvements in both pain intensity and pain interference in the sample as a whole. Thus, of the 17 possible mediators examined, there were relatively few that serve as mediators for the beneficial effects of specific treatments; a larger number of variables predicted treatment outcome overall. The extent to which these variables are treatment mediators (i.e., are responsible for, rather than merely associated with, treatment-related improvements) will require further research.
Learn More >It is not known how specific the neural mechanisms underpinning empathy for different domains are. In the present study, we set out to test whether shared neural representations between first-hand pain and empathy for pain are pain-specific or extend to empathy for unpleasant affective touch as well. Using functional magnetic resonance imaging and psychopharmacological experiments, we investigated if placebo analgesia reduces first-hand and empathic experiences of affective touch, and compared them with the effects on pain. Placebo analgesia also affected the first-hand and empathic experience of unpleasant touch, implicating domain-general effects. However, and in contrast to pain and pain empathy, administering an opioid antagonist did not block these effects. Moreover, placebo analgesia reduced neural activity related to both modalities in the bilateral insular cortex, while it specifically modulated activity in the anterior midcingulate cortex for pain and pain empathy. These findings provide causal evidence that one of the major neurochemical systems for pain regulation is involved in pain empathy, and crucially substantiates the role of shared representations in empathy.
Learn More >SARS-CoV-2 is a novel coronavirus that infects cells through the angiotensin-converting enzyme 2 receptor, aided by proteases that prime the spike protein of the virus to enhance cellular entry. Neuropilin 1 and 2 (NRP1 and NRP2) act as additional viral entry factors. SARS-CoV-2 infection causes COVID-19 disease. There is now strong evidence for neurological impacts of COVID-19, with pain as an important symptom, both in the acute phase of the disease and at later stages that are colloquially referred to as "long COVID." In this narrative review, we discuss how COVID-19 may interact with the peripheral nervous system to cause pain in the early and late stages of the disease. We begin with a review of the state of the science on how viruses cause pain through direct and indirect interactions with nociceptors. We then cover what we currently know about how the unique cytokine profiles of moderate and severe COVID-19 may drive plasticity in nociceptors to promote pain and worsen existing pain states. Finally, we review evidence for direct infection of nociceptors by SARS-CoV-2 and the implications of this potential neurotropism. The state of the science points to multiple potential mechanisms through which COVID-19 could induce changes in nociceptor excitability that would be expected to promote pain, induce neuropathies, and worsen existing pain states.
Learn More >Lateral and ventral lateral subregions of the periaqueductal gray (l/vlPAG) have been proved to be pivotal components in descending circuitry of itch processing, and their effects are related to the subclassification of neurons that were meditated. In the present study, lateral parabrachial nucleus (LPB), one of the most crucial relay stations in the ascending pathway, was taken as the input nucleus to examine the modulatory effect of l/vlPAG neurons that received LPB projections. Anatomical tracing, chemogenetic, optogenetic and local pharmacological approaches were utilized to investigate the participation of the LPB-l/vlPAG pathway in itch and pain sensation in mice. First, morphological evidence for projections from vesicular glutamate transporter-2 (VGluT2)-containing neurons in the LPB to l/vlPAG involved in itch transmission has been provided. Furthermore, chemogenetic and optogenetic activation of the LPB-l/vlPAG pathway resulted in both antipruritic effect and analgesic effect, whereas pharmacogenetic inhibition strengthened nociceptive perception without affecting spontaneous scratching behavior. Finally, in vivo pharmacology was combined with optogenetics which revealed that AMPA receptor-expressing neurons in l/vlPAG might play a more essential role in pathway modulation. These findings provide a novel insight about the connections between two prominent transmit nuclei, LPB and l/vlPAG, in both pruriceptive and nociceptive sensations, and deepen the understanding of l/vlPAG modulatory roles in itch sensation by chosen LPB as source of ascending efferent projections.
Learn More >Translational regulation permeates neuronal function. Nociceptors are sensory neurons responsible for the detection of harmful stimuli. Changes in their activity, termed plasticity, are intimately linked to the persistence of pain. While inhibitors of protein synthesis robustly attenuate pain associated behavior, the underlying targets that support plasticity are largely unknown. Here, we examine the contribution of protein synthesis in regions of RNA annotated as non-coding. Based on analyses of previously reported ribosome profiling data, we provide evidence for widespread translation in non-coding transcripts and regulatory regions of mRNAs. We identify an increase in ribosome occupancy in the 5' untranslated regions of the calcitonin gene-related peptide (CGRP/Calca). We validate the existence of an upstream Open Reading Frame (uORF) using a series of reporter assays. Fusion of the uORF to a luciferase reporter revealed active translation in DRG neurons following nucleofection. Injection of the peptide corresponding to the CGRP encoded uORF resulted in pain associated behavioral responses in vivo and nociceptor sensitization in vitro. An inhibitor of heterotrimeric G protein signaling blocks both effects. Collectively, the data suggest pervasive translation in regions of the transcriptome annotated as non-coding in DRG neurons and identify a specific uORF encoded peptide that promotes pain sensitization through GPCR signaling.
Learn More >UVB irradiation induces hyperalgesia in human and animal pain models. We investigated mechanical sensitization, increase in axonal excitability and spontaneous activity in different C-nociceptor classes following UVB in pig skin. We focused on units with receptive fields covering both irradiated and non-irradiated skin allowing intra-individual comparisons. 35 pigs were irradiated in a chessboard pattern and extracellular single-fibre recordings were obtained 10-28 h later (152 fibers). Units from the contralateral hindlimb served as control (n=112). Irradiated and non-irradiated parts of the same innervation territory were compared in 36 neurons: low threshold C-touch fibers (n=10) and sympathetic efferents (n=2) were unchanged, but lower mechanical thresholds and higher discharge frequency at threshold were found in mechanosensitive nociceptors (n=12). Half of them could be activated with non-noxious brush stimuli in the sunburn. 4 of 12 mechano-insensitive nociceptors were found sensitized to mechanical stimulation in the irradiated part of the receptive field. Activity dependent slowing of conduction was reduced in the irradiated and in the non-irradiated skin as compared to the control leg whereas increased ability to follow high stimulation frequencies was restricted to the sunburn (108.5 ± 37 Hz UVB vs. 6.3 ± 1 Hz control). Spontaneous activity was more frequent in the sunburn (72/152 vs. 31/112). Mechanical sensitization of primary nociceptors and higher maximum following frequency are suggested to contribute to primary hyperalgesia, whereas spontaneous activity of silent nociceptors might offer a mechanistic link contributing to ongoing pain and facilitated induction of spinal sensitization.
Learn More >While knee and hip replacements are intended to relieve pain and improve function, up to 44% of knee replacement patients and 27% of hip replacement patients report persistent postoperative joint pain. Improving surgical pain management is essential. We conducted a single-site, three-arm, parallel-group randomized clinical trial conducted at an orthopedic clinic, among patients undergoing total joint arthroplasty (TJA) of the hip or knee. Mindfulness meditation (MM), hypnotic suggestion (HS), and cognitive-behavioral pain psychoeducation (CBE) were each delivered in a single, 15-minute group session as part of a 2-hour, preoperative education program. Preoperative outcomes – pain intensity, pain unpleasantness, pain medication desire, and anxiety – were measured with numeric rating scales. Postoperative physical functioning at 6-week follow-up was assessed with the Patient-Reported Outcomes Measurement Information System Physical Function computer adaptive test. TJA patients were randomized to preoperative MM, HS, or CBE (n=285). MM and HS led to significantly less preoperative pain intensity, pain unpleasantness, and anxiety. MM also decreased preoperative pain medication desire relative to CBE and increased postoperative physical functioning at 6-week follow-up relative to HS and CBE. Moderation analysis revealed surgery type did not differentially impact the three interventions. Thus, a single session of a simple, scripted MM intervention may be able to immediately decrease TJA patients' preoperative clinical symptomology and improve postoperative physical function. As such, embedding brief MM interventions in surgical care pathways has the potential to improve surgical outcomes for the millions of patients receiving TJA each year.
