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The aim of this study was to examine the association between the length of time between an emergency department (ED) visit and the subsequent initiation of physical therapist intervention for low back pain (LBP) on 1-year LBP-related health care utilization (ie, surgery, advanced imaging, injections, long-term opioid use, ED visits) and costs.
Learn More >Fibromyalgia is characterized by chronic widespread pain, fatigue, sleep disturbances and functional symptoms. The etiopathogenesis, diagnostic criteria and classification criteria of fibromyalgia are still debated and, consequently, so are the strategies for treating this condition. Fibromyalgia is the third most frequent musculoskeletal condition, and its prevalence increases with age. However, although diagnosis has improved with the evolution of more accurate diagnostic criteria, a considerable proportion of physicians still fail to recognize the syndrome. Many factors contribute to the development of fibromyalgia in a unique manner: genetic predisposition, personal experiences, emotional-cognitive factors, the mind-body relationship and a biopsychological ability to cope with stress. The multiple components of the pathogenesis and maintenance of the condition necessitate a multi-modal treatment approach. Individually tailored treatment is an important consideration, with the increasing recognition that different fibromyalgia subgroups exist with different clinical characteristics. Consequently, although an evidence-based approach to fibromyalgia management is always desirable, the approach of physicians is inevitably empirical, and must have the aim of creating a strong alliance with the patient and formulating shared, realistic treatment goals.
Learn More >Astrocytes are critical regulators of CNS function and are proposed to be heterogeneous in the developing brain and spinal cord. Here we identify a population of astrocytes located in the superficial laminae of the spinal dorsal horn (SDH) in adults that is genetically defined by Hes5. In vivo imaging revealed that noxious stimulation by intraplantar capsaicin injection activated Hes5 SDH astrocytes via α-adrenoceptors (α-ARs) through descending noradrenergic signaling from the locus coeruleus. Intrathecal norepinephrine induced mechanical pain hypersensitivity via α-ARs in Hes5 astrocytes, and chemogenetic stimulation of Hes5 SDH astrocytes was sufficient to produce the hypersensitivity. Furthermore, capsaicin-induced mechanical hypersensitivity was prevented by the inhibition of descending locus coeruleus-noradrenergic signaling onto Hes5 astrocytes. Moreover, in a model of chronic pain, α-ARs in Hes5 astrocytes were critical regulators for determining an analgesic effect of duloxetine. Our findings identify a superficial SDH-selective astrocyte population that gates descending noradrenergic control of mechanosensory behavior.
Learn More >Obesity affects over 2 billion people worldwide and is accompanied by peripheral neuropathy (PN) and an associated poorer quality of life. Despite high prevalence, the molecular mechanisms underlying the painful manifestations of PN are poorly understood, and therapies are restricted to use of painkillers or other drugs that do not address the underlying disease. Studies have demonstrated that the gut microbiome is linked to metabolic health and its alteration is associated with many diseases, including obesity. Pathologic changes to the gut microbiome have recently been linked to somatosensory pain, but any relationships between gut microbiome and PN in obesity have yet to be explored. Our data show that mice fed a Western diet developed indices of PN that were attenuated by concurrent fecal microbiome transplantation (FMT). In addition, we observed changes in expression of genes involved in lipid metabolism and calcium handling in cells of the peripheral nerve system (PNS). FMT also induced changes in the immune cell populations of the PNS. There was a correlation between an increase in the circulating short-chain fatty acid butyrate and pain improvement following FMT. Additionally, butyrate modulated gene expression and immune cells in the PNS. Circulating butyrate was also negatively correlated with distal pain in 29 participants with varied body mass index. Our data suggest that the metabolite butyrate, secreted by the gut microbiome, underlies some of the effects of FMT. Targeting the gut microbiome, butyrate, and its consequences may represent novel viable approaches to prevent or relieve obesity-associated neuropathies.
Learn More >Global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues unabated. Binding of SARS-CoV-2's Spike protein to host angiotensin converting enzyme 2 triggers viral entry, but other proteins may participate, including neuropilin-1 receptor (NRP-1). As both Spike protein and vascular endothelial growth factor-A (VEGF-A) – a pro-nociceptive and angiogenic factor, bind NRP-1, we tested if Spike could block VEGF-A/NRP-1 signaling. VEGF-A-triggered sensory neuronal firing was blocked by Spike protein and NRP-1 inhibitor EG00229. Pro-nociceptive behaviors of VEGF-A were similarly blocked via suppression of spontaneous spinal synaptic activity and reduction of electrogenic currents in sensory neurons. Remarkably, preventing VEGF-A/NRP-1 signaling was antiallodynic in a neuropathic pain model. A 'silencing' of pain via subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals.
Learn More >Depression and anxiety are frequently observed in patients suffering from neuropathic pain. The underlying mechanisms remained unclear. The ventrolateral orbital cortex (VLO) has attracted considerable interest in its role in antidepressive effect in rodents. In the present study, we further investigated the role of the VLO in the anxiodepressive consequences of neuropathic pain in a chronic constriction injury of infraorbital nerve-induced trigeminal neuralgia (TN) mouse model. Elevated plus maze, open field, forced swimming, tail suspension, and sucrose preference tests were used to evaluate anxiodepressive-like behaviors. The results show that chemogenetic activation of bilateral VLO neurons, especially CaMK2A+ pyramidal neurons, blocked the TN-induced anxiodepressive-like behaviors. Chemogenetic and optogenetic activation of VGLUT2+ or inhibition of VGAT+ VLO neurons was sufficient to produce an antianxiodepressive effect in TN mice. Pharmacological activation of D1-like receptors (D1Rs) but not D2Rs in the VLO significantly alleviated TN-induced depressive-like behaviors. Electrophysiological recordings revealed a decreased excitability of VLO excitatory neurons following neuropathic pain. Furthermore, activation of submedius thalamic nucleus-VLO (Sm-VLO) projection mimicked the antianxiodepressive effect of VLO excitation. Conversely, activation of VLO-periaqueductal gray matter (PAG) projection had no effect on TN-induced anxiodepressive behaviors. This study provides a potentially novel mechanism-based therapeutic strategy for the anxiodepressive consequences of neuropathic pain.
Learn More >Understanding the mechanisms that drive transition from acute to chronic pain is essential to identify new therapeutic targets. The importance of endogenous resolution pathways acting as a "brake" to prevent development of chronic pain has been largely ignored. We examined the role of interleukin-10 (IL-10) in resolution of neuropathic pain induced by cisplatin. In search of an underlying mechanism, we studied the effect of cisplatin and IL-10 on spontaneous activity (SA) in dorsal root ganglia neurons. Cisplatin (2 mg/kg daily for 3 days) induced mechanical hypersensitivity that resolved within 3 weeks. In both sexes, resolution of mechanical hypersensitivity was delayed in Il10 mice, in WT mice treated intrathecally with neutralizing anti-IL-10 antibody, and in mice with cell-targeted deletion of IL-10R1 on advillin-positive sensory neurons. Electrophysiologically, small- to medium-sized dorsal root ganglia neurons from cisplatin-treated mice displayed an increase in the incidence of SA. Cisplatin treatment also depolarized the resting membrane potential, and decreased action potential voltage threshold and rheobase, while increasing ongoing activity at -45 mV and the amplitude of depolarizing spontaneous fluctuations. In vitro addition of IL-10 (10 ng/mL) reversed the effect of cisplatin on SA and on the depolarizing spontaneous fluctuation amplitudes, but unexpectedly had little effect on the other electrophysiological parameters affected by cisplatin. Collectively, our findings challenge the prevailing concept that IL-10 resolves pain solely by dampening neuroinflammation and demonstrate in a model of chemotherapy-induced neuropathic pain that endogenous IL-10 prevents transition to chronic pain by binding to IL-10 receptors on sensory neurons to regulate their activity.
Learn More >Pain is a percept of critical importance to our daily survival. In most cases, it serves both an adaptive function by helping us respond appropriately in a potentially hostile environment and also a protective role by alerting us to tissue damage. Normally, it is evoked by the activation of peripheral nociceptive nerve endings and the subsequent relay of information to distinct cortical and sub-cortical regions, but under pathological conditions that result in chronic pain, it can become spontaneous. Given that one in three chronic pain patients do not respond to the treatments currently available, the need for more effective analgesics is evident. Two principal obstacles to the development of novel analgesic therapies are our limited understanding of how neuronal circuits that comprise these pain pathways transmit and modulate sensory information under normal circumstances and how these circuits change under pathological conditions leading to chronic pain states. In this review, we focus on the role of inhibitory interneurons in setting pain thresholds and, in particular, how disinhibition in the spinal dorsal horn can lead to aberrant sensory processing associated with chronic pain states.
Learn More >The innate immune system responds to infections that give rise to pain. How the innate immune system interacts with the sensory nervous system and contributes to pain is poorly understood. Here we report that hyperactivity of innate immunity primes and initiates pain states via the TLR2-interleukin-33 (IL-33) axis. Toll-like receptors (TLRs) are upregulated in the complete Freund's adjuvant (CFA) pain model, and knockout of TLR2 abolishes CFA-induced pain. Selective activation of TLR2/6 triggers acute pain via upregulation of IL-33 in the hindpaw, dorsal root ganglia (DRG), and spinal cord in an NLRP3-dependent manner. The IL-33 increase further initiates priming of nociceptive neurons and pain states. Finally, blocking IL-33 receptors at the spinal level mediates analgesia during acute and chronic inflammatory pain, underscoring an important function of IL-33 in pain signaling. Collectively, our data reveal a critical role of the TLR2-IL-33 axis in innate immune activation for pain initiation and maintenance.
Learn More >Chronic complications of traumatic brain injury (TBI) represent one of the greatest financial burdens and sources of suffering in society today. A substantial number of these patients suffer from post-traumatic headache (PTH), which is typically associated with tactile allodynia. Unfortunately, this phenomenon has been under-studied, in large part due to the lack of well-characterized laboratory animal models. We have addressed this gap in the field by characterizing the tactile sensory profile of two non-penetrating models of PTH. We show that multimodal TBI, administered by a jet-flow overpressure chamber that delivers a severe compressive impulse accompanied by a variable shock front and acceleration-deceleration insult, produces long term tactile hypersensitivity and widespread sensitization. These are phenotypes reminiscent of PTH in patients, in both cephalic and extracephalic regions. By contrast, closed head injury induces only transient cephalic tactile hypersensitivity, with no extracephalic consequences. Both models show a more severe phenotype with repetitive daily injury for three days, compared to either one or three successive injuries in a single day, providing new insight into patterns of injury that may place patients at greater risk of developing PTH. After recovery from transient cephalic tactile hypersensitivity, mice subjected to closed head injury demonstrate persistent hypersensitivity to established migraine triggers, including calcitonin gene-related peptide (CGRP) and sodium nitroprusside, a nitric oxide donor. Our results offer the field new tools for studying PTH, as well as preclinical support for a pathophysiologic role of CGRP in this condition.
