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Prdm12 is a key transcription factor in nociceptor neurogenesis. Mutations of Prdm12 cause congenital insensitivity to pain (CIP) from failure of nociceptor development. However, precisely how deletion of Prdm12 during development or adulthood affects nociception is unknown. Here, we employ tissue- and temporal-specific knockout mouse models to test the function of Prdm12 during development and in adulthood. We find that constitutive loss of Prdm12 causes deficiencies in proliferation during sensory neurogenesis. We also demonstrate that conditional knockout from dorsal root ganglia (DRGs) during embryogenesis causes defects in nociception. In contrast, we find that, in adult DRGs, Prdm12 is dispensable for most pain-sensation and injury-induced hypersensitivity. Using transcriptomic analysis, we find mostly unique changes in adult Prdm12 knockout DRGs compared with embryonic knockout and that PRDM12 is likely a transcriptional activator in the adult. Overall, we find that the function of PRDM12 changes over developmental time.
Learn More >This is the first double-blind, randomized, controlled trial evaluating the efficacy and safety of intravenous immunoglobulin (IVIg) versus placebo in patients with idiopathic small fiber neuropathy (I-SFN).
Learn More >Cluster headache is a debilitating primary headache disorder that affects approximately 0.1% of the population worldwide. Cluster headache attacks involve severe unilateral pain in the trigeminal distribution together with ipsilateral cranial autonomic features and a sense of agitation. Acute treatments are available and are effective in just over half of the patients. Until recently, preventive medications were borrowed from non-headache indications, so management of cluster headache is challenging. However, as our understanding of cluster headache pathophysiology has evolved on the basis of key bench and neuroimaging studies, crucial neuropeptides and brain structures have been identified as emerging treatment targets. In this Review, we provide an overview of what is known about the pathophysiology of cluster headache and discuss the existing treatment options and their mechanisms of action. Existing acute treatments include triptans and high-flow oxygen, interim treatment options include corticosteroids in oral form or for greater occipital nerve block, and preventive treatments include verapamil, lithium, melatonin and topiramate. We also consider emerging treatment options, including calcitonin gene-related peptide antibodies, non-invasive vagus nerve stimulation, sphenopalatine ganglion stimulation and somatostatin receptor agonists, discuss how evidence from trials of these emerging treatments provides insights into the pathophysiology of cluster headache and highlight areas for future research.
Learn More >Evidence from human genetic pain disorders shows that voltage-gated sodium channel α-subtypes Nav1.7, Nav1.8 and Nav1.9 are important in the peripheral signalling of pain. Nav1.7 is of particular interest because individuals with Nav1.7 loss-of-function mutations are congenitally insensitive to acute and chronic pain, and there is considerable hope that phenocopying these effects with a pharmacological antagonist will produce a new class of analgesic drug. However, studies in these rare individuals do not reveal how and where voltage-gated sodium channels contribute to pain signalling, which is of critical importance for drug development. More than a decade of research utilizing rodent genetic models and pharmacological tools to study voltage-gated sodium channels in pain has begun to unravel the role of different subtypes. Here, we review the contribution of individual channel subtypes in three key physiological processes necessary for transmission of sensory information to the CNS: transduction of stimuli at peripheral nerve terminals, axonal transmission of action potentials and neurotransmitter release from central terminals. These data suggest that drugs seeking to recapitulate the analgesic effects of loss of function of Nav1.7 will need to be brain-penetrant – which most of those developed to date are not.
Learn More >Teeth are composed of many tissues, covered by an inflexible and obdurate enamel. Unlike most other tissues, teeth become extremely cold sensitive when inflamed. The mechanisms of this cold sensation are not understood. Here, we clarify the molecular and cellular components of the dental cold sensing system and show that sensory transduction of cold stimuli in teeth requires odontoblasts. TRPC5 is a cold sensor in healthy teeth and, with TRPA1, is sufficient for cold sensing. The odontoblast appears as the direct site of TRPC5 cold transduction and provides a mechanism for prolonged cold sensing via TRPC5's relative sensitivity to intracellular calcium and lack of desensitization. Our data provide concrete functional evidence that equipping odontoblasts with the cold-sensor TRPC5 expands traditional odontoblast functions and renders it a previously unknown integral cellular component of the dental cold sensing system.
Learn More >Tension-type headache (TTH) is the most prevalent neurological disorder worldwide and is characterized by recurrent headaches of mild to moderate intensity, bilateral location, pressing or tightening quality, and no aggravation by routine physical activity. Diagnosis is based on headache history and the exclusion of alternative diagnoses, with clinical criteria provided by the International Classification of Headache Disorders, third edition. Although the biological underpinnings remain unresolved, it seems likely that peripheral mechanisms are responsible for the genesis of pain in TTH, whereas central sensitization may be involved in transformation from episodic to chronic TTH. Pharmacological therapy is the mainstay of clinical management and can be divided into acute and preventive treatments. Simple analgesics have evidence-based effectiveness and are widely regarded as first-line medications for the acute treatment of TTH. Preventive treatment should be considered in individuals with frequent episodic and chronic TTH, and if simple analgesics are ineffective, poorly tolerated or contraindicated. Recommended preventive treatments include amitriptyline, venlafaxine and mirtazapine, as well as some selected non-pharmacological therapies. Despite the widespread prevalence and associated disability of TTH, little progress has been made since the early 2000s owing to a lack of attention and resource allocation by scientists, funding bodies and the pharmaceutical industry.
Learn More >In humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief of allodynia. Searches in PubMed and EMBASE identified 31 unique studies. Four meta-analyses were conducted. The first analysis included 19 comparisons on a single ketamine dose and measurement of effect within 3 hours of dosing and showed an appreciable effect (standardized mean difference 1.6, 95% confidence interval 1.1-2.1). Subgroup analyses showed no effect of species, administration route, or dose. A single administration was insufficient to sustain relief of allodynia at 24 or 72 hours after dosing, as observed in our second analysis (7 comparisons) with similar effects in ketamine-treated and control animals. Chronic ketamine administration (9 comparisons) caused profound relief of allodynia when tested during ketamine exposure (effect size 5.1, 3.7-6.5). The final analysis (6 comparisons) showed that chronic administration caused a slow loss of relief of allodynia with 70% loss of effect 24 days after end of treatment. No subgroups analyses were possible in the last 3 meta-analyses due to small group sizes. These results indicate long-term ketamine anti-allodynic effects after chronic exposure (>3 days) but not after a single administration. Given several limitations, extrapolation of the animal data to the human condition is tenuous.
Learn More >The effectiveness of µ-opioid receptor (MOPr) agonists for treatment of visceral pain is compromised by constipation, respiratory depression, sedation and addiction. We investigated whether a fentanyl analogue, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), which preferentially activates MOPr in acidified diseased tissues, would inhibit pain in a preclinical model of inflammatory bowel disease (IBD) without side effects in healthy tissues.
Learn More >Chronic pain, highly prevalent throughout the course of Parkinson's disease (PD), has been ranked as one of the top ten most bothersome symptoms people with Parkinson's (PwP) are experiencing. Yet, robust evidence-based treatment strategies are lacking. This unmet need is partly attributable to the multifaceted nature of PD-related pain, which results in part from a complex and poorly understood interplay involving a range of neurotransmitter pathways. Degeneration of nigrostriatal dopaminergic pathways and alterations of central nervous system extra-striatal dopaminergic, noradrenergic, serotoninergic, glutamatergic, opioidergic and endocannabinoid circuits may all promote a heightened experience of pain in PwP. Thus, the potential targets for mechanism-based pain-relieving strategies in PwP are several. These targets are discussed herein.
Learn More >Because somatosensory PNS neurons, in particular nociceptors, are specially tuned to be able to detect a wide variety of both exogenous and endogenous signals, one might assume that these neurons express a greater variety of receptor genes. This assumption has not been formally tested. Because cells detect such signals via cell surface receptors, we sought to formally test the hypothesis that PNS neurons might express a broader array of cell surface receptors than CNS neurons using existing single cell RNA sequencing resources from mouse. We focused our analysis on ion channels, G-protein coupled receptors (GPCRS), receptor tyrosine kinase and cytokine family receptors. In partial support of our hypothesis, we found that mouse PNS somatosensory, sympathetic and enteric neurons and CNS neurons have similar receptor expression diversity in families of receptors examined, with the exception of GPCRs and cytokine receptors which showed greater diversity in the PNS. Surprisingly, these differences were mostly driven by enteric and sympathetic neurons, not by somatosensory neurons or nociceptors. Secondary analysis revealed many receptors that are very specifically expressed in subsets of PNS neurons, including some that are unique among neurons for nociceptors. Finally, we sought to examine specific ligand-receptor interactions between T cells and PNS and CNS neurons. Again, we noted that most interactions between these cells are shared by CNS and PNS neurons despite the fact that T cells only enter the CNS under rare circumstances. Our findings demonstrate that both PNS and CNS neurons express an astonishing array of cell surface receptors and suggest that most neurons are tuned to receive signals from other cells types, in particular immune cells.