Learn More >Photobiomodulation therapy (PBMT) has been used in several musculoskeletal disorders to reduce pain, inflammation and promoting tissue regeneration. The current evidence about the effects of PBMT on low back pain are still conflicting. We aimed to evaluate the effects of photobiomodulation therapy against placebo on pain intensity and disability in patients with chronic non-specific low back pain. This was a prospectively registered, randomised placebo-controlled trial, with blinded patients, therapists and assessors. The study was conducted on an outpatient physical therapy clinic in Brazil, between April 2017 and May 2019. A total of 148 patients with chronic non-specific low back pain were randomised to either active photobiomodulation therapy (n=74) or placebo (n=74). Patients from both groups received 12 treatment sessions, 3 times a week, for 4 weeks. Patients from both groups also received an educational booklet based on 'The Back Book'. Clinical outcomes were measured at baseline and at follow-up appointments at 4 weeks, 3, 6 and 12 months after randomization. The primary outcomes were pain intensity and disability measured at 4 weeks. We estimated the treatment effects using linear mixed models following the principles of intention to treat. There was no clinical important between-group differences in terms of pain intensity (Mean Difference=0.01 point; 95% CI=-0.94 to 0.96) and disability (Mean Difference=-0.63 points; 95% CI=-2.23 to 0.97) at 4 weeks. Patients did not report any adverse events. Photobiomodulation therapy was not better than placebo to reduce pain and disability in patients with chronic non-specific low back pain.
Learn More >Pain is a frequent reason for patients to ask for medical services. However, systematic information about the extent and impact of pain, especially in developing countries, has not been available up to now. We evaluated, whether the 11th edition of the ICD can fill this gap by coding all electronic out-patient medical records of the pain clinic at Siriraj Hospital in Thailand in 2019 (8714 visits), using the ICD-10 and ICD-11 browsers referenced on the WHO websites. The three most frequent pain-related codes in ICD-10 were R52.2 "Other chronic pain" (29%), M54.5 "Low back pain" (18%), and M79.6 "Pain in limb" (13%). In ICD-11, the three most frequent codes were MG30.31 "Chronic secondary musculoskeletal pain associated with structural changes" (28%), MG30.51 "Chronic peripheral neuropathic pain" (26%), and MG30.10 "Chronic cancer pain" (23%). Thus, using the currently valid ICD-10 system, roughly one third of patient encounters were coded as "Other chronic pain", and the next two were specifying the pain region rather than any underlying cause. In contrast, ICD-11 coding of the same patients identified underlying causes (bones and joints, somatosensory nervous system, cancer or surgery), which provide guidance towards differential patient management. In our pain clinic, a majority of patients suffered from Chronic cancer pain, Chronic neuropathic pain, and Chronic secondary musculoskeletal pain, which were poorly defined or non-existent in the current ICD-10 coding system. Compared to the ICD-10, the ICD-11 provides more detailed diagnostic categories and is more informative for clinical use, research and resource allocation for pain-related conditions.
Learn More >It remains unknown why upon similar acute/subacute painful conditions, pain persists in some individuals while in others it resolves. Genetic factors, mood, and functional alterations, particularly involving the mesolimbic network, appear to be key. In order to explore potential susceptibility/resistance factors, we screened a large population of rats with a peripheral neuropathy and we isolated a small subset (<15%) that presented high thresholds (HT) to mechanical allodynia (reduced pain manifestation). The phenotype was sustained over 12 weeks and was associated with higher hedonic behavior when compared with low threshold subjects (LT). The nucleus accumbens (NAc) of HT and LT animals were isolated for proteomic analysis by Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS). Two hundred and seventy-nine proteins displayed different expression between LT and HT animals/subjects. Among several protein families, the proteasome pathway repeatedly emerged in gene ontology enrichment and KEGG analyses. Several alpha and beta 20S proteasome subunits were increased in LT when compared to HT animals (e.g., PSMα1, PSMα2, and PSMβ5). On the contrary, UBA6, an upstream ubiquitin-activating enzyme, was decreased in LT animals. Altogether these observations are consistent with an overactivation of the accumbal proteasome pathway in animals that manifest pain and depressive-like behaviors after a neuropathic injury. All the proteomic data are available via ProteomeXchange with identifier PXD022478.
Learn More >The VLPFC vs. the DLPFC in down-regulating social pain using reappraisal and distraction strategies.
The dorsolateral (DLPFC) and ventrolateral prefrontal cortices (VLPFC) are both crucial structures involved in voluntary emotional regulation. However, it remains unclear whether the functions of these two cortical regions that are involved in emotional regulation-which are usually active in non-social situations-could be generalized to the regulation of social pain as well. This study employed transcranial magnetic stimulation (TMS) to examine the causal relationship between the DLPFC/VLPFC and the emotional regulation of social pain via distraction and reappraisal. Ninety human participants (45 males and 45 females) initially underwent either active (DLPFC/VLPFC, n = 30/30) or sham (vertex, n = 30) TMS sessions. Participants were then instructed to use both distraction and reappraisal strategies to down-regulate any negative emotions evoked by social exclusion pictures. Convergent results of the subjective emotional rating and electrophysiological indices demonstrated that: 1) both the DLPFC and VLPFC highly facilitate the down-regulation of affective responses caused by social exclusion, revealing a causal role of these lateral prefrontal cortices in voluntary emotional regulation of both non-social and social pain; and 2) these two cortical regions showed relative functional specificity for distraction (DLPFC) and reappraisal (VLPFC) strategies, which helps to refine the cortical targeting of therapeutic protocols. In addition, the TMS effect was sustainable for at least one hour, showcasing the potential feasibility of using this method in clinical practice. Together, these findings provide cognitive and neural evidence for the targeting of the VLPFC and/or the DLPFC to improve emotional regulation abilities, especially in social contexts.This study aimed to examine the role of the dorsolateral and ventrolateral prefrontal cortices in emotional regulation, particularly in response to social pain through the use of distraction and reappraisal strategies, as this is a relatively underexplored area of inquiry. This study makes a significant contribution to the literature because our results provide novel empirical information on the role of these cortical structures in the processing of negative emotions elicited within certain social contexts. As such, our findings have potential clinical implications, paving the way for future clinicians to be able to accurately target specific brain regions among patients struggling with impaired social cognition abilities, including those diagnosed with post-traumatic stress disorder, autism spectrum disorder, social anxiety disorder, and depression.
Learn More >To examine the influences of depression and anxiety on headache-related disability in people with episodic migraine or chronic migraine.
Learn More >Early symptoms prior to a cluster headache bout have been reported to occur days or weeks before the actual beginning of the cluster headache bouts. This study aimed to describe the prevalence of pre-cluster (premonitory) symptoms and examine the predictability of an upcoming cluster headache bout.
Learn More >The Clinical Trials Subcommittee of the International Headache Society presents the first Health Technology Assessment for the Acute Treatment of Migraine Attacks and Prevention of Migraine. Health technology assessments are systematic evaluations of the properties, effects, and consequences of healthcare technologies; this position statement is designed to inform decision makers about access to and reimbursement for medications and devices for the acute and preventive treatment of migraine. This position statement extends beyond the already available guidelines on randomized controlled trials for migraine to incorporate real-world evidence and a synthetic approach for considering multiple data sources and modelling methods when assessing the value of migraine treatments.