Learn More >Sex differences for chronic back pain (cBP) have been reported, with females usually exhibiting greater morbidity, severity and poorer response to treatment. Genetic factors acting in an age-specific manner have been implicated but never comprehensively explored. We performed sex- and age-stratified GWAS and SNP-by-sex interaction analysis for cBP defined as "Back pain for 3+ months" in 202,077 males and 237,754 females of European ancestry from UK Biobank. Two and seven non-overlapping genome-wide significant loci were identified for males and females, respectively. A male-specific locus on chromosome 10 near SPOCK2 gene was replicated in four independent cohorts. Four loci demonstrated SNP-by-sex interaction, although none of them were formally replicated. SNP-explained heritability was higher in females (0.079 vs 0.067, p = 0.006). There was a high, although not complete, genetic correlation between the sexes (r = 0.838±0.041, different from 1 with p = 7.8E-05). Genetic correlation between the sexes for cBP decreased with age (0.858±0.049 in younger people vs 0.544±0.157 in older people; p = 4.3E-05). There was a stronger genetic correlation of cBP with self-reported diagnosis of intervertebral disc degeneration in males than in females (0.889 vs 0.638; p = 3.7E-06). Thus, the genetic component of cBP in the UK Biobank exhibits a mild sex- and age-dependency. This provides an insight into the possible causes of sex- and age-specificity in epidemiology and pathophysiology of cBP and chronic pain at other anatomical sites.
Learn More >Little is known about risk factors for emergency department (ED) attendance for chronic pain (CP) management and the relative service burden. We examined emergency department (ED) utilisation in patients with chronic pain (CP), identified risk factors associated with attendance for chronic musculoskeletal pain (CMP) and estimated the comparative cost of treatment. The study cohort comprised a random sample of 3,700 adults from the general population in Tayside, Scotland. Linked regional extracts, spanning a 12-month period, were obtained from national registers, providing information on ED attendances, community-dispensed prescribing and outpatient clinic attendances. The NHS Scotland Cost Book was used to ascertain the current average cost of an ED attendance (£130; ∼$167).All-cause ED attendance was higher in those with CP (68.5%; n=252) than without (29.3%; n=967). In the entire cohort, more patients attended the ED for the treatment of CMP than for any other medical condition (n=119; 32.3% of those with CP). Risk factors for ED attendance for CMP were: recent analgesic dose decreases (OR=4.55); and transitioning from opioid to non-opioid analgesics (OR=5.08). Characteristics protective of ED attendance for CMP were: being in receipt of strong opioids (OR=0.21); transitioning from non-opioid to opioid analgesics (OR=0.25); recent analgesic dose increases (OR=0.24); and being prescribed tricyclic antidepressants (OR=0.10), benzodiazepines (OR=0.46) or hypnotics (OR=0.45). CMP was one of the most expensive conditions to treat (£17,680 (∼$22,668) per annum), conferring a substantial burden on ED services. Improved understanding of the risk/protective factors could inform healthcare redesign to reduce avoidable ED attendances for CMP management.
Learn More >Current drug discovery efforts focus on identifying lead compounds acting on a molecular target associated with an established pathological state. Concerted molecular changes that occur in specific cell types during disease progression have generally not been identified. Here, we used constellation pharmacology to investigate rat dorsal root ganglion neurons using two models of peripheral nerve injury: chronic constriction injury (CCI) and spinal nerve ligation (SNL). In these well-established models of neuropathic pain, we show that the onset of chronic pain is accompanied by a dramatic, previously unreported increase in the number of bradykinin-responsive neurons, with larger increases observed after SNL relative to CCI. To define the neurons with altered expression, we charted the temporal course of molecular changes following 1, 3, 6, and 14 d after SNL injury and demonstrated that specific molecular changes have different time courses during the progression to a pain state. In particular, ATP receptors up-regulated on day 1 postinjury, whereas the increase in bradykinin receptors was gradual after day 3 postinjury. We specifically tracked changes in two subsets of neurons: peptidergic and nonpeptidergic nociceptors. Significant increases occurred in ATP responses in nAChR-expressing isolectin B4+ nonpeptidergic neurons 1 d postinjury, whereas peptidergic neurons did not display any significant change. We propose that remodeling of ion channels and receptors occurs in a concerted and cell-specific manner, resulting in the appearance of bradykinin-responsive neuronal subclasses that are relevant to chronic pain.
Learn More >Cortical spreading depression (SD) is an intense depolarization underlying migraine aura. Despite the weight of evidence linking SD to the pain phase of migraine, controversy remains over a causal role of SD in cephalgia because of the invasive nature of previous SD induction methods. To overcome this problem, we employed a novel minimally invasive optogenetic SD induction method and examined the effect SD on behavior.
Learn More >Neurological disorders account for a large and increasing health burden worldwide, as shown in the Global Burden of Diseases (GBD) Study 2016. Unpacking how this burden varies regionally and nationally is important to inform public health policy and prevention strategies. The population in the EU is older than that of the WHO European region (western, central, and eastern Europe) and even older than the global population, suggesting that it might be particularly vulnerable to an increasing burden of age-related neurological disorders. We aimed to compare the burden of neurological disorders in the EU between 1990 and 2017 with those of the WHO European region and worldwide.
Learn More >Accumulating evidence has established a firm role for synaptic plasticity in the pathogenesis of neuropathic pain. Recent advances have highlighted the importance of dendritic spine remodeling in driving synaptic plasticity within the CNS. Identifying the molecular players underlying neuropathic pain induced structural and functional maladaptation is therefore critical to understanding its pathophysiology. This process of dynamic reorganization happens in unique phases that have diverse pathologic underpinnings in the initiation and maintenance of neuropathic pain. Recent evidence suggests that pharmacological targeting of specific proteins during distinct phases of neuropathic pain development produces enhanced antinociception. These findings outline a potential new paradigm for targeted treatment and the development of novel therapies for neuropathic pain. We present a concise review of the role of dendritic spines in neuropathic pain and outline the potential for modulation of spine dynamics by targeting two proteins, srGAP3 and Rac1, critically involved in the regulation of the actin cytoskeleton.
Learn More >CHRONIC OPIOID THERAPY: A SCOPING LITERATURE REVIEW ON EVOLVING CLINICAL AND SCIENTIFIC DEFINITIONS.
The management of chronic non-cancer pain (CNCP) with Chronic Opioid Therapy (COT) is controversial. There is a lack of consensus on how COT is defined resulting in unclear clinical guidance. This scoping review identifies and evaluates evolving COT definitions throughout the published clinical and scientific literature. Databases searched included PubMed, Embase, and Web of Science. A total of 227 studies were identified from 8,866 studies published between January 2000 and July 2019. COT definitions were classified by pain population of application and specific dosage/duration definition parameters, with results reported according to PRISMA-ScR. Approximately half of studies defined COT as "days' supply duration >90 days" and 9.3% defined as ">120 days' supply," with other days' supply cut-off points (>30, >60, or >70) each appearing in <5% of total studies. COT was defined by number of prescriptions in 63 studies, with 16.3% and 11.0% using number of initiations or refills, respectively. Few studies explicitly distinguished acute treatment and COT. Episode duration/dosage criteria was used in 90 studies, with 7.5% by Morphine Milligram Equivalents (MME's)+days' supply and 32.2% by other "episode" combination definitions. COT definitions were applied in musculoskeletal CNCP (60.8%) most often, and typically in adults aged 18-64 (69.6%). The usage of ">90 days' supply" COT definitions increased from 3.2 publications /year before 2016 to 20.7 publications /year after 2016. An increasing proportion of studies define COT as ">90 days' supply". The most recent literature trends toward shorter duration criteria, suggesting that contemporary COT definitions are increasingly conservative. Perspective: This study summarized the most common, current definition criteria for chronic opioid therapy (COT) and recommends adoption of consistent definition criteria to be utilized in practice and research. The most recent literature trends toward shorter duration criteria overall, suggesting that COT definition criteria are increasingly stringent.
Learn More >Presents an obituary of Ronald Melzack (1929-2019). Melzack died on Sunday, December 22, 2019, at 10:00 p.m. News of his death spread like wildfire through the network of long-time friends and colleagues who had heard of his imminent passing. At that moment, the world lost a compassionate and caring soul, an advocate for chronic pain sufferers around the globe, and a giant in the international pain community. He is survived by his wife of 59 years, Lucy (née Birch), their son, Joel, and daughter, Lauren. Ron is known for four major accomplishments: establishing Canada's first multidisciplinary pain center at the Montreal General Hospital with neurosurgeon colleague and friend the late Joseph Stratford; the 1965 publication, in , of the gate control theory of pain with the late Patrick Wall; development of the McGill Pain Questionnaire and its derivatives; and later in his career, at 60 years of age, publication of the neuromatrix theory of pain, moving the field beyond the spinal gating mechanism into the brain. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >Oxylipins are lipid peroxidation products that participate in nociceptive, inflammatory, and vascular responses to injury. Effects of oxylipins depend on tissue-specific differences in accumulation of precursor polyunsaturated fatty acids and the expression of specific enzymes to transform the precursors. The study of oxylipins in nociception has presented technical challenges leading to critical knowledge gaps in the way these molecules operate in nociception. We applied a systems-based approach to characterize oxylipin precursor fatty acids, and expression of genes coding for proteins involved in biosynthesis, transport, signaling and inactivation of pro- and anti-nociceptive oxylipins in pain circuit tissues. We further linked these pathways to nociception by demonstrating intraplantar carrageenan injection induced gene expression changes in oxylipin biosynthetic pathways. We determined functional-biochemical relevance of the proposed pathways in rat hind paw and dorsal spinal cord by measuring basal and stimulated levels of oxylipins throughout the time-course of carrageenan-induced inflammation. Finally, when oxylipins were administered by intradermal injection we observed modulation of nociceptive thermal hypersensitivity, providing a functional-behavioral link between oxylipins, their molecular biosynthetic pathways, and involvement in pain and nociception. Together, these findings advance our understanding of molecular lipidomic systems linking oxylipins and their precursors to nociceptive and inflammatory signaling pathways in rats. PERSPECTIVE: We applied a systems approach to characterize molecular pathways linking precursor lipids and oxylipins to nociceptive signaling. This systematic, quantitative evaluation of the molecular pathways linking oxylipins to nociception provides a framework for future basic and clinical research investigating the role of oxylipins in pain.