Learn More >Chronic pain is prevalent among patients with rare diseases (RDs); however, little is understood about the integration of biopsychosocial mechanisms as they relate to the unique set of clinical features and therapeutic challenges inherent in the pain conditions of patients with RDs.
Learn More >Migraine is a neurovascular disorder that affects over 1 billion people worldwide. Its widespread prevalence, and associated disability, have a range of negative and substantial effects not only on those immediately affected but also on their families, colleagues, employers, and society. To reduce this global burden, concerted efforts are needed to implement and improve migraine care that is supported by informed health-care policies. In this Series paper, we summarise the data on migraine epidemiology, including estimates of its very considerable burden on the global economy. First, we present the challenges that continue to obstruct provision of adequate care worldwide. Second, we outline the advantages of integrated and coordinated systems of care, in which primary and specialist care complement and support each other; the use of comprehensive referral and linkage protocols should enable continuity of care between these systems levels. Finally, we describe challenges in low and middle-income countries, including countries with poor public health education, inadequate access to medication, and insufficient formal education and training of health-care professionals resulting in misdiagnosis, mismanagement, and wastage of resources.
Learn More >Migraine is a highly disabling neurological disorder that directly affects more than 1 billion individuals worldwide. Available treatment options differ between countries and include acute, preventive, and non-pharmacological therapies. Because of major progress in the understanding of migraine pathogenesis, novel mechanism-based medications have emerged and expanded the armamentarium of treatments. We provide a comprehensive overview of the current standard of care that will enable informed clinical management. First, we discuss the efficacy, tolerability, and safety profile of various pharmacological therapies for acute and preventive treatment of migraine. Second, we review the current knowledge on non-pharmacological therapies, such as neuromodulation and biobehavioural approaches, which can be used for a multidisciplinary approach to clinical management. Third, we emphasise that any effective treatment strategy starts with building a therapeutic plan tailored to individual clinical characteristics, preferences, and needs. Finally, we explore the outlook of emerging mechanism-based treatments that could address unmet challenges in clinical management of migraine.
Learn More >Migraine is a disabling neurological disorder, diagnosis of which is based on clinical criteria. A shortcoming of these criteria is that they do not fully capture the heterogeneity of migraine, including the underlying genetic and neurobiological factors. This complexity has generated momentum for biomarker research to improve disease characterisation and identify novel drug targets. In this Series paper, we present the progress that has been made in the search for biomarkers of migraine within genetics, provocation modelling, biochemistry, and neuroimaging research. Additionally, we outline challenges and future directions for each biomarker modality. We also discuss the advances made in combining and integrating data from multiple biomarker modalities. These efforts contribute to developing precision medicine that can be applied to future patients with migraine.
Learn More >Migraine is a prevalent and disabling neurological disease. Its genesis is poorly understood and there remains unmet clinical need. We aimed to identify mechanisms and thus novel therapeutic targets for migraine using human models of migraine and translational models in animals, with emphasis on amylin, a close relative of calcitonin gene-related peptide (CGRP).
Learn More >Psychological models of chronic pain (CP) highlight cognitive-processing biases (ie, attentional biases, interpretation biases, and attentional control) as pivotal processes that uniquely and synergistically impact the development and maintenance of CP. Very few studies explore multiple cognitive biases, and no studies have examined these 3 processes together in a CP sample. Furthermore, there is a lack of research investigating the relationship between these cognitive processes and pain-relevant variables (eg, pain intensity and pain catastrophising). The current study aimed to (1) compare attentional biases, interpretation biases, and attentional control in people with and without CP, (2) explore their interrelationships, and (3) explore their association with pain-related variables. Seventy-four participants with CP and 66 without pain volunteered. Participants completed a visual scanning task with eye tracking, a recognition task, and a flanker task. Traditional and Bayesian analysis indicated no effect of pain status on cognitive-processing biases. All participants, regardless of pain status, demonstrated attentional biases towards pain on some indices of early and late attention, but not interpretation bias or attentional control. There was weak evidence of associations between attentional biases, interpretation biases, and attentional control. Pain intensity was significantly correlated with interpretation biases, and follow-up analyses revealed people with high pain intensity demonstrated an interpretation bias towards pain significantly more than those with low pain intensity. Findings suggest that attentional biases towards pain are ubiquitous, but for people with moderate-to-severe pain, interpretation biases may have a role worthy of further research.
Learn More >Lamina I of the dorsal horn, together with its main output pathway, lamina I projection neurons, have long been implicated in the processing of nociceptive stimuli, as well as the development of chronic pain conditions. However, the study of lamina I projection neurons is hampered by technical challenges, including the low throughput and selection biases of traditional electrophysiological techniques. Here we report on a technique which employs anatomical labelling strategies and in vivo imaging to simultaneously study a network of lamina I projection neurons in response to electrical and natural stimuli. While we were able to confirm the nociceptive involvement of this group of cells, we also describe an unexpected preference for innocuous cooling stimuli. We were able to characterize the thermal responsiveness of these cells in detail and found cooling responses decline when exposed to stable cold temperatures maintained for more than a few seconds, as well as to encode the intensity of the end temperature, while heating responses showed an unexpected reliance on adaptation temperatures.
Learn More >Compared to racism and sexism, classism in pain assessment and management practices (PAMP) has been less investigated and its mediating mechanisms are still unknown. Drawing upon a social psychological model of dehumanization, this research aimed to test: (1) the effect of patient socioeconomic status (SES; a proxy of social class) on PAMP and (2) whether patient dehumanization and perceived life hardship mediated these effects. Two online experimental studies were conducted, in which patient SES was manipulated (Low vs. High) within-subjects. One-hundred sixty-two female medical students (study 1) and 105 female nurses (study 2) were presented with vignettes/pictures depicting two cases of women with chronic low-back pain, followed by videos of them performing a pain-inducing movement. Participants reported on patient dehumanization, perceived life hardship and PAMP. The Low SES patient was perceived as less pain sensitive (medical students only) but more disabled, credible and her pain more attributed to psychological causes (by nurses only). Medical students recommended less non-pharmacological treatments but prescribed slightly stronger medication. Medical students were less willing to provide individualized care to the Low SES patient, whereas nurses showed the opposite pattern. Patient mechanistic dehumanization mediated SES effects on pain disability (medical students only). Perceived life hardship mediated SES effects on pain disability, credibility (nurses only) and intentions of providing individualized care (nurses only). These finding bear novel contributions to the fields of pain, health service research and social psychology, and have important implications to the development of more effective future interventions to reduce classism in PAMP.
Learn More >Voltage-gated sodium channels initiate action potentials in nerve, skeletal muscle, and other electrically excitable cells. Mutations in them cause a wide range of diseases. These channelopathy mutations affect every aspect of sodium channel function, including voltage sensing, voltage-dependent activation, ion conductance, fast and slow inactivation, and both biosynthesis and assembly. Mutations that cause different forms of periodic paralysis in skeletal muscle were discovered first and have provided a template for understanding structure, function, and pathophysiology at the molecular level. More recent work has revealed multiple sodium channelopathies in the brain. Here we review the well-characterized genetics and pathophysiology of the periodic paralyses of skeletal muscle, and then use this information as a foundation for advancing our understanding of mutations in the structurally homologous a subunits of brain sodium channels that cause epilepsy, migraine, autism, and related co-morbidities. We include studies based on molecular and structural biology, cell biology and physiology, pharmacology, and mouse genetics. Our review reveals unexpected connections among these different types of sodium channelopathies.