Learn More >The genetic background of pain is becoming increasingly well understood, which opens up possibilities for predicting the individual risk of persistent pain and the use of tailored therapies adapted to the variant pattern of the patient's pain-relevant genes. The individual variant pattern of pain-relevant genes is accessible via next-generation sequencing, although the analysis of all "pain genes" would be expensive. Here, we report on the development of a cost-effective next generation sequencing-based pain-genotyping assay comprising the development of a customized AmpliSeq™ panel and bioinformatics approaches that condensate the genetic information of pain by identifying the most representative genes. The panel includes 29 key genes that have been shown to cover 70% of the biological functions exerted by a list of 540 so-called "pain genes" derived from transgenic mice experiments. These were supplemented by 43 additional genes that had been independently proposed as relevant for persistent pain. The functional genomics covered by the resulting 72 genes is particularly represented by mitogen-activated protein kinase of extracellular signal-regulated kinase and cytokine production and secretion. The present genotyping assay was established in 61 subjects of Caucasian ethnicity and investigates the functional role of the selected genes in the context of the known genetic architecture of pain without seeking functional associations for pain. The assay identified a total of 691 genetic variants, of which many have reports for a clinical relevance for pain or in another context. The assay is applicable for small to large-scale experimental setups at contemporary genotyping costs.
Learn More >Virtual reality (VR) has been shown to produce analgesic effects during different experimental and clinical pain states. Despite this, the top-down mechanisms are still poorly understood. In this study, we examined the influence of both a real and sham (i.e. the same images in 2D) immersive arctic VR environment on conditioned pain modulation (CPM) and in a human surrogate model of central sensitisation in 38 healthy volunteers. CPM and acute heat pain thresholds (HPT) were assessed before and during VR/sham exposure in the absence of any sensitisation. In a follow-on study, we used the cutaneous high frequency stimulation (HFS) model of central sensitisation and measured changes in mechanical pain sensitivity (MPS) in an area of heterotopic sensitisation before and during VR/sham exposure. There was an increase in CPM efficiency during the VR condition compared to baseline (P<0.01). In the sham condition, there was a decrease in CPM efficiency compared to baseline (P<0.01) and the real VR condition (P<0.001). Neither real nor sham VR had any effect on pain ratings reported during the conditioning period or on HPT. There was also an attenuation of MPS during the VR condition indicating a lower sensitivity compared to sham (P<0.05). We conclude that exposure to an immersive VR environment has no effect over acute pain thresholds but can modulate dynamic CPM responses and mechanical hypersensitivity in healthy volunteers. Perspective: This study has demonstrated that exposure to an immersive virtual reality environment can modulate perceptual correlates of endogenous pain modulation and secondary hyperalgesia in a human surrogate pain model. These results suggest that virtual reality could provide a novel mechanism-driven analgesic strategy in patients with altered central pain processing.
Learn More >C tactile (CT) fibres, responsible for the so-called "affective" touch (AT), have drawn a fair amount of attention within the scientific community for their marked social dimension. However, while the pain-relieving potential of discriminative touch (DT) has been documented, proofs of the analgesic properties of AT are still scarce. Additionally, no study has so far tested its possible pain-relieving effect on a clinically-relevant model. Temporal summation of second pain (TSSP), otherwise referred to as 'wind-up', relies on repetitive stimulation of C-nociceptors and it is thought to reflect central sensitization, a process linked to many chronic pain conditions. In the present experimental, within participants, design we induced TSSP trough trains of ascending and descending repetitive heat stimulation. Forty-two healthy participants' pain was measured during two different tactile stimulations (stroking velocities AT: 10 cm/s; DT: 0.3 cm/s) or without concomitant tactile input. Since measures of pleasantness of the tactile stimulation have been found to strongly correlate with C-tactile fibres' firing rate, these, together with participants' body awareness, were also taken into account. Our results show that AT brought about a decrease of our participants' pain as opposed to both DT and no touch, while DT did not produce any significant pain reduction. Thus, only AT successfully modulated wind-up. As expected, AT was perceived more pleasant than DT, while a clear relationship between body awareness and pain was found only during DT. Targeting CT fibres could pave the way to new treatments for chronic pain conditions whose aetiology depend on abnormal C-nociceptors' physiology.
Learn More >A Systematic Review and Meta-Analysis of the Association between Perceived Injustice and Depression.
Perceived injustice is increasingly recognised as a risk factor for problematic recovery, with a growing body of evidence documenting its association with heightened pain, disability, medication use, anger and post-traumatic stress. The aim of this paper was to systematically review and critically appraise the association between perceived injustice and depressive symptomatology across a wide range of medical and mental health populations, including acute and chronic pain samples. A search of published, English language studies in the PubMed, EMBASE, CINAHL and PsycINFO databases from 1990 to June 2020 was performed. Thirty-three studies met inclusion criteria with a total sample of 5,425 individuals (61% female), primarily with acute injury or chronic pain. Results indicated a moderate to strong positive association between perceived injustice and depressive symptomatology (meta-analysis pooled effect of r = .57, 95% CI [0.55, 0.58], p < .001). A narrative synthesis of regression models indicated standardised beta coefficients between .19 and .66, with perceived injustice consistently contributing significant unique variance to the prediction of depression in final regression equations. Selection bias and response bias were common limitations in the studies. The clinical implications of an association between injustice and depression in acute and chronic pain are discussed. PROSPERO: CRD42019143465 PERSPECTIVE: This review demonstrates that in acute injury and chronic pain samples, perceived injustice is associated with depression. These findings could help clinicians in the field of pain and rehabilitation identify who may be at greater risk for a problematic recovery trajectory.
Learn More >Opioid usage for pain therapy is limited by its undesirable clinical effects, including paradoxical hyperalgesia, also known as opioid-induced hyperalgesia, (OIH). However, the mechanisms associated with the development and maintenance of OIH remain unclear. Here, we investigated the effect of serotonin inhibition by the 5-HT receptor antagonist, ondansetron (OND), as well as serotonin deprivation via its synthesis inhibitor para-chlorophenylalanine (PCPA), on mouse OIH models, with particular focus on astrocyte activation. Co-administering of OND and morphine, in combination with serotonin depletion, inhibited mechanical hyperalgesia and astrocyte activation in the spinal dorsal horn of mouse OIH models. Although previous studies have suggested that activation of astrocytes in the spinal dorsal horn is essential for the development and maintenance of OIH, herein, treatment with carbenoxolone (CBX), a gap junction inhibitor that suppresses astrocyte activation, did not ameliorate mechanical hyperalgesia in mouse OIH models. These results indicate that serotonin in the spinal dorsal horn, and activation of the 5-HT receptor play essential roles in OIH induced by chronic morphine, while astrocyte activation in the spinal dorsal horn serves as a secondary effect of OIH. Our findings further suggest that serotonergic regulation in the spinal dorsal horn may be a therapeutic target of OIH. PERSPECTIVE: The current study revealed that the descending serotonergic pain-facilitatory system in the spinal dorsal horn is crucial in OIH, and that activation of astrocytes is a secondary phenotype of OIH. Our study offers new therapeutic targets for OIH and may help reduce inappropriate opioid use.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of cancer treatment, often associated with degeneration of sensory axons or their terminal regions. Presence of the slow Wallerian degeneration protein (WLD), or genetic deletion of sterile alpha and TIR motif containing protein 1 (SARM1), which strongly protect axons from degeneration after injury or axonal transport block, alleviate pain in several CIPN models. However, oxaliplatin can cause an acute pain response, suggesting a different mechanism of pain generation. Here, we tested whether the presence of WLD or absence of SARM1 protects against acute oxaliplatin-induced pain in mice after a single oxaliplatin injection. In BL/6 and Wld mice, oxaliplatin induced significant mechanical and cold hypersensitivities which were absent in Sarm1 mice. Despite the presence of hypersensitivity there was no significant loss of intraepidermal nerve fibers (IENFs) in the footpads of any mice after oxaliplatin treatment, suggesting that early stages of pain hypersensitivity could be independent of axon degeneration. To identify other changes that could underlie the pain response, RNA sequencing was carried out in DRGs from treated and control mice of each genotype. Sarm1 mice had fewer gene expression changes than either BL/6 or Wld mice. This is consistent with the pain measurements in demonstrating that Sarm1DRGs remain relatively unchanged after oxaliplatin treatment, unlike those in BL/6 and Wld mice. Changes in levels of four transcripts – Alas2, Hba-a1, Hba-a2, and Tfrc – correlated with oxaliplatin-induced pain, or absence thereof, across the three genotypes. Our findings suggest that targeting SARM1 could be a viable therapeutic approach to prevent oxaliplatin-induced acute neuropathic pain.