Learn More >Despite the important roles of protein kinase Cε (PKCε) and transient receptor potential vanilloind 1 (TRPV1) in inflammatory hypersensitivity, how PKCε is involved in the regulation of thermal hyperalgesia is not fully understood. We report here that PKCε is SUMOylated at a C-terminal lysine residue (K534), which enhances the sensitivity of the TRPV1 channel. We demonstrate that PKCε phosphorylation promotes its SUMOylation, which in turn regulates the phosphorylation level of TRPV1 serine 800 residue via controlling the binding of PKCε and TRPV1 and increased PKCε kinase activity. More importantly, the reduced ability of PKCε knockdown mice to develop inflammatory thermal hyperalgesia was rescued by viral infection of lumbar 4/5 dorsal root ganglia neurons of wild-type PKCε, but not the SUMOylation-deficient PKCε mutant. Therefore, the SUMOylation of PKCε potentiates inflammatory thermal hyperalgesia through stabilizing the interaction with TRPV1 to enhance its function by phosphorylation.
Learn More >Diagnostic uncertainty, the perceived lack of an accurate explanation of the patient's health problem, remains relatively unstudied in children. This study examined the prevalence, familial concordance, and correlates of diagnostic uncertainty in children and their parents presenting to a multidisciplinary pain clinic in the United States. One hundred and twenty-six parents and 91 of their children ( = 13.93 years, range = 8-18 years) completed a brief three-item measure of diagnostic uncertainty, as well as measures of pain-related distress and functioning. Forty-eight percent of children and 37% of parents believed something else was going on with the child's pain that doctors had not found out about yet. Across the three items, 66%-77% of children and their parents agreed in their endorsement of diagnostic uncertainty. Parents who believed that something else was going on with their child's pain had children with higher avoidance of pain-related activities ( = 5.601, = 0.020) and lower pain willingness ( = 4.782, = 0.032). Neither parent nor child diagnostic uncertainty was significantly related to the child's pain-related functioning. Diagnostic uncertainty, particularly in parents, is relevant in the experience of pediatric chronic pain and warrants further investigation as both a risk factor and therapeutic target.
Learn More >Acute itch is elicited by histamine, as well as non-histaminergic itch mediators including chloroquine, BAM8-22 and SLIGRL. When injected intradermally, histamine binds to histamine H1 and H4 receptors that activate TRPV1 to depolarize pruriceptors. Chloroquine, BAM-822, and SLIGRL respectively bind to Mas-related G-protein-coupled receptors MrgprA3, MrgprC11, and MrgprC11/PAR2 that in turn activate TRPA1. In this study we tested if histamine, chloroquine, BAM8-22 and SLIGRL elicit thermal hyperalgesia and mechanical allodynia in adult male mice. We measured the latency of hindpaw withdrawal from a noxious heat stimulus, and the threshold for hindpaw withdrawal from a von Frey mechanical stimulus. Intraplantar injection of histamine resulted in significant thermal hyperalgesia (p<0.01) and mechanical allodynia (p<0.0001) ipsilaterally that persisted for 1 hr. Pretreatment with the TRPV1 antagonist AMG-517 (10 or 20 μg), but not the TRPA1 antagonist HC-030031 (50 or 100 μg), significantly attenuated the magnitude and time course of thermal hyperalgesia and mechanical allodynia elicited by histamine (p<0.0001 for both), indicating that these effects are mediated by TRPV1. In contrast, pretreatment with the TRPA1 antagonist significantly reduced thermal hyperalgesia and mechanical allodynia elicited by chloroquine (p<0.001 and, p<0.0001, respectively), BAM-822 (p<0.01, p<0.001, respectively) and SLGRL (p<0.05, p<0.001, respectively), indicating that effects elicited by these non-histaminergic itch mediators require TRPA1. TRPV1 and TRPA1 channel inhibitors thus may have potential use in reducing hyperalgesia and allodynia associated with histaminergic and non-histaminergic itch, respectively.
Learn More >Clinical tools assessing tactile acuity in people with persistent pain have limitations. Therefore, a novel and semi-automated tool was developed: The Imprint Tactile Acuity Device (iTAD).
Learn More >Interdisciplinary cognitive behavioral therapy (CBT) for chronic pain is effective at improving function, mood, and pain interference among individuals with disabling chronic pain. Traditionally, CBT assumes cognitive change is an active therapeutic ingredient in the determination of treatment outcome. Pain catastrophizing, a cognitive response style that views the experience of pain as uncontrollable, permanent, and destructive, has been identified as an important maladaptive cognition which contributes to difficulties with the management of chronic pain. Consequently, pain catastrophizing is commonly targeted in CBT for chronic pain.
Learn More >To analyze a series of novel non-invasive urinary biomarkers for their ability to objectively monitor the longitudinal clinical status of UCPPS patients.
Learn More >Opioid abuse is a major health problem. The objective of the present study was to evaluate the potentially disruptive side effects and therapeutic potential of a novel antagonist (D24 M) of the mu-/delta-opioid receptor (MOR/DOR) heterodimer in male rats. Administration of high doses of D24 M (1 & 10 nmol) into the lateral ventricle did not disrupt home cage wheel running. Repeated twice daily administration of increasing doses of morphine (5 to 20 mg/kg) over 5 days depressed wheel running and induced antinociceptive tolerance measured with the hot plate test. Administration of D24 M had no effect on morphine tolerance, but tended to prolong morphine antinociception in non-tolerant rats. Spontaneous morphine withdrawal was evident as a decrease in body weight, a reduction in wheel running and an increase in sleep during the normally active dark phase of the circadian cycle, and an increase in wheel running and wakefulness in the normally inactive light phase. Administration of D24 M during the dark phase on the third day of withdrawal had no effect on wheel running. These data provide additional evidence for the clinical relevance of home cage wheel running as a method to assess spontaneous opioid withdrawal in rats. These data also demonstrate that blocking the MOR/DOR heterodimer does not produce disruptive side effects or block the antinociceptive effects of morphine. Although administration of D24 M had no effect on morphine withdrawal, additional studies are needed to evaluate withdrawal to continuous morphine administration and other opioids in rats with persistent pain.
Learn More >Oral cancer patients often have severe, chronic, and mechanically induced pain at the site of the primary cancer. Oral cancer pain is initiated and maintained in the cancer microenvironment and attributed to release of mediators that sensitize primary sensory nerves. This study was designed to investigate the histopathology associated with painful oral cancers in a preclinical model. The relationship of pain scores with pathologic variables was also investigated in a cohort of 72 oral cancer patients. Wild-type mice were exposed to the carcinogen, 4-nitroquinoline 1-oxide (4NQO). Nociceptive (pain) behavior was measured with the dolognawmeter, an operant device and assay for measuring functional and mechanical allodynia. Lesions developed on the tongues and esophagi of the 4NQO-treated animals and included hyperkeratoses, papillomas, dysplasias, and cancers. Papillomas included lesions with benign and dysplastic pathological features. Two histologic subtypes of squamous cell carcinomas (SCCs) were identified-SCCs with exophytic and invasive components associated with papillary lesions (pSCCs) and invasive SCCs without exophytic histology (iSCCs). Only the pSCC subtype of tongue cancer was associated with nociceptive behavior. Increased tumor size was associated with greater nociceptive behavior in the mouse model and more pain experienced by oral cancer patients. In addition, depth of invasion was associated with patient-reported pain. The pSCC histology identifies 4NQO-induced tongue cancers that are expected to be enriched for expression and release of nociceptive mediators.
Learn More >Differences in pain processing, muscle structure and function have been reported in patients with low back pain (LBP) with different grades of pain chronicity.
Learn More >Propranolol is a nonselective β-adrenergic receptor antagonist that is efficacious in reducing facial pain. There is evidence that its analgesic efficacy might be modified by variants of the catechol-O-methyltransferase () gene. We tested the hypothesis in a subset of 143 non-Hispanic Whites from a randomized controlled trial of patients with painful temporomandibular disorder (TMD). Patients were genotyped for rs4680, a single nucleotide polymorphism of , and randomly allocated to either propranolol 60 mg twice daily or placebo. During the 9-wk follow-up period, patients recorded daily ratings of facial pain intensity and duration; the product was computed as an index of facial pain. Postbaseline change in the index at week 9 (the primary endpoint) was analyzed as a continuous variable and dichotomized at thresholds of ≥30% and ≥50% reduction. Mixed models for repeated measures tested for the genotype × treatment group interaction and estimated means, odds ratios (ORs), and 95% confidence limits (95% CLs) of efficacy within genotypes assuming an additive genetic model. In secondary analysis, the cumulative response curves were plotted for dichotomized reductions ranging from ≥20% to ≥70%, and genotype differences in area under the curve percentages (%AUC) were calculated to signify efficacy. Mean index reduction did not differ significantly ( = 0.277) according to genotype, whereas the dichotomized ≥30% reduction revealed greater efficacy among G:G homozygotes (OR = 10.9, 95%CL = 2.4, 50.7) than among A:A homozygotes (OR = 0.8, 95%CL = 0.2, 3.2) with statistically significant interaction ( = 0.035). Cumulative response curves confirmed greater ( = 0.003) efficacy for G:G homozygotes (%AUC difference = 43.7, 95%CL = 15.4, 72.1) than for A:A homozygotes (%AUC difference = 6.5, 95%CL = -30.2, 43.2). The observed antagonistic effect of the A allele on propranolol's efficacy was opposite the synergistic effect hypothesized a priori. This unexpected result highlights the need for better knowledge of role in pain pathogenesis if the gene is to be used for precision-medicine treatment of TMD (ClinicalTrials.gov NCT02437383).
Learn More >Scopus is a leading bibliometric database. It contains the largest number of articles cited in peer-reviewed publications The journals included in Scopus are periodically re-evaluated to ensure they meet indexing criteria and some journals might be discontinued for publication concerns. These journals remain indexed and can be cited. Their metrics have yet to be studied. This study aimed to evaluate the main features and metrics of journals discontinued from Scopus for publication concerns, before and after their discontinuation, and to determine the extent of predatory journals among the discontinued journals. We surveyed the list of discontinued journals from Scopus (July 2019). Data regarding metrics, citations and indexing were extracted from Scopus or other scientific databases, for the journals discontinued for publication concerns. A total of 317 journals were evaluated. Ninety-three percent of the journals (294/318) declared they published using an Open Access model. The subject areas with the greatest number of discontinued journals were (52/317; 16%), (34/317; 11%), and (31/317; 10%). The mean number of citations per year after discontinuation was significantly higher than before (median of difference 64 citations, p<0.0001), and so was the number of citations per document (median of difference 0.4 citations, p<0.0001). Twenty-two percent (72/317) were included in the Cabell's blacklist. The DOAJ currently included only 9 journals while 61 were previously included and discontinued, most for 'suspected editorial misconduct by the publisher'. The citation count of journals discontinued for publication concerns increases despite discontinuation and predatory behaviors seemed common. This paradoxical trend can inflate scholars' metrics prompting artificial career advancements, bonus systems and promotion. Countermeasures should be taken urgently to ensure the reliability of Scopus metrics both at the journal- and author-level for the purpose of scientific assessment of scholarly publishing.