Learn More >The German Research Network on Neuropathic Pain (DFNS) quantitative sensory testing (QST) method for sensory phenotyping is used to stratify patients by mechanism associated sensory phenotype, theorised to be predictive of intervention efficacy. We hypothesised that change in pain and sensory dysfunction would relate to change in sensory phenotype. We investigated the responsiveness of sensory phenotype to surgery in patients with an entrapment neuropathy.With ethical approval and consent, this observational study recruited patients with neurophysiologically confirmed carpal tunnel syndrome. Symptom and pain severity parameters and DFNS QST were evaluated prior to and after carpal tunnel surgery. Surgical outcome was evaluated by patient-rated change. Symptom severity score of the Boston Carpal Tunnel Questionnaire and associated pain and paraesthesia subgroups were comparators for clinically relevant change.QST results (n=76) were compared to healthy controls (n=54). At 6 months post-surgery 92% participants reported a good surgical outcome and large decrease in pain and symptom severity (p<.001). Change in QST parameters occurred for thermal detection, thermal pain and mechanical detection thresholds with a moderate to large effect size. Change in mechanical pain measures were not statistically significant. Change occurred in sensory phenotype post-surgery (p<.001); sensory phenotype was associated with symptom subgroup (p=.03) and patient-rated surgical outcome (p =.02).QST derived sensory phenotype is sensitive to clinically important change. In an entrapment neuropathy model, sensory phenotype was associated with patient-reported symptoms and demonstrated statistically significant, clinically relevant change after disease modifying intervention. Sensory phenotype was independent of disease severity and may reflect underlying neuropathophysiology.
Learn More >Little is known about the effectiveness of placebo interventions in patients with non-specific low back pain (LBP). This systematic review assessed the magnitude of the effects of placebo interventions as compared to no intervention in randomized controlled trials(RCTs) including patients with LBP. Embase, Medline(Ovid) and Cochrane CENTRAL databases were searched from inception to December 5th, 2019. RCTs comparing placebo intervention versus no intervention in adult patients with non-specific LBP were included. Pain intensity, physical functioning and health-related quality of life (hrQoL) measured at short-, medium- and long-term follow-up were the outcomes of this review. Twenty-one RCTs were included; one concerning acute LBP and one sub-acute LBP, while 19 studies reported on chronic LBP. In chronic LBP, placebo interventions were more effective than no intervention at short-term for pain intensity [standardized mean difference (SMD) = -0.37, 95% CI = -0.55 to -0.18, moderate quality evidence], physical functioning (SMD -0.19, 95% CI = -0.39 to 0.01, moderate quality evidence), and physical quality of life (Mean Difference = -2.71, 95% CI = -4.71 to 0.71, high quality evidence), respectively. These effects were not significant at medium-term follow-up and no data was available at long-term follow-up. These results show placebo interventions are more effective than no intervention at short-term in patients with chronic LBP. However, the magnitude of the effects is probably not clinically relevant (approximately 8 points on a 0-100 pain scale). Future research should identify effect modifiers and causal mechanisms explaining the short-term effects of placebo interventions in patients with chronic LBP. (PROSPERO Registration number CRD42019127465).
Learn More >Migraine afflicts more than one billion individuals worldwide and is a leading cause of years lived with disability. In about a third of individuals with migraine aura occur in relation to migraine headache. The common pathophysiological mechanisms underlying migraine headache and migraine aura are yet to be identified. Based on recent data, we hypothesized that levcromakalim, an ATP-sensitive potassium channel opener, would trigger migraine attacks with aura in migraine with aura patients.
Learn More >Tricyclic antidepressants that inhibit serotonin and noradrenaline reuptake, such as amitriptyline, are among the first-line treatments for neuropathic pain, which is caused by a lesion or disease affecting the somatosensory nervous system. These treatments are, however, partially efficient to alleviate neuropathic pain symptoms and better treatments are still highly required. Interactions between neurons and glial cells participate in neuropathic pain processes, and, importantly, connexins – transmembrane proteins involved in cell-cell communication – contribute to these interactions. In a neuropathic pain model in rats, mefloquine, a connexin inhibitor, has been shown to potentiate the anti-hyperalgesic effect of amitriptyline, a widely used antidepressant. In the present study, we further investigated this improvement of amitriptyline action by mefloquine, using the cuff model of neuropathic pain in mice. We first observed that oral mefloquine co-treatment prolonged the effect of amitriptyline on mechanical hypersensitivity by 12 hours after administration. Additionally, we showed that this potentiation was not due to pharmacokinetic interactions between the two drugs. Besides, lesional and pharmacological approaches showed that the prolonged effect was induced through noradrenergic descending pathways and the recruitment of α2 adrenergic receptors. Another connexin blocker, carbenoxolone, also improved amitriptyline action. Additional in vitro studies suggested that mefloquine may also directly act on serotonin transporters and on adenosine A1 and A2A receptors, but drugs acting on these other targets failed to amplify amitriptyline action. Together, our data indicate that pharmacological blockade of connexins potentiates the therapeutic effect of amitriptyline in neuropathic pain.
Learn More >During the past few years, the research of chronic neuropathic pain has focused on neuroinflammation within the central nervous system and its impact on pain chronicity. As part of the ERA-Net NEURON consortium we aimed to identify immune cell patterns in cerebrospinal fluid (CSF) of patients with herpes zoster neuralgia (HZ) and polyneuropathy (PNP), which may contribute to pain chronicity in these neuropathic pain conditions.CSF of 41 patients (10 HZ, 31 PNP) was analyzed by flow cytometry identifying lymphocyte subsets: CD4+- (T-helper-cells), CD8+- (cytotoxic T-cells), CD19+- (B-cells), and CD56+- (natural killer; NK) cells. At baseline and at follow-up, the somatosensory phenotype was assessed with QST. Additionally, the patients answered epidemiological questionnaires and the PainDETECT. Immune cell profiles and somatosensory profiles, as well as PDQ-scores were analyzed and correlated in order to determine specific immune cell patterns, which contribute to chronic pain.We found a negative correlation (p= 0.004, r=-0.596) between the frequency of natural killer cells and mechanical pain sensitivity (MPS), one of the most relevant QST markers for central sensitization; a high frequency of NK-cells correlated with low MPS. The analysis of the individual follow-up showed a worsening of the pain condition if NK-cell frequency was low.Low NK-cell frequency is associated with signs of central sensitization (MPS), whereas high NK-cell frequency might prevent central sensitization. Therefore, NK-cells seem to play a protective role within the neuroinflammatory cascade and may be used as marker for pain chronicity.
Learn More >Neuropathic pain affects up to 10% of the total population and no specific target is ideal for therapeutic need. The sodium leak channel (NALCN), a non-selective cation channel, mediates the background Na leak conductance and controls neuronal excitability and rhythmic behaviors. Here, we show that increases of NALCN expression and function in dorsal root ganglion (DRG) and dorsal spinal cord contribute to chronic constriction injury (CCI)-induced neuropathic pain in rodents. NALCN current and neuronal excitability in acutely isolated DRG neurons and spinal cord slices of rats were increased after CCI which were decreased to normal levels by NALCN-siRNA. Accordingly, pain-related symptoms were significantly alleviated by NALCN-siRNA-mediated NALCN knockdown and completely prevented by NALCN-shRNA-mediated NALCN knockdown in rats or by conditional NALCN knockout in mice. Our results indicate that increases in NALCN expression and function contribute to CCI-induced neuronal sensitization; therefore, NALCN may be a novel molecular target for control of neuropathic pain.
Learn More >This article provides an overview of nonpharmacologic options for the treatment of pain in patients with inflammatory arthritis, such as peripheral spondyloarthritis, psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis. The experience of pain in chronic disease is a complex process influenced by multiple domains of health. The discussion focuses on the establishment of a framework for pain control that engages with factors that influence the experience of pain and explores the evidence base that supports specific modalities of nonpharmacologic pain control, such as mindfulness, cognitive behavioral therapy, exercise, massage, splinting, and heat therapy. Rheumatoid and spondyloarthritides are considered separately.
Learn More >The medicolegal landscape of cannabis continues to change, and with ever increasing access there has been a concurrent proliferation of research seeking to understand the utility of cannabinoids in treating innumerable conditions with pain at the forefront. This article seeks to summarize clinically relevant findings in cannabinoid research to better prepare clinicians in the utility of cannabis in the treatment of pain.
Learn More >Inflammatory back pain is characteristic of spondyloarthritis (SpA); however, this pain may not respond to treatment with NSAIDs or biologics. Pain is multifactorial and a combination of mechanical and inflammatory factors. A growing body of literature examines the impact of emotions on pain in SpA; many patients with this condition suffer from depression and fibromyalgia. Advanced imaging techniques can investigate the interplay of various brain networks in pain perception. Animal models have helped understand the interplay between the immune and nervous systems in pain generation and have highlighted differences in pain perception between the sexes.