Learn More >The vast majority of individuals who come to the emergency department (ED) for care after a motor vehicle collision (MVC) are diagnosed with musculoskeletal strain only and are discharged to home. A significant subset of this population will still develop persistent pain and posttraumatic psychological sequelae may play an important role in pain persistence.
Learn More >Chronic neuropathic pain and prescription opioid abuse represent highly interconnected societal problems. We used a rat model of spared nerve injury (SNI) and an intravenous drug self-administration paradigm to investigate the impact of a neuropathic pain state on morphine seeking behavior in extinction (i.e. when morphine is withheld). SNI, sham-operated and naive groups exhibited similar levels of active lever presses for morphine infusions on a fixed ratio 1 (FR1) schedule. Self-administration of morphine, but not vehicle, attenuated nerve injury-induced mechanical allodynia in SNI rats. Under these same conditions, mechanical paw withdrawal thresholds in sham-operated and naive groups were largely unaltered. However, SNI rats showed higher levels of morphine-seeking behavior compared to sham-operated or naïve groups in extinction (i.e. when vehicle was substituted for morphine). Interestingly, the perseveration of morphine-seeking behavior observed during extinction was only present in the SNI group despite the fact that all groups had a similar history of morphine self-administration intake. Our results suggest that different motivational states associated with neuropathic pain promote morphine-seeking behavior in extinction. Drug self-administration paradigms may be useful for evaluating analgesic efficacy and motivational properties associated with opioid reinforcers in pathological pain states.
Learn More >Autonomous regulation of the intestine requires the combined activity of functionally distinct neurons of the enteric nervous system (ENS). However, the variety of enteric neuron types and how they emerge during development remain largely unknown. Here, we define a molecular taxonomy of 12 enteric neuron classes within the myenteric plexus of the mouse small intestine using single-cell RNA sequencing. We present cell-cell communication features and histochemical markers for motor neurons, sensory neurons and interneurons, together with transgenic tools for class-specific targeting. Transcriptome analysis of the embryonic ENS uncovers a novel principle of neuronal diversification, where two neuron classes arise through a binary neurogenic branching and all other identities emerge through subsequent postmitotic differentiation. We identify generic and class-specific transcriptional regulators and functionally connect Pbx3 to a postmitotic fate transition. Our results offer a conceptual and molecular resource for dissecting ENS circuits and predicting key regulators for directed differentiation of distinct enteric neuron classes.
Learn More >Self-compassion is associated with disability, pain-related anxiety as well as depression and anger in patients with chronic pain. However, the unique value of self-compassion versus other concepts such as psychological flexibility and self-esteem is unknown. The present study therefore aimed to clarify these relationships. Individuals with chronic pain (N = 872) and without chronic pain (N = 356) took part in a longitudinal study. Participants completed self-report instruments: Pain Disability Index (PDI), Pain Catastrophizing Scale (PCS), Pain Anxiety Symptom Scale (PASS-20), Patient Health Questionnaire (PHQ-9), State Trait Anger Expression Inventory (STAXI), Self-Compassion Scale (SCS), Psychological Inflexibility in Pain Scale (PIPS) and Rosenberg Self-Esteem Scale (RSES). Assessments were repeated after 8 weeks. We found differences in baseline levels of all relevant variables except for anger-out and anger-control between people with and without chronic pain. Subsequently, we computed a path model analysis regarding individuals suffering from chronic pain (N), addressing the predictive value of reduced uncompassionate self-responding (RUS), compassionate self-responding (CS), avoidance (PIPS), cognitive fusion (PIPS) and self-esteem (RSES) regarding pain-related (PDI, PCS, PASS) and emotional variables (PHQ-9, STAXI). Avoidance predicted disability, catastrophizing, anxiety and depression. RUS predicted catastrophizing and pain-related anxiety. Self-esteem predicted depression. CS and cognitive fusion had no unique predictive value. The model explained 65.4%-72.1% of the variance in pain-related variables, 68.7% of the variance in depression and 38.7%-60.7% in the variance of anger-related variables. In conclusion, psychological flexibility, in terms of avoidance, seems to be more relevant for chronic pain than self-compassion. Future research should focus on subgroups and tailored-treatment approaches. SIGNIFICANCE: Applying a longitudinal design, this study examined the predictive value of self-compassion regarding pain, depression and anger. The relevance of self-compassion was compared to psychological flexibility and self-esteem. We can conclude that psychological flexibility, in terms of avoidance behaviour, is the most relevant predictor concerning pain.
Learn More >Fibromyalgia is a potentially disabling chronic disease, characterized by widespread pain and a range of comorbidities such as hypertension. Among the mechanisms involved in fibromyalgia-like pain symptoms are kinins and their B and B receptors. Moreover, angiotensin I converting enzyme (ACE) inhibitors, commonly used as antihypertensive drugs, can enhance pain by blocking the degradation of peptides such as substance P and bradykinin, besides enhancing kinin receptors signalling. We investigated the effect of ACE inhibitors on reserpine-induced fibromyalgia-like pain symptoms and the involvement of kinins in this effect in mice. Nociceptive parameters (mechanical and cold allodynia and overt nociception) were evaluated after ACE inhibitors administration in mice previously treated with reserpine. The role of kinin B and B receptors was investigated using pharmacological antagonism. Additionally, bradykinin levels, as well as the activity of ACE and kininase I, were measured in the sciatic nerve, spinal cord and cerebral cortex of the mice. The ACE inhibitors enalapril and captopril enhanced reserpine-induced mechanical allodynia, and this increase was prevented by kinin B and B receptor antagonists. Substance P and bradykinin caused overt nociception and increased mechanical allodynia in animals treated with reserpine. Reserpine plus ACE inhibitors increased bradykinin-related peptide levels and inhibited ACE activity in pain modulation structures. Since hypertension is a frequent comorbidity affecting fibromyalgia patients, hypertension treatment with ACE inhibitors in these patients should be reviewed once this could enhance fibromyalgia-like pain symptoms. Thus, the treatment of hypertensive patients with fibromyalgia could include other classes of antihypertensive drugs, different from ACE inhibitors.
Learn More >We investigated patients with chronic pain seeking medical cannabis. We assessed their demographics, patterns of cannabis use, and the long-term effectiveness of cannabis on their pain and functional domains.
Learn More >The goal of this review is to present a summary of the recent literature of a non-invasive brain stimulation (NIBS) to alleviate pain in people with chronic pain syndromes. This article reviews the current evidence for the use of transcranial direct current (tDCS) and repetitive transcranial magnetic stimulation (rTMS) to improve outcomes in chronic pain. Finally, we introduce the reader to novel stimulation methods that may improve therapeutic outcomes in chronic pain.
Learn More >Although evidence-based psychological treatments for chronic pain have been demonstrated to be effective for a variety of outcomes, modest effects observed in recent reviews indicate scope for improvement. Self-compassion promotes a proactive attitude towards self-care and actively seeking relief from suffering. Consequently, more compassionate people experience better physical, psychological, and interpersonal wellbeing.