Learn More >Accessing care in multidisciplinary pain treatment facilities continues to be a challenge in Canada.
Multidisciplinary pain treatment facilities (MPTFs) are considered the optimal settings for the management of chronic pain (CP). This study aimed (1) to determine the distribution of MPTFs across Canada, (2) to document time to access and types of services, and (3) to compare the results to those obtained in 2005-2006.
Learn More >Resolvins (RvD1, RvD2 and RvE1) are endogenous anti-inflammatory lipid mediators that display potent analgesic properties in somatic pain by modulating transient receptor potential vanilloid 1 (TRPV1) activation. To what extent these molecules could also have a beneficial effect on TRPV1 sensitisation and visceral hypersensitivity (VHS), mechanisms involved in IBS, remains unknown.
Learn More >Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with chronic abdominal pain and altered pain processing. The aim of this study was to examine whether attentional processes contribute to altered pain inhibition processes in patients with IBS. Nine female patients with IBS and nine age-/sex-matched controls were included in a pain inhibition paradigm using counter-stimulation and distraction with electroencephalography. Patients with IBS showed no inhibition of pain-related brain activity by heterotopic noxious counter-stimulation (HNCS) or selective attention. In the control group, HNCS and selective attention decreased the N100, P260 and high-gamma oscillation power. In addition, pain-related high-gamma power in sensorimotor, anterior cingulate and left dorsolateral prefrontal cortex was decreased by HNCS and selective attention in the control group, but not in patients with IBS. These results indicate that the central pain inhibition deficit in IBS reflects interactions between several brain processes related to pain and attention.
Learn More >PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of repeat intravenous (IV) doses of the calcitonin gene-related peptide-targeted monoclonal antibody eptinezumab (ALD403) for migraine prevention in adults with chronic migraine. This report describes the results of PROMISE-2 through 24 weeks of treatment.
Learn More >Voltage-gated sodium (Na) channel subtypes, including Na1.7, are promising targets for the treatment of neurological diseases, such as chronic pain. Cone snail-derived µ-conotoxins are small, potent Na channel inhibitors which represent potential drug leads. Of the 22 µ-conotoxins characterised so far, only a small number, including KIIIA and CnIIIC, have shown inhibition against human Na1.7. We have recently identified a novel µ-conotoxin, SxIIIC, from . Here we present the isolation of native peptide, chemical synthesis, characterisation of human Na channel activity by whole-cell patch-clamp electrophysiology and analysis of the NMR solution structure. SxIIIC displays a unique Na channel selectivity profile (1.4 > 1.3 > 1.1 ≈ 1.6 ≈ 1.7 > 1.2 > 1.5 ≈ 1.8) when compared to other µ-conotoxins and represents one of the most potent human Na1.7 putative pore blockers (IC 152.2 ± 21.8 nM) to date. NMR analysis reveals the structure of SxIIIC includes the characteristic α-helix seen in other µ-conotoxins. Future investigations into structure-activity relationships of SxIIIC are expected to provide insights into residues important for Na channel pore blocker selectivity and subsequently important for chronic pain drug development.
Learn More >Previous studies examining the resting-state functional connectivity of the periaqueductal gray (PAG) in chronic visceral pain have localized PAG coordinates derived from BOLD responses to provoked acute pain. These coordinates appear to be several millimeters anterior of the anatomical location of the PAG. Therefore, we aimed to determine whether measures of PAG functional connectivity are sensitive to the localization technique, and if the localization approach has an impact on detecting disease-related differences in chronic visceral pain patients. We examined structural and resting-state functional MRI (rs-fMRI) images from 209 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. We applied three different localization techniques to define a region-of-interest (ROI) for the PAG: 1) a ROI previously-published as a Montreal Neurological Institute (MNI) coordinate surrounded by a 3 mm radius sphere (MNI-sphere), 2) a ROI that was hand-traced over the PAG in a MNI template brain (MNI-trace), and 3) a ROI that was hand-drawn over the PAG in structural images from 30 individual participants (participant-trace). We compared the correlation among the rs-fMRI signals from these PAG ROIs, as well as the functional connectivity of these ROIs with the whole brain. First, we found important non-uniformities in brainstem rs-fMRI signals, as rs-fMRI signals from the MNI-trace ROI were significantly more similar to the participant-trace ROI than to the MNI-sphere ROI. We then found that choice of ROI also impacts whole-brain functional connectivity, as measures of PAG functional connectivity throughout the brain were more similar between MNI-trace and participant-trace compared to MNI-sphere and participant-trace. Finally, we found that ROI choice impacts detection of disease-related differences, as functional connectivity differences between pelvic pain patients and healthy controls were much more apparent using the MNI-trace ROI compared to the MNI-sphere ROI. These results indicate that the ROI used to localize the PAG is critical, especially when examining brain functional connectivity changes in chronic visceral pain patients.
Learn More >The gut-brain axis is a coordinated communication system that not only maintains homeostasis, but significantly influences higher cognitive functions and emotions as well as neurological and behavioral disorders. Among the large populations of sensory and motor neurons that innervate the gut, insights into the function of primary afferent nociceptors whose cell bodies reside in the dorsal root ganglia and nodose ganglia, have revealed their multiple crosstalk with several cell types within the gut wall, including epithelial, vascular and immune cells. These bi-directional communications have immunoregulatory functions, control host response to pathogen, and modulate sensation associated with gastrointestinal disorders, through activation of immune cells and glia in the peripheral and central nervous system, respectively. Here we will review the cellular and neurochemical basis of these interactions at the periphery, in dorsal root ganglia and in the spinal cord. We will discuss the research gaps that should be addressed to get a better understanding of the multifunctional role of sensory neurons in maintaining gut homeostasis and regulating visceral sensitivity.
Learn More >Chronic postoperative pain affects approximately 20% of patients with knee osteoarthritis after total knee replacement. Circulating microRNAs can be found in serum and might act as biomarkers in a variety of diseases. The current study aimed to investigate the preoperative expression of circulating microRNAs as potential predictive biomarkers for the development of chronic postoperative pain in the year following total knee replacement.
Learn More >Pain is the most frequent cause triggering patients to visit a physician. The worldwide incidence of chronic pain is in the range of 20% of adults, and chronic pain conditions are frequently associated with several comorbidities and a drastic decrease in patients' quality of life. Although several approved analgesics are available, such therapy is often not satisfying due to insufficient efficacy and/or severe side effects. Therefore, novel strategies for the development of safe and highly efficacious pain killers are urgently needed. To reach this goal, it is necessary to clarify the causes and signal transduction cascades underlying the onset and progression of the different types of chronic pain. The papers in this Special Issue cover a wide variety of mechanisms involved in different pain types such as inflammatory, neuropathic or cancer pain. Therefore, the results summarized here might contribute to a better understanding of the mechanisms in chronic pain and thereby to the development of novel therapeutic strategies for pain patients.
Learn More >Neuropathic pain is a major problem following spinal cord injury (SCI). Central mechanisms involved in the modulation of nociceptive signals have been shown to be altered at the chronic stage, and it has been hypothesized that they might play a role in the development of chronic pain.
Learn More >Compared to the field of anxiety research, the use of fear conditioning paradigms for studying chronic pain is relatively novel. Developments in identifying the neural correlates of pain-related fear are important for understanding the mechanisms underlying chronic pain and warrant synthesis to establish the state-of-the-art. Using effect-size signed differential mapping, this meta-analysis combined nine MRI studies and compared the overlap in these correlates of pain-related fear to those of other non-pain-related conditioned fears (55 studies). Pain-related fear was characterized by neural activation of the supramarginal gyrus, middle temporal gyrus, inferior/middle frontal gyri, frontal operculum and insula, pre-/post-central gyri, medial frontal and (para-)cingulate cortex, hippocampus, thalamus, and putamen. There were differences with other non-pain-related conditioned fears, specifically in the inferior frontal gyrus, medial superior frontal gyrus, post-central gyrus, middle temporal gyrus, parieto-occipital sulcus, and striatum. We conclude that pain-related and non-pain-related conditioned fears recruit overlapping but distinguishable networks, with potential implications for understanding the mechanisms underlying different psychopathologies.
Learn More >The term 'mixed pain' is increasingly applied for specific clinical scenarios, such as low back pain, cancer pain and postsurgical pain, in which there "is a complex overlap of the different known pain types (nociceptive, neuropathic, nociplastic) in any combination, acting simultaneously and/or concurrently to cause pain in the same body area." Whether mixed pain is the manifestation of neuropathic and nociceptive mechanisms operating simultaneously or concurrently, or the result of an entirely independent pathophysiological mechanism – distinct from nociceptive, nociplastic and neuropathic pain – is currently unknown. At present, the diagnosis of mixed pain is made based on clinical judgement following detailed history-taking and thorough physical examination, rather than by formal confirmation following explicit screening or diagnostic criteria; this lack of formalized screening or diagnostic tools for mixed pain is problematic for physicians in primary care, who encounter patients with probable mixed pain states in their daily practice. This article outlines a methodical approach to clinical evaluation of patients presenting with acute, subacute or chronic pain, and to possibly identifying those who have mixed pain. The authors propose the use of nine simple key questions, which will provide the practicing clinician a framework for identifying the predominant pain mechanisms operating within the patient. A methodical, fairly rapid, and comprehensive assessment of a patient in chronic pain – particularly one suffering from pain with both nociceptive and neuropathic components – allows validation of their experience of chronic pain as a specific disease and, importantly, allows the institution of targeted treatment.
Learn More >Chronic pain is a life-altering condition affecting millions of people. Current treatments are inadequate and prolonged therapies come with severe side effects, especially dependence and addiction to opiates. Identification of non-narcotic analgesics is of paramount importance. Preclinical and clinical studies suggest that sphingolipid metabolism alterations contribute to neuropathic pain development. Functional sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) antagonists, such as FTY720/fingolimod, used clinically for non-pain conditions, are emerging as non-narcotic analgesics, supporting the repurposing of fingolimod for chronic pain treatment and energizing drug discovery focused on S1P signaling. Here, we summarize the role of S1P in pain to highlight the potential of targeting the S1P axis towards development of non-narcotic therapeutics, which, in turn, will hopefully help lessen misuse of opioid pain medications and address the ongoing opioid epidemic.
Learn More >Functional bowel disorders (FBDs) are the most common gastrointestinal problems managed by physicians. We aimed to assess the burden of chronic symptomatic FBDs on ambulatory care delivery in the United States and evaluate patterns of treatment.