Learn More >Spinal pain is the most common form of musculoskeletal pain. Chronic low back pain may contain nociceptive, neuropathic, and central components. Children are at risk of developing spinal pain. An increasing proportion of children develop low back pain as they become adolescents. In most adolescents, no specific diagnosis is identified. Psychological factors play a role in adolescents with back pain. Lumbar spinal stenosis causes neurogenic claudication in older patients. Magnetic resonance imaging is the best radiographic technique to detect nerve compression. Surgical decompression with or without fusion may offer greater short-term benefit but may not be significantly better than medical therapy.
Learn More >Patients with rheumatic diseases often have mixed pain states, with varying degrees of nociceptive, neuropathic, and nociplastic mechanisms, which exist on a continuum. When individuals with any chronic pain have a nociplastic component to their symptoms, they are less likely to respond to treatments (eg, injections, surgery, biologics, and opioids) that work better for acute or purely nociceptive pain.
Learn More >Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common, difficult-to-treat, and dose-limiting side effect associated with Oxaliplatin (OXA) treatment. In this study, we evaluated the effect of three antioxidants – namely N-acetylcysteine, α-lipoic acid and vitamin E – upon nociceptive parameters and antitumor efficacy of OXA in a tumor-bearing Swiss mice model. Oral treatment with antioxidants inhibited both mechanical and cold allodynia when concomitantly administrated with OXA (preventive protocol), as well as in animals with previously established CIPN (therapeutic protocol). OXA increased Reactive Oxygen Species (ROS) production and lipoperoxidation, and augmented the content of pro-inflammatory cytokines (IL-1β and TNF-α) and expression of the astrocytic marker Gfap mRNA in the spinal cord. Antioxidants decreased ROS production and lipoperoxidation, and abolished neuroinflammation in OXA-treated animals. Toll-like receptor 4 (Tlr4) and inflammasome enzyme caspase-1/11 knockout mice treated with OXA showed reduced levels of pro-inflammatory cytokines (but not oxidative stress) in the spinal cord, which were associated with resistance to OXA-induced mechanical allodynia. Lastly, antioxidants affected neither antitumor activity nor hematological toxicity of OXA in vivo. The herein presented results are provocative for further evaluation of antioxidants in clinical management of chemotherapy-induced peripheral neuropathy. Perspectives: This study reports preventive and therapeutic efficacy of orally administrated antioxidants (N-acetylcysteine, α-lipoic-acid and Vitamin-E) for alleviating oxaliplatin-induced peripheral neuropathy in tumor-bearing mice. Antioxidants' anti-nociceptive effects are associated with inhibition of ROS-dependent neuroinflammation, and occur at no detriment of OXA antitumor activity, therefore indicating a translational potential of these compounds.
Learn More >Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of Trpa1 revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain.
Learn More >Although the mechanisms responsible for migraine initiation remain unknown, recent evidence shows that brain function is different immediately preceding a migraine. This is consistent with the idea that altered brain function, particularly in brainstem sites, may either trigger a migraine or facilitate a peripheral trigger that activates the brain, resulting in pain. The aim of this longitudinal study is therefore to expand on the above findings, and to determine if brainstem function oscillates over a migraine cycle in individual subjects. We performed resting state functional magnetic resonance imaging in three migraineurs and five controls each weekday for four weeks. We found that although resting activity variability was similar in controls and interictal migraineurs, brainstem variability increased dramatically during the 24-hour period preceding a migraine. This increase occurred in brainstem areas in which orofacial afferents terminate: the spinal trigeminal nucleus and dorsal pons. These increases were characterized by increased power at infra-slow frequencies, principally between 0.03 and 0.06 Hz. Furthermore, these power increases were associated with increased regional homogeneity, a measure of local signal coherence. The results show within-individual alterations in brain activity immediately preceding migraine onset and support the hypothesis that altered regional brainstem function before a migraine attack is involved in underlying migraine neurobiology.
Learn More >Neuropeptide Y Y1 receptor-expressing neurons in the dorsal horn of the spinal cord contribute to chronic pain. For the first time, we characterized the firing patterns of Y1-expressing neurons in Y1eGFP reporter mice. Under hyperpolarized conditions, most Y1eGFP neurons exhibited fast A-type potassium currents and delayed, short-latency firing (DSLF). Y1eGFP DSLF neurons were almost always rapidly adapting and often exhibited rebound spiking, characteristics of spinal pain neurons under the control of T-type calcium channels. These results inspire future studies to determine whether tissue or nerve injury downregulates the channels that underlie A-currents, thus unmasking membrane hyperexcitability in Y1-expressing dorsal horn neurons, leading to persistent pain.
Learn More >Mechanistic theories of itch are based on neuronal specificity, stimulus intensity, and temporal or spatial discharge patterns. Traditionally, these theories are conceptualized as mutually exclusive, assuming that finding evidence for one theory would exclude the others and could sufficiently explain itch. Current experimental data primarily support the specificity or pattern theory of itch. However, in contrast to an assumed inherent exclusivity, recent results have shown that even within itch-specific pathways in the spinal cord, temporal discharge patterns are important as sustained pruriceptor is required to allow successful transsynaptic signal progression. Also, optogenetic activation of pruriceptors suggest that the combination of neuronal specificity and temporal pattern determines the sensory effect: tonic activation of pruriceptors is required to induce scratching behavior whereas short-lasting stimulation rather causes withdrawal. In addition to the mere duration of discharge, also the temporal pattern or spatial aspects could critically contribute to elicit pruritus instead of pain. Basic neurophysiological studies trying to validate neuronal theories for pruritus in their pure form provide unitary concepts leading from neuronal discharge to the itch sensation. However, the crucial clinical questions have the opposite perspective: which mechanisms explain the chronic itch in a given patient or a given disease? In trying to solve these clinical problems we should not feel bound to the mutual exclusive nature of itch theories, but rather appreciate blending several theories and also accept combinations of itch and pain. Thus, blended versions of itch theories might better suffice for an explanation of chronic itch in patients and will improve the basis for mechanistic treatment options.
Learn More >A critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions.
Learn More >The aim of this work was to investigate whether different clinical pain phenotypes of diabetic polyneuropathy (DPN) are distinguished by functional connectivity at rest.
Learn More >Offset analgesia (OA), a large reduction in pain after a brief increase in intensity of an otherwise stable painful stimulus, has been established by a large body of research. But the opposite effect, onset hyperalgesia (OH), a disproportional hyperalgesic response after a briefly decreased intensity of a painful stimulus, has only been investigated in one previous study.
Learn More >Intensive interdisciplinary pain treatment (IIPT) programs have been shown to restore function, improve coping, and reduce pain in adolescents with chronic pain. Yet, little is known about patients' sleep during IIPT and whether or not improvements in pain treatment outcomes are associated with changes in sleep pre-to-post IIPT treatment. The objectives of the current study were to describe sleep among adolescents entering IIPT and examine associations between sleep parameters and IIPT treatment effects.
Learn More >The two voltage gated sodium channels Nav1.7 and Nav1.8 are expressed in the peripheral nervous system and involved in various pain conditions including inflammatory and neuropathic pain. Rodent models bearing deletions or mutations of the corresponding genes, Scn9a and Scn10a, were created in order to understand the role of these channels in the pathophysiological mechanism underlying pain symptoms. This review summarizes the pain behavior profiles reported in Scn9a and Scn10a rodent models. The complete loss-of-function or knockout (KO) of Scn9a or Scn10a and the conditional KO (cKO) of Scn9a in specific cell populations were shown to decrease sensitivity to various pain stimuli. The Possum mutant mice bearing a dominant hypermorphic mutation in Scn10a revealed higher sensitivity to noxious stimuli. Several gain-of-function mutations were identified in patients with painful small fiber neuropathy. Future knowledge obtained from preclinical models bearing these mutations will allow understanding how these mutations affect pain. In addition, the review gives perspectives for creating models that better mimic patients' pain symptoms in view to developing novel analgesic strategies.
Learn More >Management of chronic pain is an essential aspect of HIV primary care. Previous literature in the general population has elucidated racial disparities in the evaluation and treatment of pain. This study examined racial/ethnic differences in patient satisfaction and barriers to pain management among a cohort of PWH receiving LTOT.
Learn More >Given the complex and unclear etiology of neck pain, it is important to understand the differences in central sensitization as well as psychosocial factors in individuals with chronic neck pain and healthy controls. The purpose of this study was to benchmark differences in central sensitization, psychosocial factors, and range of motion between people with nonspecific chronic neck pain and healthy controls and to analyze the correlation between pain intensity, neck disability, and psychosocial factors in people with chronic neck pain.