Learn More >Pharmacological agents directed to either opioid receptors or peroxisome proliferator-activated receptor gamma (PPARγ) at peripheral tissues reduce behavioral signs of persistent pain. Both receptors are expressed in muscle tissue, but the contribution of PPARγ activation to muscle pain and its modulation by opioid receptors remains unknown. To address this question, we first tested whether the endogenous PPARγ ligand 15d-PGJ2 would decrease mechanical hyperalgesia induced by carrageenan administration into the gastrocnemius muscle of rats. Next, we used receptor antagonists to determine whether the antihyperalgesic effect of 15-deoxyΔ-12,14-prostaglandin J2 (15d-PGJ2) was PPARγ- or opioid receptor-dependent. Three hours after carrageenan, muscle hyperalgesia was quantified with the Randall-Selitto test. 15d-PGJ2 prevented carrageenan-induced muscle hyperalgesia in a dose-dependent manner. The antihyperalgesic effect of 15d-PGJ2 was dose-dependently inhibited by either the PPARγ antagonist, 2-chloro-5-nitro-N-phenylbenzamide, or by the opioid receptor antagonist, naloxone. We conclude that 15d-PGJ2 targets PPARγ and opioid receptors to prevent muscle hyperalgesia. We suggest that local PPARγ receptors are important pharmacological targets for inflammatory muscle pain.
Learn More >Pain is a prevalent biopsychosocial condition that poses a significant challenge to healthcare providers, contributes substantially to disability, and is a major economic burden worldwide. An overreliance on opioid analgesics, which primarily target the μ-opioid receptor, has caused devastating morbidity and mortality in the form of misuse and overdose-related death. Thus, novel analgesic medications are needed that can effectively treat pain and provide an alternative to opioids. A variety of cellular ion channels contribute to nociception, the response of the sensory nervous system to a noxious stimulus that commonly leads to pain. Ion channels involved in nociception may provide a suitable target for pharmacologic modulation to achieve pain relief. This narrative review summarizes the evidence for two ion channels that merit consideration as targets for non-opioid pain medications: ryanodine receptors (RyRs), which are intracellular calcium channels, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which belong the superfamily of voltage-gated K+ channels. The role of these channels in nociception and neuropathic pain is discussed and suitability as targets for novel analgesics and antihyperalgesics is considered.
Learn More >The kappa opioid receptor (KOR), a G protein-coupled receptor, and its endogenous ligands, the dynorphins, are prominent members of the opioid neuromodulatory system. The endogenous kappa opioid system is expressed in the central and peripheral nervous systems, and has a key role in modulating pain in central and peripheral neuronal circuits and a wide array of physiological functions and neuropsychiatric behaviors (e.g., stress, reward, emotion, motivation, cognition, epileptic seizures, itch, and diuresis). We review the latest advances in pharmacology of the KOR, chemical developments on KOR ligands with advances and challenges, and therapeutic and potential applications of KOR ligands. Diverse discovery strategies of KOR ligands targeting natural, naturally derived, and synthetic compounds with different scaffolds, as small molecules or peptides, with short or long-acting pharmacokinetics, and central or peripheral site of action, are discussed. These research efforts led to ligands with distinct pharmacological properties, as agonists, partial agonists, biased agonists, and antagonists. Differential modulation of KOR signaling represents a promising strategy for developing pharmacotherapies for several human diseases, either by activating (treatment of pain, pruritus, and epilepsy) or blocking (treatment of depression, anxiety, and addiction) the receptor. We focus on the recent chemical and pharmacological advances on diphenethylamines, a new class of structurally distinct, selective KOR ligands. Design strategies and investigations to define structure-activity relationships together with in vivo pharmacology of diphenethylamines as agonists, biased agonists, and antagonists and their potential use as therapeutics are discussed.
Learn More >Studies of Internet-delivered acceptance and commitment therapy (ACT) for chronic pain have shown small to moderate positive effects for pain interference and pain acceptance. Effects on pain intensity, depression, anxiety and quality of life (QoL) have been less favourable, and improvements for values and sleep are lacking. In this randomized controlled trial iACT – a novel format of Internet-ACT using daily microlearning exercises – was examined for efficacy compared to a waitlist condition.
Learn More >Temporomandibular disorder (TMD) is one of the most common orofacial pain conditions. Alteration in immune functioning is one promising biological mechanism underlying pain in TMD. However, there is a gap in the understanding of molecular bases contributing to altered immune functioning in these patients.
Learn More >Persistent post-mastectomy pain (PPMP) is a significant negative outcome occurring after breast surgery, and understanding which individual women are most at risk is essential to targeting of preventive efforts. The biopsychosocial model of pain suggests that factors from many domains may importantly modulate pain processing and predict the progression to pain persistence.
Learn More >Preclinical opioid research using animal models not only provides mechanistic insights into the modulation of opioid analgesia and its associated side effects, but also validates drug candidates for improved treatment options for opioid use disorder. Non-human primates (NHPs) have served as a surrogate species for humans in opioid research for more than five decades. The translational value of NHP models is supported by the documented species differences between rodents and primates regarding their behavioral and physiological responses to opioid-related ligands and that NHP studies have provided more concordant results with human studies. This review highlights the utilization of NHP models in five aspects of opioid research, i.e., analgesia, abuse liability, respiratory depression, physical dependence, and pruritus. Recent NHP studies have found that (1) mixed mu opioid and nociceptin/orphanin FQ peptide receptor partial agonists appear to be safe, non-addictive analgesics and (2) mu opioid receptor- and mixed opioid receptor subtype-based medications remain the only two classes of drugs that are effective in alleviating opioid-induced adverse effects. Given the recent advances in pharmaceutical sciences and discoveries of novel targets, NHP studies are posed to identify the translational gap and validate therapeutic targets for the treatment of opioid use disorder. Pharmacological studies using NHPs along with multiple outcome measures (e.g., behavior, physiologic function, and neuroimaging) will continue to facilitate the research and development of improved medications to curb the opioid epidemic.
Learn More >Cognitive-behavioral therapy (CBT) can reduce preoperative pain catastrophizing and may improve postsurgical pain outcomes. We hypothesized that CBT would reduce pain catastrophizing more than no-CBT controls and result in improved pain outcomes.
Learn More >The role of lipids in modulating membrane protein function is an emerging and rapidly growing area of research. The rational design of lipids that target membrane proteins for the treatment of pathological conditions is a novel extension in this field and provides a step forward in our understanding of membrane transporters. Bioactive lipids show considerable promise as analgesics for the treatment of chronic pain and bind to a high-affinity allosteric binding site on the human glycine transporter 2 (GlyT2 or SLC6A5). Here we use a combination of medicinal chemistry, electrophysiology, and computational modelling to develop a rational structure activity relationship for lipid inhibitors and demonstrate the key role of the lipid tail interactions for GlyT2 inhibition. Specifically, we examine how lipid inhibitor head group stereochemistry, tail length and double bond position promote enhanced inhibition. Overall, the L-stereoisomer is generally a better inhibitor than the D-stereoisomer, longer tail length correlates with greater potency, and the position of the double bond influences the activity of the inhibitor. We propose that the binding of the lipid inhibitor deep into the allosteric binding pocket is critical for inhibition. Furthermore, this provides insight into the mechanism of inhibition of GlyT2 and highlights how lipids can modulate the activity of membrane proteins by binding to cavities between helices. The principles identified in this work have broader implications for the development of a larger class of compounds that could target SLC6 transporters for disease treatment.
Learn More >Calcium (Ca) is the primary stimulus for transmembrane protein 16 (TMEM16) Ca-activated chloride channels and phospholipid scramblases, which regulate important physiological processes ranging from smooth muscle contraction to blood coagulation and tumor progression. Binding of intracellular Ca to two highly conserved orthosteric binding sites in transmembrane helices (TMs) 6-8 efficiently opens the permeation pathway formed by TMs 3-7. Recent structures of TMEM16K and TMEM16F scramblases revealed an additional Ca binding site between TM2 and TM10, whose functional relevance remains unknown. Here, we report that Ca binds with high affinity to the equivalent third Ca site in TMEM16A to enhance channel activation. Our cadmium (Cd) metal bridging experiments reveal that the third Ca site's conformational states can profoundly influence TMEM16A's opening. Our study thus confirms the existence of a third Ca site in TMEM16A, defines its functional importance in channel gating, and provides insight into a long-range allosteric gating mechanism of TMEM16 channels and scramblases.