Learn More >Accumulating evidence has highlighted the essential roles of cytokines in itch processing. Although IL-23 and Th17 cytokines are elevated in inflammatory skin disorders, their role in itch is unknown. Here we investigated the role of IL-23 and IL-17A in itch response using an in vitro calcium imaging of mouse dorsal root ganglion (DRG) neurons and an in vivo behavior test. Calcium imaging studies revealed that a few DRG neurons (~5%) responded to either IL-23 or IL-17A. Pre-treatment cells with IL-23 significantly reduced calcium responses to histamine and capsaicin but not chloroquine. Behavior experiments showed neither IL-23 nor IL-17A evoked scratching. IL-23 significantly decreased histamine-evoked scratching without affecting chloroquine-evoked scratching. There was no difference in scratching between IL-17A- and vehicle-treated groups. These results indicate that IL-23 might play a role in regulating histaminergic itch via modulation of TRPV1 activity.
Learn More >Migraine is a highly heritable complex brain disorder, imposing a huge burden of disability on sufferers. The genetic architecture of migraine ranges from the rare Mendelian forms whereby a single gene mutation is sufficient to cause disease to gene variants that individually impart only a small increase in migraine risk. Despite the considerable advances in the last decade, there are significant challenges to translate genetic findings into drug targets and eventually successful treatments. The need for such treatments remains, even with the new wave of biological therapies targeting CGRP or the CGRP receptor. This will require integration of genetic data with new technologies such as human stem cell models of migraine that allow the interpretation of genetic risk into disease relevant cellular phenotypes. This was recently undertaken for the first time in migraine, whereby stem cells from patients with the rare TRESK frameshift mutation converted into pain sensory neurons demonstrated hyper-excitability. The continued study of the molecular basis of migraine thus offers new paths to drug targets and precision medicine approaches.
Learn More >The current review provides a recapitulation of recent advances in pharmacological neuroimaging in headache, a promising tool to understanding of how a drug works in the brain and how it may lead to new insights of disease mechanisms of headache.
Learn More >The visual network is crucially implicated in the pathophysiology of migraine. Several lines of evidence indicate that migraine is characterized by an altered visual cortex excitability both during and between attacks. Visual symptoms, the most common clinical manifestation of migraine aura, are likely the result of cortical spreading depression originating from the extrastriate area V3A. Photophobia, a clinical hallmark of migraine, is linked to an abnormal sensory processing of the thalamus which is converged with the non-image forming visual pathway. Finally, visual snow is an increasingly recognized persistent visual phenomenon in migraine, possibly caused by increased perception of subthreshold visual stimuli. Emerging research in non-invasive brain stimulation (NIBS) has vastly developed into a diversity of areas with promising potential. One of its clinical applications is the single-pulse transcranial magnetic stimulation (sTMS) applied over the occipital cortex which has been approved for treating migraine with aura, albeit limited evidence. Studies have also investigated other NIBS techniques, such as repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS), for migraine prophylaxis but with conflicting results. As a dynamic brain disorder with widespread pathophysiology, targeting migraine with NIBS is challenging. Furthermore, unlike the motor cortex, evidence suggests that the visual cortex may be less plastic. Controversy exists as to whether the same fundamental principles of NIBS, based mainly on findings in the motor cortex, can be applied to the visual cortex. This review aims to explore existing literature surrounding NIBS studies on the visual system of migraine. We will first provide an overview highlighting the direct implication of the visual network in migraine. Next, we will focus on the rationale behind using NIBS for migraine treatment, including its effects on the visual cortex, and the shortcomings of currently available evidence. Finally, we propose a broader perspective of how novel approaches, the concept of brain networks and the integration of multimodal imaging with computational modeling, can help refine current NIBS methods, with the ultimate goal of optimizing a more individualized treatment for migraine.
Learn More >Calcitonin Gene-Related Peptide (CGRP) plays a pivotal role in migraine pathophysiology. Two types of CGRP function-blocking modalities, monoclonal antibodies, and small molecules (gepants), have been developed to target the CGRP ligands and CGRP receptors. Four CGRP monoclonal antibodies have received FDA approval for the prevention of migraine: erenumab, fremanezumab, galcanezumab, and eptinezumab. Two gepants have been approved by the FDA for the acute treatment of migraine: ubrogepant and rimegepant. Multiple clinical trials of the CGRP monoclonal antibodies and gepants, and now some open-label long-term extension data, established their efficacy, safety, and tolerability. In this chapter, we summarize the major clinical trials, pharmacokinetic insights, safety and tolerability profiles, and real-world data (if available) of the CGRP monoclonal antibodies and gepants.
Learn More >The noradrenergic locus coeruleus nucleus is an important station in both the ascending and descending pain regulatory pathways. These neurons discharge in tonic and phasic modes in response to sensory stimuli. However, few studies have set out to characterize the electrophysiological response of the locus coeruleus to noxious stimuli in conditions of neuropathic pain. Thus, the effects of mechanical nociceptive stimulation of the sciatic nerve area on spontaneous (tonic) and sensory-evoked (phasic) locus coeruleus discharge were studied by extracellular recording in anesthetized rats seven, fourteen and twenty-eight days after chronic constriction injury. Minor significant electrophysiological changes were found seven and fourteen days after nerve injury. However, alterations to the spontaneous activity in both the ipsilateral and contralateral locus coeruleus were found twenty-eight days after nerve constriction, as witnessed by an increase of burst firing incidence and irregular firing patterns. Furthermore, noxious-evoked responses were exacerbated in the contralateral and ipsilateral nucleus at twenty-eight days after injury, as were the responses evoked when stimulating the uninjured paw. In addition, mechanical stimulation of the hindpaw produced a significant sensitization of neuronal tonic activity after 28 days of neuropathy. In summary, long-term nerve injury led to higher spontaneous activity and exacerbated noxious-evoked responses in the locus coeruleus to stimulation of nerve-injured and even uninjured hindpaws, coinciding temporally with the development of depressive and anxiogenic-like behavior.
Learn More >PKC and PKA phosphorylation inhibit TREK-1 channels downstream of G protein-coupled receptor activation in vitro. However, the role of phosphorylation of TREK-1 in neuropathic pain is unknown. The purpose of this study was to investigate whether altered TREK-1 channel function by PKA and PKC modulators contributes to antiallodynia in neuropathic rats. Furthermore, we investigated if the in vitro described sites for PKC and PKA phosphorylation (S300 and S333, respectively) participate in the modulation of TREK-1 in naïve and neuropathic rats. L5/L6 spinal nerve ligation (SNL) induced tactile allodynia. Intrathecal injection of BL-1249 (TREK-1 activator) reversed nerve injury-induced tactile allodynia, whereas spadin (TREK-1 blocker) produced tactile allodynia in naïve rats and reversed the antiallodynic effect induced by BL-1249 in neuropathic rats. Intrathecal administration of rottlerin or Rp-cAMPs (PKC and PKA inhibitors, respectively) enhanced the antiallodynia observed with BL-1249 in neuropathic rats. In contrast, pretreatment with PdBu or forskolin (PKC and PKA activators, respectively) reduced the BL-1249-induced antiallodynia. Intrathecal injection of two high-activity TREK-1 recombinant channels, using a in vivo transfection method with lipofectamine, with mutations at PKC/PKA phosphosites (S300A and S333A) reversed tactile allodynia in neuropathic rats, with no effect in naïve rats. In contrast, transfection of two low-activity TREK-1 recombinant channels with phosphomimetic mutations at those sites (S300D and S333D) produced tactile allodynia in naïve rats and interfered with antiallodynic effects of rottlerin/BL-1249 or Rp-cAMPs/BL-1249. Data suggest that TREK-1 channel activity can be dynamically tuned in vivo by PKC/PKA to provoke allodynia and modulate its antiallodynic role in neuropathic pain.
Learn More >Chronic pain is a leading cause of disability in low- and middle-income countries; however, pain assessment tools have generally been developed and validated in high-income countries. This study examines the psychometric properties of a set of translated pain (and distress) questionnaires in Mongolia and documents the characteristics of people seeking treatment for chronic pain in Mongolia, compared with those in New Zealand, which is representative of high-income countries.
Learn More >To develop and internally validate a multivariable predictive model for days with new-onset migraine headaches based on patient self-prediction and exposure to common trigger factors.
Learn More >The double-blind, phase 3 PREEMPT trials demonstrated the efficacy and tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. This post hoc analysis evaluated the effect of onabotulinumtoxinA on clinically meaningful changes in headache severity, headache-related impact, and quality of life.
Learn More >The phase 3 PREEMPT trials demonstrated efficacy and tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. OnabotulinumtoxinA significantly reduced headache frequency from baseline vs. placebo at 24 weeks; however, this measure may not fully capture the benefits of treatment. We evaluated the impact of onabotulinumtoxinA on patient-reported outcomes according to headache responder status.
Learn More >Slowly depolarizing currents applied for 1 min have been shown to activate C-nociceptors and provoke increasing pain in patients with neuropathy. This study examined the effect of transcutaneous slowly depolarizing currents on pruritus in patients with atopic dermatitis. C-nociceptor-specific electrical stimu-lation was applied to areas of eczema-affected and non-affected skin in 26 patients with atopic dermatitis. Single half-sine wave pulses (500 ms, 0.2-1 mA) induced itch in 9 patients in the eczema (numerical rating scale 5 ± 1), but pain in control skin (numerical rating scale 6 ± 1). Sinusoidal stimuli (4 Hz, 10 pulses, 0.025-0.4 mA) evoked itch in only 3 patients, but on delivering pulses for 1 min (0.05-0.2 mA) approximately 50% of the patients (n = 12) reported itch with numerical rating scale 4 ± 1 in areas of eczema-affected skin. The number of patients reporting itch increased with longer stimulation (p < 0.005). These results indicate a reduced adaptation of peripheral C-fibres conveying itch in patients with AD. Also, sensitized spinal itch processing may underlie chronic itch in these patients, who might benefit from centrally acting antipruritic therapy.
Learn More >The pathophysiological differences between menstrually-related migraine (MRM) and pure menstrual migraine (PMM) are largely unclear. The aim of this study was to investigate the potential differences in brain structure and function between PMM and MRM. Forty-eight menstrual migraine patients (32 MRM; 16 PMM) were recruited for this study. Voxel-based morphometry (VBM) was applied on structural magnetic resonance imaging (sMRI), and the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) in resting state functional MRI (rsfMRI) were calculated. No significant between-group difference was observed in the grey matter volume (GMV). MRM patients exhibited lower ALFF values at the dorsolateral prefrontal cortex (DLPFC) and medial prefrontal cortex (mPFC) than PMM patients. Moreover, the MRM group showed significantly higher ReHo values in the DLPFC. Higher values in the mPFC were related to higher expression of calcitonin gene-associated peptide (CGRP) in the PMM group (r = 0.5, P = 0.048). Combined ALFF and ReHo analyses revealed significantly different spontaneous neural activity in the DLPFC and mPFC, between MRM and PMM patients, and ALFF values in the mPFC were positively correlated with CGRP expression, in the PMM group. This study enhances our understanding of the relationship between neural abnormalities and CGRP expression in individuals with PMM.