Learn More >Although millions of people are diagnosed with cancer each year, survival has never been greater thanks to early diagnosis and treatments. Powerful chemotherapeutic agents are highly toxic to cancer cells, but because they typically do not target cancer cells selectively, they are often toxic to other cells and produce a variety of side effects. In particular, many common chemotherapies damage the peripheral nervous system and produce neuropathy that includes a progressive degeneration of peripheral nerve fibers. Chemotherapy-induced peripheral neuropathy (CIPN) can affect all nerve fibers, but sensory neuropathies are the most common, initially affecting the distal extremities. Symptoms include impaired tactile sensitivity, tingling, numbness, paraesthesia, dysesthesia, and pain. Since neuropathic pain is difficult to manage, and because degenerated nerve fibers may not grow back and regain normal function, considerable research has focused on understanding how chemotherapy causes painful CIPN so it can be prevented. Due to the fact that both therapeutic and side effects of chemotherapy are primarily associated with the accumulation of reactive oxygen species (ROS) and oxidative stress, this review focuses on the activation of endogenous antioxidant pathways, especially PPARγ, in order to prevent the development of CIPN and associated pain. The use of synthetic and natural PPAR а agonists to prevent CIPN is discussed.
Learn More >Cannabinoid (CB) receptor agonists show robust antinociceptive effects in various pain models. However, most of the clinically potent CB1 receptor-active drugs derived from cannabis are considered concerning due to psychotomimetic side effects. Selective CB receptor ligands that do not induce CNS side effects are of clinical interest. The venoms of marine snail Conus are a natural source of various potent analgesic peptides, some of which are already FDA approved. In this study we evaluated the ability of several Conus venom extracts to interact with CB1 receptor. HEK293 cells expressing CB1 receptors were treated with venom extracts and CB1 receptor internalization was analyzed by immunofluorescence. Results showed C. textile (C. Tex) and C. miles (C. Mil) samples as the most potent. These were serially subfractionated by HPLC for subsequent analysis by internalization assays and for analgesic potency evaluated in the formalin test and after peripheral nerve injury. Intrathecal injection of C. Tex and C. Mil subfractions reduced flinching/licking behavior during the second phase of formalin test and attenuated thermal and mechanical allodynia in nerve injury model. Treatment with proteolytic enzymes reduced CB1 internalization of subfractions, indicating the peptidergic nature of CB1 active component. Further HPLC purification revealed two potent antinociceptive subfractions within C. Tex with CB1 and possible CB2 activity, with mild to no side effects in the CB tetrad assessment. CB conopeptides can be isolated from these active Conus venom-derived samples and further developed as novel analgesic agents for the treatment of chronic pain using cell based or gene therapy approaches.
Learn More >African American older adults living in disadvantaged communities are disproportionately burdened by disabling pain. To address their needs, we tested the feasibility and potential effects of a cognitive-behavioral chronic pain self-management program delivered by community health workers.
Learn More >For many medical professionals dealing with patients with persistent pain following spine surgery, the term Failed back surgery syndrome (FBSS) as a diagnostic label is inadequate, misleading, and potentially troublesome. It misrepresents causation. Alternative terms have been suggested, but none has replaced FBSS. The International Association for the Study of Pain (IASP) published a revised classification of chronic pain, as part of the new International Classification of Diseases (ICD-11), which has been accepted by the World Health Organization (WHO). This includes the term Chronic pain after spinal surgery (CPSS), which is suggested as a replacement for FBSS.
Learn More >Historically, marginalized patients were prescribed less opioid medication than affluent, white patients. However, because of persistent differential access to non-opioid pain treatments, this direction of disparity in opioid prescribing may have reversed.
Learn More >To estimate the effectiveness and safety of Pain Neurophysiology Education (PNE) on pain, disability, and psychological distress at post-intervention and long-term (closest to twelve months after initiating the intervention) in musculoskeletal pain (MSKP).
Learn More >Discomfort provoked by normally innocuous visual stimuli has been reported by people with chronic pain. Visual discomfort may be higher in pain conditions in which central sensitization is implicated, such as Complex Regional Pain Syndrome (CRPS) and fibromyalgia. In an online study, we validated the Leiden Visual Sensitivity Scale (L-VISS) and Visual Discomfort Scale (VDS) in people with CRPS (=57), fibromyalgia (=75), and general chronic pain (=53); investigated whether these groups and pain-free controls (=125) differed in visual discomfort; and evaluated the effect of age. The L-VISS and VDS had good internal consistency. Both scales were positively related with experimentally induced visual distortions for mid-spatial frequency striped patterns, suggesting good construct validity. The scales were positively related with each other, and dissociated between the pain and pain-free groups in similar ways, suggesting good construct validity. There was no relationship between age and L-VISS scores and a small negative relationship between age and VDS scores. Visual discomfort was highest in the fibromyalgia group, followed by the CRPS group. This research confirms the utility of the L-VISS and VDS for measuring visual sensitivity in chronic pain and adds to evidence that central sensitization is an important mechanism of visual discomfort.
Learn More >To evaluate the efficacy of lasmiditan (LTN) in treating migraine attacks of mild vs. moderate or severe pain intensity.
Learn More >Previous studies suggested that reactive oxygen species (ROS) produced by NADPH oxidase 4 (Nox4) affect the processing of neuropathic pain. However, mechanisms underlying Nox4-dependent pain signaling are incompletely understood. In this study, we aimed to identify novel Nox4 downstream interactors in the nociceptive system. Mice lacking Nox4 specifically in sensory neurons were generated by crossing Advillin-Cre mice with Nox4 mice. Tissue-specific deletion of Nox4 in sensory neurons considerably reduced mechanical hypersensitivity and neuronal action potential firing after peripheral nerve injury. Using a proteomic approach, we detected various proteins that are regulated in a Nox4-dependent manner after injury, including the small calcium-binding protein S100A4. Immunofluorescence staining and western blot experiments confirmed that S100A4 expression is massively up-regulated in peripheral nerves and dorsal root ganglia after injury. Furthermore, mice lacking S100A4 showed increased mechanical hypersensitivity after peripheral nerve injury and after delivery of a ROS donor. Our findings suggest that S100A4 expression is up-regulated after peripheral nerve injury in a Nox4-dependent manner and that deletion of S100A4 leads to an increased neuropathic pain hypersensitivity.
Learn More >Little is known about the effects of sleep disturbance (SD) on clinical outcomes after spine surgery.
Learn More >Complex regional pain syndrome (CRPS) is a progressive and painful disease of the extremities that is characterized by continuous pain inconsistent with the initial trauma. CRPS is caused by a multi-mechanism process that involves both the peripheral and central nervous system, with a prominent role of inflammation in CRPS pathophysiology. This review examines what is currently known about the CRPS inflammatory and pain mechanisms, as well as the possible impact of neurostimulation therapies on the neuroimmune axis of CRPS.
Learn More >OnabotulinumtoxinA (BT-A) quarterly was the first treatment approved specifically for chronic migraine (CM). It is unclear whether three cycles are better than two to assess early BT-A response.
Learn More >To examine associations of combined pain and fatigue severity with physical performance and quality of life in people with chronic knee pain.
Learn More >Neuropathic pain following peripheral nerve injury (PNI) is linked to neuroinflammation in the spinal cord marked by astrocyte activation and upregulation of interleukin 6 (IL6 chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 1 (CXCL1), with inhibition of each individually being beneficial in pain models.
Learn More >To classify paediatric chronic pain referrals in Ireland using the ICD-11 classification. In addition, differences between primary and secondary pain groups were assessed.
Learn More >This retrospective analysis aimed to characterize patients with migraine initiating erenumab and the shifting or trend of patient characteristics over time in a real-world setting.
Learn More >Mas-related G-protein-coupled receptor X1 (MrgprX1) is a human-specific Mrgpr and its expression is restricted to primary sensory neurons. However, its role in nociception and pain signaling pathways is largely unknown. This study aims to investigate a role for MrgprX1 in nociception via interaction with the pain receptor, Transient Receptor Potential Ankyrin 1 (TRPA1), using in-vitro and in-vivo human neuronal models. MrgprX1 protein expression in human trigeminal nociceptors was investigated by the immunolabeling of the dental pulp and cultured peripheral neuronal equivalent (PNE) cells. MrgprX1 receptor signaling was monitored by Fura-2-based Ca imaging using PNEs and membrane potential responses were measured using FluoVolt . Immunofluorescent staining revealed MrgprX1 expression in-vivo in dental afferents, which was more intense in inflamed compared to healthy dental pulps. Endogenous MrgprX1 protein expression was confirmed in the in-vitro human PNE model. MrgprX1 receptor signaling and the mechanisms through which it couples to TRPA1 were studied by Ca imaging. Results showed that MrgprX1 activates TRPA1 and induces membrane depolarization in a TRPA1 dependent manner. In addition, MrgprX1 sensitizes TRPA1 to agonist stimulation via Protein Kinase C (PKC). The activation and sensitization of TRPA1 by MrgprX1 in a model of human nerves suggests an important role for this receptor in the modulation of nociception.