Learn More >The aim of the present study was to investigate the analgesic effects of repetitive transcranial magnetic stimulation over the primary motor cortex (M1-rTMS) using different stimulation parameters to explore the optimal stimulus condition for treating neuropathic pain.
Learn More >The present study aims to describe state-of-the-art of preclinical studies that have investigated peripheral receptors and neuromediators involved in the antihyperalgesic effects of acupuncture. The PubMed, Scopus, and Web of Science databases were searched using the integrative review method. Preclinical articles that involved the study of peripheral receptors and neuromediators on the pain control effects of acupuncture in rats or mice were selected using a predefined search strategy. From this search, 456 articles were found, and 29 of them met the inclusion criteria of the study. The selected articles addressed the following peripheral receptors: opioid (n = 9), adenosine (n = 5), cannabinoid (n = 5), transient receptor potential vanilloid (TRPV) (n = 3), histamine (n = 2), adrenergic (n = 1), muscarinic (n = 1), corticotrophin-releasing factor (CRF) (n = 2), IL-1 (n = 1), and endothelin (n = 1) receptors. The peripheral neuromediators correlated with the peripheral pain control effect were as follows: opioid peptides (n = 4), adenosine (n = 3), histamine (n = 1), substance P (n = 1) calcitonin gene-related peptide (CGRP) (n = 1), anandamide (n = 1), nitric oxide (n = 1), and norepinephrine (n = 1). This review summarizes the methods used to investigate the peripheral effects of acupuncture and discusses the main findings on each family of receptors and neuromediators. Ten families of peripheral receptors and 8 types of neuromediators were correlated with the antihyperalgesic effects of acupuncture in preclinical studies. Considering the benefits of a better understanding of the role of peripheral receptors and neuromediators in the context pain management, the findings of the present study highlight the importance of deepening the exploration of the peripheral mechanisms of acupuncture.
Learn More >We review the relevance of quantitative sensory testing (QST) in light of acute and chronic postoperative pain and associated challenges.
Learn More >Cluster headache is a highly disabling neurological disorder.
Learn More >Exercise therapy is the most recommended treatment for chronic low back pain (LBP). Effect sizes for exercises are usually small to moderate and could be due to the heterogeneity of people presenting with LBP. Thus, if patients could be better matched to exercise based on individual factors, then the effects of treatment could be greater. A recently published study provided evidence of better outcomes when patients are matched to the appropriate exercise type. The study demonstrated that a 15-item questionnaire, the Lumbar Spine Instability Questionnaire (LSIQ), could identify patients who responded best to one of the two exercise approaches for LBP (motor control and graded activity). The primary aim of the current study isill be to evaluate whether preidentified baseline characteristics, including the LSIQ, can modify the response to two of the most common exercise therapies for non-specific LBP. Secondary aims include an economic evaluations with a cost-effectiveness analysis.
Learn More >The physiological mechanisms underlying the pain-modulatory effects of clinical neurostimulation therapies, such as spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRGS), are only partially understood. In this pilot prospective study, we used patient-reported outcomes (PROs) and quantitative sensory testing (QST) to investigate the physiological effects and possible mechanisms of action of SCS and DRGS therapies.
Learn More >Pain is common but often underrecognized after stroke. Poststroke pain (PSP) hinders recovery, impairs quality of life, and is associated with the psychological state of patients with stroke. The most common subtypes of PSP include central PSP, complex regional pain syndrome, shoulder pain, spasticity-related pain, and headache. The pathophysiologies of these PSP subtypes are not yet clearly understood, and PSP is refractory to conventional treatment in many patients. However, recent studies have proposed potential pathophysiologies of PSP subtypes, which may help prioritize therapies that target specific mechanisms.
Learn More >Opioid use has increased globally for the management of chronic non-cancer-related pain. There are concerns regarding the misuse of opioids leading to persistent opioid use and subsequent hospitalisation and deaths in developed countries. Hospital admissions related to surgery or trauma have been identified as contributing to the increasing opioid use internationally. There are minimal data on persistent opioid use and opioid-related harm in New Zealand (NZ), and how hospital admission for surgery or trauma contributes to this. We aim to describe rates and identify predictors of persistent opioid use among opioid-naïve individuals following hospital discharge for surgery or trauma.
Learn More >This scoping review examines the current research on the effect of cannabis upon pain intensity in spinal cord injury (SCI) pain. Chronic pain is a significant secondary condition following SCI, and traditional treatments (e.g. opioids, NSAIDs) are often criticized for providing inadequate relief. As a result, there is increasing interest in and use of cannabis and cannabinoid-based medications as an alternative means of pain control.
Learn More >P2X7 receptors are responsible for triggering inflammatory responses contributing to processes of pain in articular tissues. This study aimed to investigate whether the activation of the P2X7 receptor located in the temporomandibular joint (TMJ) tissues induces nociception through an inflammatory mechanisms and/or the activation of C-fibers (small-diameter primary afferents) of rats' TMJ.
Learn More >Serotonin (5-HT) acts as a neurotransmitter in the central nervous system (CNS) and as a mediator released by enterochromaffin cells to regulate intestinal motility. However, this amine also plays an important role as an inflammatory mediator and induces phenotypic changes of nociceptors. Despite the wide knowledge of the role of 5-HT in nociception, most studies have focused on its role in the CNS, while a clear information about its role in peripheral tissues is still lacking. In the present study, we investigated the role of peripheral 5-HT receptors in the nociceptive response induced by 5-HT or carrageenan in mice by using antagonists that target different 5-HT receptors. Mechanical nociceptive threshold was measured with an analgesimeter and evaluated after intraplantar (i.pl.) injection of 5-HT or carrageenan. 5-HT antagonists were injected via the i.pl. route. 5-HT (10, 20, 40 or 80 μg/paw) or carrageenan (100 μg/paw) induced mechanical allodynia. Pretreatment with isamoltane (5 μg; 5-HT antagonist) or ketanserine (1 μg; 5-HT antagonist) did not affect the mechanical allodynia induced by 5-HT. This response was inhibited by BRL 15572 (10 μg; 5-HT antagonist) or SB 269970 (25 μg; 5-HT antagonist). On the other hand, mechanical allodynia induced by 5-HT or carrageenan was exacerbated by ondansetron (10, 20 or 40 μg; 5-HT antagonist). The results indicate that activation of 5-HT and 5-HT receptors plays a role in the mechanical allodynia induced by 5-HT in mice. This study also demonstrates the inhibitory role of peripheral 5-HT receptors in the nociceptive response induced by 5-HT or carrageenan.
Learn More >Poor sleep is commonly reported in pediatric chronic pain. There are signals that intensive interdisciplinary pain treatments (IIPT) may inadvertently improve objective sleep, but this claim cannot be substantiated without baseline sleep data prior to IIPT. This study followed the objective sleep/wake patterns (e.g., duration, quality, timing, consistency) of pediatric patients with severely functionally disabling chronic pain before, during, and after inpatient IIPT (the Functional Independence Restoration Program-"FIRST Program"), alongside a similarly-disabled chronic pain Comparison Group. The final sample included = 10 FIRST Patients and = 9 Comparison Group patients. At baseline, the whole sample showed healthy sleep duration (~9 h), average sleep efficiency <90%, late sleep onset and offset (mean = 11:56 p.m.-8:50 a.m.), and highly inconsistent sleep schedules night to night. During IIPT, FIRST Patients maintained healthy sleep durations, moved sleep schedules 2 h earlier, and decreased timing and duration variability by >60 min while the Comparison Group maintained similar sleep to baseline. At follow up (1-2 months later), FIRST Patients' sleep schedules shifted later but were still less variable than at baseline. Results point to the malleability of sleep/wake patterns within treatment contexts with strict environmental control but suggest that these gains may be difficult for youth with chronic pain to maintain in the home environment.