Learn More >Pain is an increasingly recognized non-motor symptom of Parkinson's disease (PD), with significant prevalence and strong impact on quality of life of patients. Moreover, pain can occur with various features in PD and several subtypes may coexist in a same patient, leading to a complex presentation and difficult diagnosis and treatment. In this paper we review the clinical manifestations of painful phenomena in PD, with focus on classifications and algorithms allowing to standardize the diagnosis of pain and PD. We also discuss the pathophysiological mechanisms underlying pain in PD, particularly parkinsonian central pain, in regard to recent clinical, neurophysiological and imaging studies.
Learn More >Low dose ketamine is a leading medication used to provide analgesia in pre-hospital and hospital settings. Low dose ketamine is increasingly used off-label to treat conditions such as depression. In animals, ketamine stimulates the sympathetic nervous system and increases blood pressure, but these physiological consequences have not been studied in conscious humans. Our data suggest that low dose ketamine administration blunts pain perception and reduces blood pressure, but not muscle sympathetic nerve activity burst frequency, responses during a cold pressor test in healthy humans. These mechanistic, physiological results inform risk-benefit analysis for clinicians administering low dose ketamine in humans.
Learn More >P2X3 monomeric receptors (P2X3Rs) and P2X2/3 heteromeric receptors (P2X2/3Rs) in primary sensory neurons and microglial P2X4 monomeric receptors (P2X4Rs) in the spinal dorsal horn (SDH) play important roles in neuropathic pain. In particular, P2X4R in the spinal microglia during peripheral nerve injury (PNI), experimental autoimmune neuritis, and herpes models are useful to explore the potential strategies for developing new drugs to treat neuropathic pain. Recently, novel P2X4 antagonists, NP-1815-PX and NC-2600, were developed, which demonstrated potent and specific inhibition against rodent and human P2X4Rs. The phase I study of NC-2600 has been completed, and no serious side effects were reported. The roles played by purinergic receptors in evoking neuropathic pain provide crucial insights into the pathogenesis of neuropathic pain.
Learn More >The development of persistent pain following total knee arthroplasty (TKA) is common, but its underlying mechanisms are unknown. The goal of the study was to assess brain grey matter structure and its correlation with function of the nociceptive system in people with good and poor outcomes following TKA.
Learn More >Musculoskeletal pain alters physiological function, which may be evidenced as early as middle age. Previous research has concluded that middle-aged adults are a high-risk group for musculoskeletal pain and report functional limitations similar to older adults. However, few studies have examined the relationships between musculoskeletal pain and physical function, using objective performance measures in a sample of racially and socioeconomically diverse adults. Thus, this study examined musculoskeletal pain in relation to physical function in middle-aged (30-64 years) White and Black adults, and investigated whether the relationship varied by sociodemographic characteristics.
Learn More >Migraine is a common and highly disabling headache disorder associated with a substantial socioeconomic burden. Migraine treatments can be categorized as preventive treatment, aimed at reducing the frequency and severity of migraine attacks, and acute therapy, intended to abort attacks. Traditionally, acute treatment can be classified as specific (ergot derivatives and triptans) or nonspecific (analgesics and nonsteroidal anti-inflammatory drugs). Triptans, a class of 5-HT receptor agonists with some affinity for the 5-HT receptor subtype, have been proven to be efficacious for acute treatment of moderate to severe migraine and have been deemed the gold standard. The availability of triptans in non-oral formulations, such as subcutaneous (SC) and intranasal forms, can be beneficial for patients who suffer from prominent nausea or vomiting, have a suboptimal response to oral agents, and/or seek a more rapid onset of treatment effects. However, triptans are contraindicated in patients with preexisting cardiovascular and/or cerebrovascular diseases due to their 5-HT-mediated vasoconstrictive action. For this reason, studies have focused on the development of ditans, a group of antimigraine drugs targeting 5-HT and 5-HT receptors. Unfortunately, 5-HT receptor agonists have been shown to be ineffective in the acute treatment of migraine. Several ditans targeting the 5-HT receptor have been developed and have shown no vasoconstrictive effect in preclinical studies, but only two of them, lasmiditan and LY334370, have been tested in clinical trials for migraine, and only lasmiditan has reached to Phase III clinical trials. These Phase III trials have demonstrated the efficacy and safety of lasmiditan, a selective 5-HT receptor agonist, in acute migraine treatment. Lasmiditan might offer an alternative migraine therapy without cardiovascular risks. This review will summarize the development of agents targeting the 5-HT and 5-HT receptors and the clinical evidence supporting the use of these agents for acute migraine treatment.
Learn More >Migraine is among the most common and disabling neurological diseases in the world. Cortical spreading depression (CSD) is a wave of near-complete depolarization of neurons and glial cells that slowly propagates along the cortex creating the perception of aura. Evidence suggests that CSD can trigger migraine headache. Experimental models of CSD have been considered highly translational as they recapitulate migraine-related phenomena and have been validated for screening migraine therapeutics. Here we outline the essential components of validated experimental models of CSD and provide a comprehensive review of potential modulators and targets against CSD. We further focus on novel interventions that have been recently shown to suppress CSD susceptibility that may lead to therapeutic targets in migraine.
Learn More >The earliest descriptions of botulism were in the early 19th century, and was reported by the German physician Justinus Kerner. The term "botulism" was derived from the Latin word botulus, indicating its original association with sausages. It took another 150 years or so to come into clinical use. The first clinical application was strabismus, and was developed by the American ophthalmologist Alan B. Scott, whose effort led to the pharmaceutical product known as onabotulinumtoxinA today. The therapeutic benefit in migraine was an incidental finding in a report by the American plastic surgeon William J. Binder, which inspired a series of clinical studies in headache disorders. The doses and injection techniques in the earlier reports were variable, so were the results. It was until the Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) 1 and 2 studies when its efficacy and safety, as well as the indication, i.e., chronic migraine (CM), were ascertained. Even though there were criticisms regarding the heterogeneities in the results between the PREEMPT 1 and 2 studies, the data on efficacy endpoints and safety were generally consistent, which were subsequently confirmed by the open-label extension of the PREEMPT 1 and 2 studies, and three open-label studies, namely the Chronic Migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL), the REal-life use of botulinum toxin for the symptomatic treatment of adults with chronic migraine, measuring healthcare resource utilization, and Patient-reported OutcomeS observed in practice (REPOSE) studies, and the CM Post-Authorization Safety Study (CM PASS) studies. On the other hand, the results were challenged by the Chronification and Reversibility of Migraine (CHARM) study, which involved CM patients with medication overuse. It was concluded that the clinical improvement was attributed to early withdrawal of the overused acute medications, rather than onabotulinumtoxinA injections. However, fundamental differences in the patient profile and methodology between the CHARM and PREEMPT studies existed, and cautious should be exercised when interpreting and comparing the results. According to the practical guidelines and reimbursement regulations in many countries, its use is limited to CM patients, and is reserved for those who fail at least 2-3 preventive medications, due to either lack of efficacy or intolerability. Cessation of treatment is recommended in patients who do not respond to 2-3 injection cycles, or in patients whose headache frequency has dropped to <10-15 days a month. Even in the era of calcitonin-gene-related peptide monoclonal antibodies, onabotulinumtoxinA injection remains a treatment option of reasonable cost-effectiveness in carefully selected patients.
Learn More >Chronic pelvic pain (CPP) affects a significant number of women worldwide. Internationally, people with endometriosis report significant negative impact across many areas of their life. We aimed to use an online survey using the EndoCost tool to determine if there was any difference in the impact of CPP in those with vs. those without a confirmed diagnosis of endometriosis, and if there was any change in diagnostic delay since the introduction of clinical guidelines in 2005. 409 responses were received; 340 with a diagnosis of endometriosis and 69 with no diagnosis. People with CPP, regardless of diagnosis, reported moderate to severe dysmenorrhea and non-cyclical pelvic pain. Dyspareunia was also common. Significant negative impact was reported for social, academic, and sexual/romantic relationships in both cohorts. In the endometriosis cohort there was a mean diagnostic delay of eight years, however there was a reduction in both the diagnostic delay (p < 0.001) and number of doctors seen before diagnosis (p < 0.001) in those presenting more recently. Both endometriosis and CPP have significant negative impact. Whilst there is a decrease in the time to diagnosis, there is an urgent need for improved treatment options and support for women with the disease once the diagnosis is made.
Learn More >Although pain treatment has been described as a fundamental human right, the Coronavirus disease 2019 (COVID-19) pandemic forced healthcare systems worldwide to redistribute healthcare resources toward intensive care units and other COVID-19 dedicated sites. As most chronic pain services were subsequently deemed non-urgent, all outpatient and elective interventional procedures have been reduced or interrupted during the COVID-19 pandemic in order to reduce the risk of viral spread. The shutdown of pain services jointly to the home lockdown imposed by governments has affected chronic pain management worldwide with additional impact on patients' psychological health. Therefore, the aim of this review is to analyze the impact of COVID-19 pandemic on chronic pain treatment and to address what types of strategies can be implemented or supported in order to overcome imposed limitations in delivery of chronic pain patient care.
Learn More >Alcohol use disorder (AUD) is a chronic, relapsing psychiatric disorder that is characterized by the emergence of negative affective states. The transition from recreational, limited intake to uncontrolled, escalated intake is proposed to involve a transition from positive to negative reinforcement mechanisms for seeking alcohol. Past work has identified the emergence of significant hyperalgesia/allodynia in alcohol-dependent animals, which may serve as a key negative reinforcement mechanism. Chronic pain has been associated with enhanced extracellular signal-regulated kinase (ERK) activity in cortical and subcortical nociceptive areas. Additionally, both pain and AUD have been associated with increased activity of the glucocorticoid receptor (GR), a key mediator of stress responsiveness. The objectives of the current study were to first determine relationships between thermal nociceptive sensitivity and alcohol drinking in male Wistar rats. While inflammatory pain induced by complete Freund's adjuvant (CFA) administration did not modify escalation of home cage drinking in animals over four weeks, the relationship between drinking levels and hyperalgesia symptoms reversed between acute (1 week) and chronic (3-4 week) periods post-CFA administration, suggesting that either the motivational or analgesic effects of alcohol may be altered over the time course of chronic pain. We next examined ERK and GR phosphorylation in pain-related brain areas (including the central amygdala and prefrontal cortex subregions) in animals experiencing acute withdrawal from binge alcohol administration (2 g/kg, 6 h withdrawal) and CFA administration (four weeks) to model the neurobiological consequences of binge alcohol exposure in the context of pain. We observed a significant interaction between alcohol and pain state, whereby alcohol withdrawal increased ERK phosphorylation across all four frontocortical areas examined, although this effect was absent in animals experiencing chronic inflammatory pain. Alcohol withdrawal also increased GR phosphorylation across all four frontocortical areas, but these changes were not altered by CFA. Interestingly, we observed significant inter-brain regional correlations in GR phosphorylation between the insula and other regions investigated only in animals exposed to both alcohol and CFA, suggesting coordinated activity in insula circuitry and glucocorticoid signaling in this context. The results of these studies provide a greater understanding of the neurobiology of AUD and will contribute to the development of effective treatment strategies for comorbid AUD and pain.