Learn More >Together, neck pain and back pain are the first cause of disability worldwide, accounting for more than 10% of the total years lived with disability. In this context, chiropractic care provides a safe and effective option for the management of a large proportion of these patients. Chiropractic is a healthcare profession mainly focused on the spine and the treatment of spinal disorders, including spine pain. Basic studies have examined the influence of chiropractic spinal manipulation on a variety of peripheral, spinal, and supraspinal mechanisms involved in spine pain. While spinal cord mechanisms of pain inhibition contribute at least partly to the pain-relieving effects of chiropractic treatments, the evidence is weaker regarding peripheral and supraspinal mechanisms, which are important components of acute and chronic pain. This narrative review highlights the most relevant mechanisms of pain relief by spinal manipulation and provides a perspective for future research on spinal manipulation and spine pain, including the validation of placebo interventions that control for placebo effects and other non-specific effects that may be induced by spinal manipulation.
Learn More >The humanized anti-CGRP monoclonal antibody eptinezumab has been evaluated in five large-scale clinical trials conducted in patients with migraine. This integrated analysis was conducted to evaluate the comprehensive safety and tolerability of eptinezumab in patients with migraine across these studies.
Learn More >Prior studies have established an association between a history of abuse and the development of migraine. This cross-sectional observational study explored the relationship between self-reported abuse history with migraine-related sensory hypersensitivity symptoms.
Learn More >Remifentanil is widely used to control intraoperative pain. However, its analgesic effect is limited by the generation of postoperative hyperalgesia. In this study, we investigated whether the impairment of transmembrane protein 16C (TMEM16C)/Slack is required for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) activation in remifentanil-induced postoperative hyperalgesia. Remifentanil anesthesia reduced the paw withdrawal threshold from 2 h to 48 h postoperatively, with a decrease in the expression of TMEM16C and Slack in the dorsal root ganglia (DRG) and spinal cord. Knockdown of TMEM16C in the DRG reduced the expression of Slack and elevated the basal peripheral sensitivity and AMPAR expression and function. Overexpression of TMEM16C in the DRG impaired remifentanil-induced ERK1/2 phosphorylation and behavioral hyperalgesia. AMPAR-mediated current and neuronal excitability were downregulated by TMEM16C overexpression in the spinal cord. Taken together, these findings suggest that TMEM16C/Slack regulation of excitatory synaptic plasticity via GluA1-containing AMPARs is critical in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats.
Learn More >Opioid use disorder in the United States' Medicare population increased from 10 to 24 per 1000 from 2012 to 2018. Understanding the changes in the patterns of opioid overdose mortality over time holds broad clinical and public health relevance.
Learn More >The endogenous amide -Oleoylglycine (OlGly) and its analog -Oleoylalanine (OlAla), have been shown to interfere with the affective and somatic responses to acute naloxone-precipitated MWD in male rats. Here we evaluated the potential of a single dose (5 mg/kg, ip) which alleviates withdrawal of these endogenous fatty acid amides to modify tolerance to anti-nociception, hyperthermia, and suppression of locomotion produced by morphine in male Sprague-Dawley rats. Although rats did develop tolerance to the hypolocomotor and analgesic effects of morphine, they did not develop tolerance to the hyperthermic effects of this substance. Administration of neither OlGly nor OlAla interfered with the establishment of morphine tolerance, nor did they modify behavioral responses elicited by morphine on any trial. These results suggest that the effects of OlGly and OlAla on opiate dependence may be limited to naloxone-precipitated withdrawal effects.
Learn More >Opioid misuse is now considered a major public health epidemic in North America, with substantial social and financial consequences. As well as socio-economic and commercial drivers, modifiable risk-factors that have resulted in this crisis have been identified. The purpose of this study was to identify whether, within England, modifiable drivers for persistent postoperative opioid use were present. This was a retrospective cohort study of practice at 14 National Health Service hospitals across England. Data were collected retrospectively and validated for adult patients undergoing elective intermediate and major or complex major general surgical procedures between 1 and 31 March 2019. Of the 509 patients enrolled from 14 centres, 499 were included in the data analysis. In total, 31.5% (157/499) patients were in the intermediate surgery cohort and 68.5% (342/499) were in the major or complex major surgery cohort, with 21.0% (33/157) and 21.6% (74/342) discharged with opioid medicines to be taken at regular intervals, respectively. There were similar median oral morphine equivalent doses prescribed at discharge. Of patients prescribed regular opioid medicines, 76.6% (82/107) had a specified duration at discharge. However, 72.9% (78/107) had no written deprescribing advice on discharge. Similarly, of patients prescribed 'when required' opioids, 59.6% (93/156) had a specified duration of their prescription and 33.3% (52/156) were given written deprescribing advice. This study has identified a pattern of poor prescribing practices, a lack of guidance and formal training at individual institutions and highlights opportunities for improvement in opioid-prescribing practices within England.
Learn More >Galcanezumab is a monoclonal antibody (mAb) that binds calcitonin gene-related peptide (CGRP) and is indicated for the preventive treatment of migraine. Galcanezumab demonstrated early onset of effect in patients with migraine but it is unknown whether the same holds true for patients who have not benefited from multiple prior migraine preventives.
Learn More >Previous studies have demonstrated improvements in pain following short-term medical cannabis (MC) use, suggesting long-term MC treatment may alleviate symptoms associated with chronic pain. The goal of this observational and longitudinal study was to examine patients using MC to treat chronic pain pre versus post MC treatment. These interim analyses included 37 patients with chronic pain evaluated prior to initiation of MC treatment and following 3 and 6 months of MC use; pain, clinical state, sleep, quality of life, and conventional medication use were assessed. Correlation analyses examined the relationship between changes in pain and other clinical measures, assessed the impact of cannabinoid exposure on pain and clinical ratings, and assessed whether baseline cannabis expectancies influenced outcome variables. Additionally, a pilot group of treatment-as-usual patients (n = 9) who did not use MC were examined at baseline and 3 months later. Relative to baseline, following 3 and 6 months of treatment, MC patients exhibited improvements in pain which were accompanied by improved sleep, mood, anxiety, and quality of life, and stable conventional medication use. Reduced pain was associated with improvements in aspects of mood and anxiety. The results generally suggest increased THC exposure was related to pain-related improvement, while increased CBD exposure was related to improved mood. Cannabis expectancies were not related to observed improvements. Pilot analyses revealed that treatment-as-usual patients do not demonstrate the same pattern of improvement. Findings highlight the potential efficacy of MC treatment for pain and underscore the unique impact of individual cannabinoids on specific aspects of pain and comorbid symptoms. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Learn More >A plethora of evidence supports the existence of neuromuscular changes in people with chronic spinal pain (neck and low back pain), yet it is unclear whether neuromuscular adaptations persist for people with recurrent spinal pain when in a period of remission. This systematic review aimed to synthesise the evidence on neuromuscular adaptations in people with recurrent spinal pain during a period of remission. Electronic databases, grey literature, and key journals were searched from inception up to the 4th of September 2020. Eligibility criteria included observational studies investigating muscle activity, spine kinematics, muscle properties, sensorimotor control, and neuromuscular performance in adults (≥ 18 years) with recurrent spinal pain during a period of remission. Screening, data extraction, and quality assessment (Newcastle-Ottawa Scale) were conducted independently by two reviewers. Data synthesis was conducted per outcome domain. A meta-analysis with a random-effects model was performed where possible. The overall strength of evidence was rated using the Grading of Recommendations, Assessment, Development and Evaluation guidelines (GRADE). From 8292 records, 27 and five studies were included in a qualitative and quantitative synthesis, respectively. Very low level of evidence supports muscle activity changes in people with recurrent low back pain, especially greater co-contraction, redistribution of muscle activity, and delayed postural control of deeper trunk muscles. Reduced range of motion of the lumbar spine was also found. Meaningful conclusions regarding other outcome domains or people with recurrent neck pain could not be drawn. In conclusion, people with recurrent low back pain during a period of remission show muscle activity and spine kinematics adaptations. Future research should investigate the long-term impact of these changes, as well as adaptations in people with recurrent neck pain.