Learn More >Patients with irritable bowel syndrome (IBS) in referral practice commonly report mental disorders and functional impairment. Our aim was to determine the prevalence of mental, physical and sleep-related comorbidities in a nationally representative sample of IBS patients and their impact on functional impairment.
Learn More >Gabapentin is an antiepileptic drug currently licensed to treat epilepsy and neuropathic pain but has been used off-label to treat acute postoperative pain. The GAP study will compare the effectiveness, cost-effectiveness and safety of gabapentin as an adjunct to standard multimodal analgesia versus placebo for the management of pain after major surgery.
Learn More >Disrupted connectivity within visual, attentional and salience networks in the visual snow syndrome.
Here we investigate brain functional connectivity in patients with visual snow syndrome (VSS). Our main objective was to understand more about the underlying pathophysiology of this neurological syndrome. Twenty-four patients with VSS and an equal number of gender and age-matched healthy volunteers attended MRI sessions in which whole-brain maps of functional connectivity were acquired under two conditions: at rest while watching a blank screen and during a visual paradigm consisting of a visual-snow like stimulus. Eight unilateral seed regions were selected a priori based on previous observations and hypotheses; four seeds were placed in key anatomical areas of the visual pathways and the remaining were derived from a pre-existing functional analysis. The between-group analysis showed that patients with VSS had hyper and hypoconnectivity between key visual areas and the rest of the brain, both in the resting state and during a visual stimulation, compared with controls. We found altered connectivity internally within the visual network; between the thalamus/basal ganglia and the lingual gyrus; between the visual motion network and both the default mode and attentional networks. Further, patients with VSS presented decreased connectivity during external sensory input within the salience network, and between V5 and precuneus. Our results suggest that VSS is characterised by a widespread disturbance in the functional connectivity of several brain systems. This dysfunction involves the pre-cortical and cortical visual pathways, the visual motion network, the attentional networks and finally the salience network; further, it represents evidence of ongoing alterations both at rest and during visual stimulus processing.
Learn More >This study examined the prevalence of chronic pain alone, posttraumatic stress disorder (PTSD) alone, and both chronic pain and PTSD among U.S. Army soldiers during the postdeployment year.
Learn More >Biofeedback is used to optimise muscle activation patterns in people with neck pain.
Learn More >Lung nociceptor neurons amplify immune cell activity and mucus metaplasia in response to an inhaled allergen challenge in sensitized mice.
Learn More >The purpose of this study was to determine whether sagittal neck sitting posture subgroup membership in late adolescence was a risk factor for persistent neck pain (PNP) in young adults.
Learn More >Studies have reported relief of chronic shoulder pain with non-ablative pulsed neuromodulatory [pRF] or ablative radiofrequency [aRF] procedures on innervation of the shoulder joint but interpretation of these reports is hampered by inconsistent indications, anatomic targets, and follow-up. This systematic review was conducted to synthesize the existing literature on procedures employing pRF or aRF for treating chronic shoulder pain.
Learn More >Chronic pain is associated with substantial decreases in physical and emotional health. Psychosocial and physical restoration interventions, although potentially helpful, typically show small-to-moderate improvements that are limited to the short term, and often exhibit problematic adherence. Here, we present GetActive-Fitbit, a novel 10-week group program that integrates mind-body skills, pain coping and gradual increases in activity reinforced by a commercially available digital monitoring device (Fitbit). We illustrate the program among a group of 4 adults with heterogeneous chronic pain. We also highlight pre to post-program improvements in physical function (objective, performance-based and self-report), emotional function (depression and anxiety) and other relevant outcomes targeted by the program (e.g., pain intensity, catastrophizing, mindfulness, coping, kinesiophobia, emotional support, social isolation, pain resilience, program satisfaction and impression of change). Group participants' experiences suggest that GetActive-Fitbit is credible, useful, and shows potential to improve physical and emotional function among this challenging population.Clinical trial number: NCT03412916.
Learn More >Trigeminal neuropathic pain is very common clinically, but effective treatments are lacking. Chemokines and their receptors have been implicated in the pathogenesis of chronic pain. This study explored the role of the chemokine CXCL10 and its receptor, CXCR3, in trigeminal neuropathic pain in mice.
Learn More >Chronic pain is one of the most common and debilitating health conditions. Treatments for chronic low back pain typically focus on biomedical treatment approaches. While psychosocial treatments exist, multiple barriers prevent broad access. There is a significant unmet need for integrative, easily accessible, non-opioid solutions for chronic pain. Virtual reality (VR) is an immersive technology allowing innovation in the delivery of behavioral pain treatments. Behavioral skills-based VR is effective at facilitating pain management and reducing pain-related concerns. Continued research on these emerging approaches is needed.
Learn More >Spinal cord stimulation (SCS) has been shown to provide pain relief for chronic back and leg pain due to failed back surgery syndrome. But many patients with chronic back pain have not had major back surgery or are not good candidates for surgery, and conventional medical management (CMM) provides limited relief. We have termed this condition nonsurgical refractory back pain (NSRBP). Level 1 evidence does not yet exist showing the therapeutic benefit of SCS for NSRBP.
Learn More >Pain is caused by tissue injury, inflammatory disease, pathogen invasion, or neuropathy. The perception of pain is attributed to the neuronal activity in the brain. However, the dynamics of neuronal activity underlying pain perception are not fully known. Herein, we examined theta-oscillation dynamics of local field potentials in the primary somatosensory cortex of a mouse model of formalin-induced pain, which usually shows a bimodal behavioral response interposed between pain-free periods. We found that formalin injection exerted a reversible shift in the theta-peak frequency toward a slower frequency. This shift was observed during nociceptive phases but not during the pain-free period and was inversely correlated with instantaneous pain intensity. Furthermore, instantaneous oscillatory analysis indicated that the probability of slow theta oscillations increased during nociceptive phases with an association of augmented slow theta power. Finally, cross-frequency coupling between theta and gamma oscillations indicated that the coupling peak frequency of theta oscillations was also shifted toward slower oscillations without affecting coupling strength or gamma power. Together, these results suggest that the dynamic changes in theta oscillations in the mouse primary somatosensory cortex represent the ongoing status of pain sensation.
Learn More >Co-occurring musculoskeletal pain is common among people with persistent low back pain (LBP) and associated with more negative consequences than LBP alone. The distribution and prevalence of musculoskeletal pain co-occurring with persistent LBP has not been systematically described, which hence was the aim of this review.
Learn More >To elucidate the relationship between chronic pain conditions with cast immobilization and autonomic function, we investigated the functional changes of the autonomic nervous system in conscious rats with chronic post-cast pain (CPCP) induced by a two-week cast immobilization of one hind limb. We telemetrically examined the time courses of systolic arterial blood pressure (SBP), heart rate (HR), and the middle-frequency (MF) component obtained from the power spectral analysis of SBP variability as a vasomotor sympathetic index. We also investigated the baroreflex sensitivity to phentolamine, an α-adrenoceptor antagonist, and the SBP and HR responses to a low ambient temperature (LT; 9.0 ± 0.2°C) exposure, a sympathetic stimulant. Rats exposed to cast immobilization exhibited mechanical allodynia lasting for at least 10 weeks after cast removal in the calf area (skin and muscle) of the bilateral hind limbs. Under resting conditions, the SBP, HR, and MF components were significantly increased during cast immobilization (all p < 0.001). Following cast removal, these parameters gradually decreased and within 1 week reached lower than baseline levels, lasting for over 10 weeks. Phentolamine administration (10 mg/kg, intraperitoneally) significantly decreased the SBP before and during cast immobilization (before, p < 0.001; during, p = 0.001) but did not lower the SBP after cast removal. The baroreflex gain after phentolamine administration, calculated as the HR increase divided by the SBP reduction, was significantly increased after cast removal (p = 0.002). The SBP increase on LT exposure was significantly greater after cast removal than that before cast immobilization, suggesting hypersensitivity to sympathetic neurotransmitters. These results revealed that, in the CPCP model, sympathetic activation was augmented during cast immobilization, which then decreased after cast removal and remained below normal levels with persisting pain behaviors. Additionally, the responsiveness of the autonomic nervous system was impaired in the CPCP model.