Learn More >Migraine patients prioritize early complete relief of headache and associated symptoms, sustained freedom of pain, and good tolerability. One major obstacle for the successful use of drug treatment of migraine attack is that the speed of action of triptans, 5-HT receptor agonists, is delayed.
Learn More >The goal of this study is to determine the strength of association between treatment with triptans and acute myocardial infarction, heart failure, and death.
Learn More >Complex regional pain syndrome (CRPS) is a complex and often poorly understood condition, and people with CRPS will have diverse beliefs about their symptoms. According to the self-regulation model, these beliefs (termed "illness perceptions") influence health behaviors and outcomes. Previous studies have found that psychological factors influence CRPS outcomes, but few studies have investigated CRPS patients' illness perceptions specifically. The present study examined whether illness perceptions were related to pain intensity and other relevant outcomes in people with CRPS.
Learn More >To evaluate whether quarterly or monthly administration of fremanezumab for migraine prevention exhibits a pattern of decreased efficacy towards the end of the dosing interval (wearing-off effect).
Learn More >An itch is defined as an unpleasant sensation that evokes a desire to scratch. Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system and has a crucial role in pruriceptive processing in the spinal dorsal horn. It is well known that glutamate exerts its effects by binding to various glutamate receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and that AMPA/kainate receptors play a crucial role in pruriceptive processing; however, the precise role of AMPA receptors remains uncertain. Perampanel, an antiepileptic drug, is an antagonist of AMPA receptors. Pretreatment with perampanel dose-dependently attenuated the induction of scratching, a behavior typically associated with pruritus, by intradermal administration of the pruritogen chloroquine. In addition, the induction of scratching in mice painted with diphenylcyclopropenone and NC/Nga mice treated with Biostir AD, animal models of contact dermatitis and atopic dermatitis, respectively, was dose-dependently alleviated by administration of perampanel. These findings indicate that AMPA receptors play a crucial role in pruriceptive processing in mice with acute or chronic pruritus.
Learn More >This international multidisciplinary consensus statement was developed to provide balanced guidance on the safe peri-operative use of opioids in adults. An international panel of healthcare professionals evaluated the literature relating to postoperative opioid-related harm, including persistent postoperative opioid use; opioid-induced ventilatory impairment; non-medical opioid use; opioid diversion and dependence; and driving under the influence of prescription opioids. Recommended strategies to reduce harm include pre-operative assessment of the risk of persistent postoperative opioid use; use of an assessment of patient function rather than unidimensional pain scores alone to guide adequacy of analgesia; avoidance of long-acting (modified-release and transdermal patches) opioid formulations and combination analgesics; limiting the number of tablets prescribed at discharge; providing deprescribing advice; avoidance of automatic prescription refills; safe disposal of unused medicines; reducing the risk of opioid diversion; and better education of healthcare professionals, patients and carers. This consensus statement provides a framework for better prescribing practices that could help reduce the risk of postoperative opioid-related harm in adults.
Learn More >Although exercise is associated with better outcomes in patients with some peripheral neuropathies, data in idiopathic peripheral neuropathies is lacking. This study was completed to do a comprehensive data analysis about the benefits of regular exercise in a well-characterized cohort of patients with idiopathic distal, symmetrical, axonal polyneuropathy enrolled in the Peripheral Neuropathy Research Registry (PNRR) at Johns Hopkins University School of Medicine.
Learn More >Pruritus is one of the leading symptoms of dermatitis herpetiformis (DH), however, studies on the pathogenesis of pruritus are scarce. Currently, skin mast cells (MCs) have been indicated to play a role in pruritus in autoimmune bullous disease.
Learn More >Sensitization mechanisms are thought to play a role in the perception of pain in people with cluster headache. No study has investigated the relation between the spatial extent of pain in cluster headache and measures of sensitization or other clinical features. : Our aim was to investigate if the size of the painful area in people with cluster headache relates to widespread pressure sensitivity, headache features, and psychological outcomes. : Forty men with episodic cluster headache reported their symptoms on a digital body chart and pain extent was calculated. Pressure pain thresholds were assessed locally over the temporalis muscle and the C5-C6 joint and at a remote site over the tibialis anterior to assess widespread pressure sensitivity. Clinical features of headache attacks, and anxiety/depressive levels were also assessed. Patients were assessed during a period of remission 6 months after their last pain attack and after treatment discontinuation. : Thirty-two (80%) and thirty (75%) patients reported their headaches in the orbital and the frontal areas, respectively. No significant associations (rho values ranging from -0.228 to 0.187, values ranging from 0.157 to 0.861) were found between pain extent and pressure pain thresholds in trigeminal, extra-trigeminal, and distant pain-free areas, headache clinical features, and anxiety and depressive levels. : Pain extent in the trigemino-cervical area was not related to the degree of pressure pain sensitivity or headache features in men with episodic cluster headache during a period of remission.
Learn More >There is growing consensus that pain in pediatric inflammatory bowel disease (IBD) is not fully explained by disease-related processes. However, previous studies have largely measured individual biological, psychological, or social risk factors for pain in isolation. Further, not all youth with IBD presenting to clinic will report presence of pain, and those who do vary in their reports of pain intensity. This study therefore extends prior research by determining biopsychosocial correlates of both presence and intensity of pain in adolescents with IBD, in order to inform targeted pain management intervention approaches. Adolescents with IBD followed at SickKids, Toronto, and their parents were consecutively enrolled from outpatient clinic. IBD characteristics (diagnosis, time since diagnosis, patient-reported disease activity) were collected. Adolescents reported on current pain (NRS-10), internalizing symptoms (Strengths and Difficulties Questionnaire), and pain catastrophizing (Pain Catastrophizing Scale-Child). Parents reported on protective responses to child pain (Adult Responses to Child Pain) and pain catastrophizing (Pain Catastrophizing Scale-Child). Hurdle models were conducted to examine predictors of presence and intensity of pain in the same model. Biological (patient-reported disease activity, IBD diagnosis subtype, illness duration), psychological (internalizing symptoms, pain catastrophizing), and social (parent pain catastrophizing, parent protective responses) factors were entered as predictors, adjusting for age and sex. Participants included 100 adolescents (12-18; = 15 years) with IBD (60% Crohn's Disease, 40% Ulcerative Colitis or IBD-unclassified) and 76 parents. The majority of the sample was in clinical remission or reported minimal symptoms. Half of participants reported no current pain; for those reporting pain, intensity ranged 1-7 ( = 3.43, SD = 1.98). Disease activity (OR = 53.91, < 0.001) and adolescent internalizing symptoms (OR = 7.62, = 0.03) were significant predictors of presence of pain. Disease activity (RR = 1.37, = 0.03) and parent protective responses (RR = 1.45, = 0.02) were significant predictors of intensity of pain. Results suggest that the experience of pain in pediatric IBD is biopsychosocially determined. Patient-reported disease activity and internalizing symptoms predicted presence of pain, while disease activity and parent protective responses predicted intensity of pain. While medical intervention in pediatric IBD is focused on disease management, results suggest that depression/anxiety symptoms as well as parent protective responses may be important targets of pain management interventions in pediatric IBD.
Learn More >Murine models have demonstrated that the major histocompatibility complex (MHC) is associated with pain-like behavior in peripheral nerve injury, however, the same association has not been shown when considering injury to the central nervous system (CNS), which more closely mimics the damage to the CNS experienced by MS patients. Previous research has indicated the DQB103:02 allele of the class II HLA genes as being associated with development of neuropathic pain in persons undergoing inguinal hernia surgery or with lumbar spinal disk herniation. Whether this HLA allele plays a part in susceptibility to pain, has not, as far as we are aware, been previously investigated. This study utilizes information on DQB103:02 alleles as part of the EIMS, GEMS, and IMSE studies in Sweden. It also uses register data for 3,877 MS patients, and 4,548 matched comparators without MS, to assess whether the DQB103:02 allele is associated with prescribed pain medication use, and whether associations with this genotype differ depending on MS status. Our results showed no association between the DQB103:02 genotype and pain medication in MS patients, with an adjusted odds ratio (OR) of 1.02 (95% CI 0.85-1.24). In contrast, there was a statistically significant association of low magnitude in individuals without MS [adjusted OR 1.18 (95% CI 1.03-1.35)], which provides support for HLA influence on susceptibility to pain in the general population. Additionally, the effect of zygosity was evident for the non-MS cohort, but not among MS patients, suggesting the DQB103:02 allele effect is modified by the presence of MS.
Learn More >Long-term opioid therapy has the potential for serious adverse outcomes and is often used in a vulnerable population. Because adverse effects or failure to maintain benefits is common with long-term use, opioid taper or discontinuation may be indicated in certain patients. Concerns about the adverse individual and population effects of opioids have led to numerous strategies aimed at reductions in prescribing. Although opioid reduction efforts have had generally beneficial effects, there have been unintended consequences. Abrupt reduction or discontinuation has been associated with harms that include serious withdrawal symptoms, psychological distress, self-medicating with illicit substances, uncontrolled pain, and suicide. Key questions remain about when and how to safely reduce or discontinue opioids in different patient populations. Thus, health care professionals who reduce or discontinue long-term opioid therapy require a clear understanding of the associated benefits and risks as well as guidance on the best practices for safe and effective opioid reduction. An interdisciplinary panel of pain clinicians and one patient advocate formulated recommendations on tapering methods and ongoing pain management in primary care with emphasis on patient-centered, integrated, comprehensive treatment models employing a biopsychosocial perspective.