Learn More >People with chronic low back pain (LBP) exhibit changes in postural control. Stereotypical muscle activations resulting from external perturbations include anticipatory (APAs) and compensatory (CPAs) postural adjustments. The aim and objective of this study was to determine differences in postural control strategies (peak amplitude, APAs and CPAs) between symptomatic and asymptomatic adults with and without Lumbar Disc Degeneration (LDD) using surface electromyography during forward postural perturbation. Ninety-seven subjects participated in the study (mean age 50 years (SD 12)). 3T MRI was used to acquire T2 weighted images (L1-S1). LDD was determined using Pfirrmann grading. A bespoke translational platform was designed to deliver horizontal perturbations in sagittal and frontal planes. Electromyographic activity was analysed bilaterally from 8 trunk and lower limb muscles during four established APA and CPA epochs. A Kruskal-Wallis H test with Bonferroni correction for multiple comparisons was conducted. Four groups were identified: no LDD no pain (n = 19), LDD no pain (n = 38), LDD pain (n = 35) and no LDD pain (n = 5). There were no significant differences in age or gender between groups. The most significant difference between groups was observed during forward perturbation. In the APA and CPA phases of predictable forward perturbation there were significant differences ankle strategy between groups (p = 0.007-0.008); lateral gastrocnemius and tibialis anterior activity was higher in the LDD pain than the LDD no pain group. There were no significant differences in the unpredictable condition (p>0.05). These findings were different from the remaining groups, where significant differences in hip strategy were observed during both perturbation conditions (p = 0.004-0.006). Symptomatic LDD patients exhibit different electromyographic strategies to asymptomatic LDD controls. Future LBP electromyographic research should benefit from considering assessment of both lower limbs in addition to the spine. This approach could prevent underestimation of postural control deficits and guide targeted rehabilitation.
Learn More >Orofacial pain is among the most common chronic pain conditions and can result from temporomandibular disorders (TMDs) of the temporomandibular joint (TMJ). Matrix metalloproteinases (MMPs) drive degeneration of TMJ tissues and likely mediate pain in TMJ disorders given their role in nociception. However, few studies have assessed MMPs in the TMJ innervated tissues nor in the context of pain. This study defined the extent of MMP-1, MMP-9, and MMP-2 in TMJ tissues from patients undergoing total joint replacement (TJR) or arthroplasty discectomy for painful TMJ disorders. Protein expression was probed by Western blot in TMJ disc and capsular ligaments taken during TJR (n=6) or discectomy (n=3) for osteoarthritis or internal derangement in an IRB-approved study. Pro- and active MMP-1, active MMP-9, and pro- and active MMP-2 are detectable. MMP-1 and MMP-9 correlate positively to each other (Kendall's τ=0.63; p=0.01), strengthening the hypothesis that they are mechanistically related in regulatory cascades. Active MMP-1 and active MMP-9 correlate positively with self-reported pain scores (τ≥0.51; p≤0.04) suggesting their involvement in peripheral nociception. Overall, neither MMPs nor pain correlate with functional vertical opening of the jaw. MMP-1 varies with the observed stage of degeneration during surgery (p=0.04). Neither overall MMPs nor pain correlate with the overall MRI scores, corroborating the longstanding, but confounding, clinical observation that pain and radiological evidence of joint damage are not always related. Clinical significance: These findings suggest that MMPs mediate pain in innervated soft tissues and may be targets for diagnosing disease stage and treatments in painful TMJ disorders. This article is protected by copyright. All rights reserved.
Learn More >Persons living with dementia have an elevated risk of falling and chronic pain. This study investigates the relationship of pain medication use with falls among community-dwelling adults based on their cognitive status.
Learn More >Chronic pain is a widespread public and physical health crisis, as it is one of the most common reasons adults seek medical care and accounts for the largest medical reason for disability in the USA (Glombiewski et al., J Consult Clin Psychol. 86(6):533-545, 2018; Schemer et al., Eur J Pain. 23(3):526-538, 2019). Chronic pain is associated with decreased functional status, opioid dependence and substance abuse disorders, mental health crises, and overall lower perceived quality of life (Korff et al., J Pain. 17(10):1068-1080, 2016). For example, the leading cause of chronic pain and the leading cause of long-term disability is low back pain (LBP) (Bjorck-van Dijken et al. J Rehabil Med. 40:864-9, 2008). Evidence suggests that persistent low back pain (pLBP) is a multidimensional biopsychosocial problem with various contributing factors (Cherkin et al., JAMA. 315(12):1240-1249, 2016). Emotional distress, pain-related fear, and protective movement behaviors are all unhelpful lifestyle factors that previously were more likely to go unaddressed when assessing and treating patient discomfort (Pincus et al., Spine. 38:2118-23, 2013). Those that are not properly assisted with these psychosocial issues are often unlikely to benefit from treatment in the primary care setting and thus are referred to multidisciplinary pain rehabilitation physicians. This itself increases healthcare costs, and treatments can be invasive and have risks of their own. Therefore, less expensive and more accessible management strategies targeting these psychosocial issues should be started to facilitate improvement early. As a biopsychosocial disorder, chronic pain is influenced by a range of factors including lifestyle, mental health status, familial culture, and socioeconomic status. Physicians have moved toward multi-modal pain approaches in order to combat this public health dilemma, ranging from medications with several different mechanisms of action, lifestyle changes, procedural pain control, and psychological interventions (Fashler et al., Pain Res Manag. 2016:5960987, 2016). Part of the rehabilitation process now more and more commonly includes cognitive behavioral and cognitive functional therapy. Cognitive functional therapy (CFT) and cognitive behavioral therapy (CBT) are both multidimensional psychological approaches to combat the mental portion of difficult pain control. While these therapies are quite different in their approach, they lend to the idea that chronic pain can and should be targeted using coping mechanisms, helping patients understand the pathophysiological process of pain, and altering behavior.
Learn More >Melanocortin-4 receptor (MC4R) has been investigated as a potential drug target for the treatment of neuropathic pain. The objective of the study was to systematically identify the effects of MC4R antagonists on hypersensitivity in rat models of neuropathic pain. A systematic search was conducted using the following databases: WoS, PubMed, SCOPUS, and MEDLINE. Inclusion criteria were: rat hypersensitivity induced by models of neuropathic pain with reported effects of MC4R antagonist. Two researchers performed the selection process and data extraction. SYRCLE risk of bias tool was used. Standard mean differences (SMD) were calculated and pooled by meta-analysis using random effect models. Ten articles met the eligibility criteria and were included in the systematic review and meta-analysis. The results reveal that, in animals exposed to neuropathic pain, administration of MC4R antagonists significantly increased paw withdrawal threshold (SHU9119 SMD = 1.67, 95% CI: [0.91, 2.44], I = 0%; HS014 SMD = 2.2, 95% CI: [0.53, 3.87], I = 71%) and heat withdrawal latency (HS014 SMD = 3.35, 95% CI: [0.56, 6.14], I = 83%) compared to vehicle-treated animals. MC4R antagonists are effective in the alleviation of hypersensitivity in rodent neuropathic pain models. SHU9119 and HS014 antagonists showed the most prominent results. However, further investigation is needed to determine the optimal dose and time of treatment.
Learn More >The quality of subgroup analyses (SGAs) in chronic non-cancer pain trials is uncertain. The purpose of this study was to address this issue. We conducted a comprehensive search in MEDLINE and EMBASE from January 2012 to September 2018 to identify eligible trials. Two pairs of reviewers assessed the quality of the SGAs and the credibility of subgroup claims using the 10 criteria developed by Sun et al. in 2012. The associations between the quality of the SGAs and the studies' characteristics including risk of bias, funding sources, sample size, and the latest impact factor, were assessed using multivariable logistic regression. Our search retrieved 3,401 articles of which 66 were eligible. The total number of SGAs was 177 of which 52 (29.4%) made a subgroup claim. Of these, only 15 (8.5%) were evaluated as being of high quality. Among the 30 SGAs that claimed subgroup effects using an appropriate method of performing interaction tests, the credibility of only 5 were assessed as high. None of the subgroup claims met all the credibility criteria. No significant association was found between the quality of SGAs and the studies' characteristics. The quality of the SGAs performed in chronic pain trials was poor. To enhance the quality of SGAs, scholars should consider the developed criteria when designing and conducting trials, particularly those which need to be specified a .