Learn More >Psoriasis and atopic dermatitis (AD) are two common chronic inflammatory skin diseases. Although showing different etiology and clinical manifestations, patients with either disease suffer from low health-related quality of life due to pruritus (dermal itch). Recent studies have revealed that more than 85% of psoriasis patients suffer from pruritus, and it is also the dominating symptom of AD. However, as this is a non-life treating symptom, it was partly neglected for years. In this review, we focus on current findings as well as the impact and potential treatments of pruritus in these two skin diseases. We first distinguish the type of itch based on involved mediators and modulators. This clear delineation between the types of pruritus based on involved receptors and pathways allows for precise treatment. In addition, insights into recent clinical trials aimed to alleviate pruritus by targeting these receptors are presented. We also report about novel advances in combinatorial treatments, dedicated to the type of pruritus linked to a causal disease. Altogether, we suggest that only a focused treatment tailored to the primary disease and the underlying molecular signals will provide fast and sustained relief of pruritus associated with psoriasis or AD.
Learn More >Intravenous opioids are a mainstay for the management of moderate to severe acute pain. Opioid administration provides effective pain control at the cost of significant side effects. Commonly used opioids like morphine are nonselective μ-receptor agonists, which stimulate both the G-protein pathway, associated with the analgesic effect, and the β-arrestin pathway, associated with the side effects. Oliceridine is a G-protein selective ligand at the μ-receptor with less activation of the β-arrestin pathway. The drug has recently been US FDA approved. This review will focus on the efficacy and safety of intravenous oliceridine in the treatment of moderate to severe acute pain.
Learn More >The present study investigated pain trajectories of husbands and wives over their mid-later years, the grouping of these trajectories, and differences in baseline biopsychosocial profiles and health and well-being outcomes in later years across the pain trajectory groups.
Learn More >The study evaluated if chronic musculoskeletal (MSK) pain predicts the severity of insomnia, and whether the effect is moderated by age, gender, and number of comorbid diseases in older people. An 18-month prospective study was performed within the framework of a community health program in Hong Kong. A total of 498 older people aged ≥ 60 with multimorbidity were recruited. The predictors included the presence of chronic MSK pain, pain measured by the Brief Pain Inventory (BPI), insomnia measured by baseline Insomnia Severity Index (ISI), and number of co-morbid diseases, age, and gender. The outcome was ISI repeated at 18 months. The moderators included age, gender, and number of comorbid diseases. Multivariate linear regression and moderation analysis were conducted. We found that the presence of chronic MSK pain (β = 1.725; 95% CI, 0.607-2.842; P < 0.01) predicted the severity of ISI, after controlling for age, gender, BMI, and the number of comorbid diseases. Participants with chronic MSK pain throughout the period had worse trend of improvement in ISI compared to those who were "pain-free" (β = 2.597; 95% CI, 1.311-3.882; P < 0.001). Age, gender, and number of comorbid diseases did not moderate the longitudinal relationship. We propose that pain management should prioritized in the prevention of insomnia.
Learn More >Sensory and sympathetic nerves have been shown to promote the progression of endometriosis through the release of neuromediators and the lesional activation of respective receptors. The role of vagus nerves (VN) in lesional progression, however, is completely unclear, despite the signs suggestive of increased sympathetic tone in women with endometriosis. This study was undertaken to investigate whether VN plays any role in the progression of endometriosis. We recruited 45 patients with endometriosis and 42 healthy women, who were given electrocardiogram test and their heart rate variability was evaluated. In addition, three prospective, and randomized mouse experiments were conducted that evaluated, respectively, the effect of vagotomy, the effect of VN stimulation (VNS), and the therapeutic potential of VNS after the endometriosis was well established. All lesions were excised, weighed, and processed for immunohistochemistry and histochemistry analysis of select markers for lesional progression and fibrosis. We found that endometriosis patients exhibited reduced vagal activity as compared with controls, indicative of disrupted autonomic balance. Vagotomy increased while VNS decreased the lesion weight as compared with control mice, concomitant with more progressive and retarded lesion development and fibrogenesis, respectively. In addition, VNS demonstrated promising therapeutic effect, as evidenced by significantly reduced lesion weight, more attenuated lesional progression concomitant with improved hyperalgesia. Taken together, our data indicate that VN activity may play a dampening role in the progression of endometriosis. Consequently, boosting the VN activity may have therapeutic potentials for patients with endometriosis.
Learn More >Topical TRPM8 Agonist for Relieving Neuropathic Ocular Pain in Patients with Dry Eye: A Pilot Study.
Activation of TRPM8, a cold-sensing receptor located on the cornea and eyelid, has the potential to relieve the neuropathic ocular pain (NOP) in dry eye (DE) by inhibiting other aberrant nociceptive inputs. We aimed to investigate the effect of a topical TRPM8 agonist, cryosim-3 (C3), on relieving DE-associated NOP.
Learn More >Over the last two decades, the use of opioids for the treatment of chronic pain in England has steadily increased despite lack of evidence of both long-term effectiveness in pain relief and significant, well-documented physical and mental adverse events. Guidelines recommend tapering when harms outweigh benefits, but the addictive nature of opioids hinders simple dose-reduction strategies. Improving the Well-being of people with Opioid Treated CHronic pain (I-WOTCH) trial tests a multicomponent self-management intervention aimed to help patients with chronic non-malignant pain taper opioid doses. This paper outlines the methods to be used for the economic analysis of the I-WOTCH intervention compared with the best usual care.
Learn More >1) Describe frequency of back pain only, neck pain only, and co-occurring pain in Veterans with upper limb amputation (ULA); 2) examine changes in pain over one year; and 3) quantify the association of pain and health-related quality of life (HRQoL) and disability.
Learn More >Virtual reality, via integration of immersive visual and auditory modalities, offers an innovative approach to pain management. The purpose of this review is to investigate the clinical application of virutal reality as an adjunct analgesic to standard of care, particularly in pediatric and burn patients.
Learn More >Pain is a highly prevalent and burdensome symptom among people with HIV (PWH). This study aims to identify how the experience of living with HIV and chronic pain influences pain beliefs, health-seeking and pain management. Thirty-nine purposively sampled PWH with chronic pain (sample characteristics = 61% women, 79% Black, Asian and minority ethnic groups, 18% men who have sex with men, 45-54 median age category) participated in focus groups in London. Focus groups were co-facilitated with community members. Transcripts wereanalysed using a thematic approach. Findings revealed that HIV stigma, fractured care pathways, and general practitioners' lack of HIV training are barriers to supported pain management. Unaddressed pain results in poorer mental health and reduced quality of life, which has important clinical implications for HIV treatment adherence. Creating HIV-specific pain resources, activating social networks, and pain self-management techniques are potential solutions. Person-centred assessment and HIV training is needed to help clinicians identify PWH with chronic pain. Clear guidelines need to be developed to identify which health service providers are responsible for chronic pain management in PWH. This study generated a refined version of the Fear Avoidance Model that introduces a dimension of HIV-specific behaviours that impact PWHs seeking chronic pain management.
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