Learn More >Apelin is an endogenous neuropeptide, which has wide distribution in central nervous system and peripheral tissues. Pyroglutamyl apelin-13 [(pyr)apelin-13] is the major apelin isoform in human plasma. However, the role of peripheral (pyr)apelin-13 in pain regulation is unknown. The aim of this study was to investigate the effect of the peripheral injection of (pyr)apelin-13 on inflammatory pain using the formalin test as well as to evaluate the mechanistic basis for the effect. Results showed intravenous (i.v.) injection of (pyr)apelin-13 (10, 20 mg/kg) to significantly decrease licking/biting time during the second phase of the mouse formalin test. In contrast, i.v. injection of apelin-13 had no influence on such effect. Intramuscular injection of (pyr)apelin-13 reduced licking/biting time during the second phase only at a dose of 20 mg/kg. The antinociception of i.v. (pyr)apelin-13 was antagonized by the apelin receptor (APJ, angiotensin II receptor-like 1) antagonist, apelin-13(F13A). (pyr)apelin-13 (i.v. 20 mg/kg) markedly upregulated and gene expression in the prefrontal cortex, whereas gene expression was downregulated. The antinociception of i.v. (pyr)apelin-13 was blocked by the opioid receptor antagonist naloxone and the specific kappa opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI). (pyr)Apelin-13 upregulated the dynorphin and KOR gene expression and protein levels in the mouse prefrontal cortex, not in striatum. (pyr)Apelin-13 did not influence the motor behavior. Our results demonstrate that i.v. injection of (pyr)apelin-13 induces antinociception via the KOR in the inflammatory pain mouse model.
Learn More >Both parental and child factors have been previously associated with persistent or recurrent postoperative pain in children. Yet, little is known about the relative contribution of parent factors or whether child symptom factors might impact the association between parent factors and long-term pain. The aim of this study was to explore the associations between parent factors, child symptomology and the child's long-term pain outcomes after surgery.
Learn More >This is a comprehensive review of the current literature on the usage of galcanezumab for migraine treatment. It reviews the biology, pathophysiology, epidemiology, diagnosis, and conventional treatment of migraines, then compares the literature available for galcanezumab with historical treatment options.
Learn More >Current therapies for the treatment of chronic pain provide inadequate relief for millions of suffering patients, demonstrating the need for better therapies that will treat pain effectively and improve the quality of patient's lives. Better understanding of the mechanisms that mediate chronic pain is critical for developing drugs with improved clinical outcomes. Adenosine triphosphate (ATP) is a key modulator in nociceptive pathways. Release of ATP from injured tissue or sympathetic efferents has sensitizing effects on sensory neurons in the periphery, and presynaptic vesicular release of ATP from the central terminals can increase glutamate release thereby potentiating downstream central sensitization mechanisms, a condition thought to underlie many chronic pain conditions. The purinergic receptors on sensory nerves primarily responsible for ATP signaling are P2X3 and P2X2/3. Selective knockdown experiments, or inhibition with small molecules, demonstrate P2X3-containing receptors are key targets to modulate nociceptive signals. Preclinical studies have identified that P2X3-containing receptors are critical for sensory transduction for bladder function, and clinical studies have shown promise in treatment for bladder pain and pain associated with osteoarthritis. Further clinical characterization of antagonists to P2X3-containing receptors may lead to improved therapies in the treatment of chronic pain.
Learn More >Melatonin is a ubiquitously distributed molecule that possesses diverse functions. Melatonin plays a key role in the endogenous circadian rhythms of humans via light stimulation in the hypothalamus. In addition, melatonin has roles in the opioid system, the nitric oxide pathway, free radical scavenging, inflammation, and antinociception. Melatonin is nontoxic and relatively safe. Recently, exogenous melatonin has been shown to have significant effects in the treatment of migraine. Further, it has demonstrated efficacy in the treatment of sleep disorders, including insomnia, circadian rhythm sleep-wake disorders, parasomnias, and sleep breathing disorders. Sleep disorders are commonly reported by those who experience migraine, and migraine and sleep disorders have been reported to be closely associated in cross-sectional studies. Longitudinal studies have shown that some sleep disorders and migraine show bidirectional comorbidities. Therefore, the identification and treatment of sleep disorders is important when treating migraine. Melatonin represents a promising treatment strategy for both disorders, especially when these conditions are combined.
Learn More >Medication overuse headache (MOH), previously known as analgesic abuse headache or medication misuse headaches, is a common form of chronic headache disorder that has a detrimental impact on health and society. Although it has been widely accepted that overusing abortive medications is paradoxically the cause of MOH and drug discontinuation is the treatment of choice, ongoing debates exist as to whether drug consumption per se is the cause or consequence of headache chronification. Certain features in MOH such as their compulsive drug-seeking behavior, withdrawal headaches and high relapse rates share similarities with drug dependence, suggesting that there might be common underlying biological and psychobehavioral mechanisms. In this regard, this article will discuss the updated evidence and current debates on the possible biobehavioral overlap between MOH and drug dependence. To begin with, we will discuss whether MOH has characteristics of substance dependence based on standard psychiatry diagnostic criteria and other widely used dependence scales. Recent epidemiological studies underscoring common psychiatric comorbidities between the two disorders will also be presented. Although both demonstrate seemingly distinct personality traits, recent studies revealed similar decision-making impairment from a cognitive perspective, indicating the presence of a maladaptive reward system in both disorders. In addition, emerging imaging studies also support this notion by showing reversible morphological and functional brain changes related to the mesocorticolimbic reward circuitry in MOH, with a strong resemblance to those in addiction. Finally, an increased familial risk for drug dependence and genetic association with dopaminergic and drug dependence molecular pathways in MOH also support a possible link between MOH and addiction. Understanding the role of dependence in MOH will have a great impact on disease management as this will provide the missing piece of the puzzle in current therapeutic strategies.
Learn More >Migraine is a prevalent disorder with high disability and socioeconomic costs. Preventive treatment has been shown to decrease headache frequency, improve quality of life and minimize the medical expenses. Although many medications have been proved effective, they are underutilized. For the past several years, significant progress has been made with the emerging options of calcitonin-gene related peptide (CGRP) monoclonal antibodies and antagonists. The choices of these medications depend on not only the evidences of effects and possible side effects of the medications but also comorbidities, preferences and even special considerations of the individual patient such as breast feeding and reproduction.
Learn More >To test the relationship between the supply of select nonpharmacologic providers (physical therapy (PT) and mental health (MH)) and use of nonpharmacologic services among older adults with a persistent musculoskeletal pain (MSP) episode.
Learn More >Chronic pain is typically defined as pain that persists after acute tissue damage and inflammation or as pain that follows a chronic disease process and lasts more than three months. Because of its debilitating impact on the quality of life of patients, recent research aims to investigate the mechanisms behind nociception to discover novel therapeutic agents to alleviate pain. One such target is the neuropeptide calcitonin gene-related peptide (CGRP), which has shown to play an integral role in migraine pathophysiology. Effective treatments of migraines with CGRP antagonists have stimulated our efforts toward checking a possible involvement of CGRP in nonheadache pain conditions such as hypertension, congestive heart failure, Alzheimer's disease, and vascular ischemia. Here, we provide a brief overview of chronic pain, with a particular emphasis on the role of CGRP as a fundamental mediator of nociceptive pain as well as a target for novel therapeutic agents.
Learn More >Fibromyalgia is a complex disease process that is as prevalent as it is poorly understood. Research into the pathophysiology is ongoing, and findings will likely assist in identifying new therapeutic options to augment those in existence today that are still insufficient for the care of a large population of patients. Recent evidence describes the use of cannabinoids in the treatment of fibromyalgia. This study provides a systematic, thorough review of the evidence alongside a review of the seminal data regarding the pathophysiology, diagnosis, and current treatment options. Fibromyalgia is characterized by widespread chronic pain, fatigue, and depressive episodes without an organic diagnosis, which may be prevalent in up to 10% of the population and carries a significant cost in healthcare utilization, morbidity, a reduced quality of life, and productivity. It is frequently associated with psychiatric comorbidities. The diagnosis is clinical and usually prolonged, and diagnostic criteria continue to evolve. Some therapies have been previously described, including neuropathic medications, milnacipran, and antidepressants. Despite some level of efficacy, only physical exercise has strong evidence to support it. Cannabis has been used historically to treat different pain conditions since ancient times. Recent advances allowed for the isolation of the active substances in cannabis and the production of cannabinoid products that are nearly devoid of psychoactive influence and provide pain relief and alleviation of other symptoms. Many of these, as well as cannabis itself, are approved for use in chronic pain conditions. Evidence supporting cannabis in chronic pain conditions is plentiful; however, in fibromyalgia, they are mostly limited. Only a handful of randomized trials exists, and their objectivity has been questioned. However, many retrospective trials and patient surveys suggest the significant alleviation of pain, improvement in sleep, and abatement of associated symptoms. Evidence supporting the use of cannabis in chronic pain and specifically in fibromyalgia is being gathered as the use of cannabis increases with current global trends. While the current evidence is still limited, emerging data do suggest a positive effect of cannabis in fibromyalgia. Cannabis use is not without risks, including psychiatric, cognitive, and developmental as well as the risks of addiction. As such, clinical judgment is warranted to weigh these risks and prescribe to patients who are more likely to benefit from this treatment. Further research is required to define appropriate patient selection and treatment regimens.
Learn More >Migraine is a debilitating neurological condition with symptoms typically consisting of unilateral and pulsating headache, sensitivity to sensory stimuli, nausea, and vomiting. The World Health Organization (WHO) reports that migraine is the third most prevalent medical disorder and second most disabling neurological condition in the world. There are several options for preventive migraine treatments that include, but are not limited to, anticonvulsants, antidepressants, beta blockers, calcium channel blockers, botulinum toxins, NSAIDs, riboflavin, and magnesium. Patients may also benefit from adjunct nonpharmacological options in the comprehensive prevention of migraines, such as cognitive behavior therapy, relaxation therapies, biofeedback, lifestyle guidance, and education. Preventative therapies are an essential component of the overall approach to the pharmacological treatment of migraine. Comparative studies of newer therapies are needed to help patients receive the best treatment option for chronic migraine pain.
Learn More >Early studies of deep brain stimulation (DBS) for various neurological disorders involved a temporary trial period where implanted electrodes were externalized, in which the electrical contacts exiting the patient's brain are connected to external stimulation equipment, so that stimulation efficacy could be determined before permanent implant. As the optimal brain target sites for various diseases (i.e., Parkinson's disease, essential tremor) became better established, such trial periods have fallen out of favor. However, deep brain stimulation trial periods are experiencing a modern resurgence for at least two reasons: (1) studies of newer indications such as depression or chronic pain aim to identify new targets and (2) a growing interest in adaptive DBS tools necessitates neurophysiological recordings, which are often done in the peri-surgical period. In this review, we consider the possible approaches, benefits, and risks of such inpatient trial periods with a specific focus on developing new DBS therapies for chronic pain.
Learn More >Although it is acknowledged that pain may be modulated by cognitive factors, little is known about the effect of aging on these control processes. The present study investigated electroencephalographical correlates of pain processing and its cognitive modulation in healthy older individuals.
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