Learn More >Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Chronic pain is experienced by the vast majority of patients living with Parkinson's disease. The degeneration of dopaminergic neuron acts as the essential mechanism of Parkinson's disease in the midbrain dopaminergic pathway. The impairment of dopaminergic neurons leads to dysfunctions of the nociceptive system. Key cortical areas, such as the anterior cingulate cortex (ACC) and insular cortex (IC) that receive the dopaminergic projections are involved in pain transmission. Dopamine changes synaptic transmission via several pathway, for example the D2-adenly cyclase (AC)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway and D1-G protein-coupled receptor kinase 2 (GRK2)-fragile X mental retardation protein (FMRP) pathway. The management of Parkinson's disease-related pain implicates maintenance of stable level of dopaminergic drugs and analgesics, however a more selective drug targeting at key molecules in Parkinson's disease-related pain remains to be investigated.
Learn More >The endocannabinoid system modulates a wide variety of pain conditions. Systemically administered AM404, an endocannabinoid reuptake inhibitor, exerts antinociceptive effects via activation of the endocannabinoid system. However, the mechanism and site of AM404 action are not fully understood. Here, we explored the effect of AM404 on neuropathic pain at the site of the spinal cord.
Learn More >Although chronic local inflammation in deeper tissues after skin wound healing might produce chronification of acute postsurgical pain, its mechanisms have not been fully elucidated. We hypothesized that muscle injury and severe inflammation would prolong acute postsurgical pain by its central nervous system mechanisms.
Learn More >Opioid-induced hyperalgesia (OIH) occurs when opioids paradoxically enhance the pain they are prescribed to ameliorate. To address a lack of perioperative awareness, we present an educational review of clinically relevant aspects of the disorder. Although the mechanisms of OIH are thought to primarily involve medullary descending pathways, it is likely multifactorial with several relevant therapeutic targets. We provide a suggested clinical definition and directions for clinical differentiation of OIH from other diagnoses, as this may be confusing but is germane to appropriate management. Finally, we discuss prevention including patient education and analgesic management choices. As prevention may serve as the best treatment, patient risk factors, opioid mitigation, and both pharmacologic and non-pharmacologic strategies are discussed.
Learn More >Peripheral neuropathy is the most frequent dose-limiting adverse effect of oxaliplatin. Acute pain symptoms that are induced or exacerbated by cold occur in almost all patients immediately following the first infusions. Evidence has shown that oxaliplatin causes ion channel expression modulations in dorsal root ganglia neurons, which are thought to contribute to peripheral hypersensitivity. Most dysregulated genes encode ion channels involved in cold and mechanical perception, noteworthy members of a sub-group of potassium channels of the K2P family, TREK and TRAAK. Downregulation of these K2P channels has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. We investigated the molecular mechanisms underlying this peripheral dysregulation in a murine model of neuropathic pain triggered by a single oxaliplatin administration. We found that oxaliplatin-mediated TREK-TRAAK downregulation, as well as downregulation of other K channels of the K2P and Kv families, involves a transcription factor known as the neuron-restrictive silencer factor (NRSF) and its epigenetic co-repressors histone deacetylases (HDACs). NRSF knockdown was able to prevent most of these K channel mRNA downregulation in mice dorsal root ganglion neurons as well as oxaliplatin-induced acute cold and mechanical hypersensitivity. Interestingly, pharmacological inhibition of class I HDAC reproduces the antinociceptive effects of NRSF knockdown and leads to an increased K channel expression in oxaliplatin-treated mice.
Learn More >Although cranial autonomic symptoms (CAS) are typical in cluster headache (CH), some individuals with CH show no CAS during their headache attacks. Probable cluster headache (PCH) is a subtype of CH that fulfils all but one criterion of CH. This study aimed to investigate the frequency and clinical features of CH and PCH without CAS in comparison to those with CAS. We analysed data from the Korea Cluster Headache Registry, a prospective multicentre registry involving data from 16 hospitals. Of the 216 participants with CH and 26 with PCH, 19 (8.8%) and 7 (26.9%), respectively, did not have CAS. Participants with CH without CAS exhibited less severe anxiety (General Anxiety Disorder-7 score, median [interquartile range], 2.0 [1.0-6.0] vs 8.0 [3.0-12.0], p = 0.001) and depression (Patient Health Questionnaire-9 score, 3.0 [1.0-7.0] vs 7.0 [3.0-11.0], p = 0.042) than those with CAS. Among participants with PCH, headache intensity was less severe in participants without CAS than in those with CAS (numeric rating scale, 8.0 [7.0-8.0] vs 9.5 [8.0-10.0], p = 0.015). In conclusion, a significant proportion of participants with CH and PCH did not have CAS. Some clinical features of CH and PCH differed based on the presence of CAS.
Learn More >Previous studies comparing laser (LEPs) and contact heat evoked potentials (CHEPs) consistently reported higher amplitudes following laser compared to contact heat stimulation. However, none of the studies matched the perceived pain intensity, questioning if the observed difference in amplitude is due to biophysical differences between the two methods or a mismatch in stimulation intensity. The aims of the current study were twofold: (1) to directly compare the brain potentials induced by intensity matched laser and contact heat stimulation and (2) investigate how capsaicin-induced secondary hyperalgesia modulates LEPs and CHEPs. Twenty-one healthy subjects were recruited and measured at four experimental sessions: (1) CHEPs + sham, (2) LEPs + sham, (3) CHEPs + capsaicin, and (4) LEPs + capsaicin. Baseline (sham) LEPs latency was significantly shorter and amplitude significantly larger compared to CHEPs, even when matched for perceived pain. Neither CHEPs nor LEPs was sensitive enough to detect secondary hyperalgesia. These differences provide evidence that a faster heating rate results in an earlier and more synchronized LEPs than CHEPs. To our knowledge, this was the first study to match perceived intensity of contact heat and laser stimulations, revealing distinct advantages associated with the acquisition of LEPs.
Learn More >Chronic pain constitutes a significant burden for the individuals affected, and is a frequent reason why patients seek health care services. While in-person psychosocial interventions can be of support to people living with chronic pain, such interventions are not always accessible. eHealth interventions may provide greater accessibility, but the evidence and use of digital self-management solutions for chronic pain are still limited and the lack of health care provider input in the development process of such solutions a concern. Therefore, the aim of the current study was to investigate health care providers' experiences of treating patients with chronic pain, their attitudes towards, and use of, digital solutions in pain management, and their suggestions for content and design elements for a potential digital pain self-management intervention.
Learn More >Inflammation constitutes both positive and negative aspects to recovery following peripheral nerve injury. Following damage to the peripheral nervous system (PNS), immune cells such as macrophages play a beneficial role in creating a supportive environment for regrowing axons by phagocytosing myelin and axonal debris. However, a prolonged inflammatory response after peripheral nerve injury has been implicated in the pathogenesis of negative symptoms like neuropathic pain. Therefore, the post-injury inflammation must be carefully controlled to prevent secondary damage while allowing for regeneration. CRYAB (also known as alphaB-crystallin/HSPB5) is a small heat shock protein that has many protective functions including an immunomodulatory role in mouse models of multiple sclerosis, spinal cord injury, and stroke. Because its expression wanes and rebounds in the early and late periods respectively after PNS damage, and CRYAB null mice with sciatic nerve crush injury display symptoms of pain, we investigated whether CRYAB is involved in the immune response following PNS injury.
Learn More >A recent genome-wide meta study suggested that rs67338227 in the FHL5 gene and rs10456100 in the KCNK5 gene are associated with migraine from 27 population-based cohorts excluding Chinese population. Given that migraine without aura (MO) is the most common subtype of migraine, our aim was to systematically investigate the relationship of common variants in FHL5 and KCNK5 genes with the susceptibility to MO and provide clues as to the nature of the mechanisms involved in the etiology of migraine. A total of 3306 subjects including 1042 patients with MO and 2264 controls were recruited for the discovery stage, and 2530 individuals including 842 patients with MO and 1688 controls for the replication stage. Twenty-two tag SNPs (7 from FHL5 and 15 from KCNK5) were selected for genotyping. Genetic associations were analyzed at both single-marker and haplotype levels. Potential functional consequences of the significant SNPs were analyzed using gene expression data obtained from the GTEx database. Two SNPs, rs10456100 (KCNK5, P = 9.01 × 10) and rs7775721 (FHL5, P = 6.86 × 10), were determined to be significantly associated with MO in the discovery sample and were then replicated in another sample. In the combined sample set, the T allele of both SNPs was significantly associated with the increased risk of MO. Significant eQTL signals were identified for both SNP rs10456100 and rs7775721. Our findings suggest that the T allele carriers of SNP rs10456100 and rs7775721 are at increased risk of migraine.
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