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Pain that lingers beyond the early weeks after the acute postoperative period is an important risk factor for chronic postsurgical pain. This study examined the hypothesis that patients' expectations about their postsurgical pain would be independently associated with lingering postsurgical pain.
Learn More >Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. We investigated the mechanisms responsible for higher nociceptive thresholds in red-haired mice resulting from a loss of melanocortin 1 receptor (MC1R) function and found that the increased thresholds are melanocyte dependent but melanin independent. MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired ( ) mice. Decreased peripheral α-MSH derepresses the central opioid tone mediated by the opioid receptor OPRM1, resulting in increased nociceptive thresholds. We identified MC4R as the MSH-responsive receptor that opposes OPRM1 signaling and the periaqueductal gray area in the brainstem as a central area of opioid/melanocortin antagonism. This work highlights the physiologic role of melanocytic MC1R and circulating melanocortins in the regulation of nociception and provides a mechanistic framework for altered opioid signaling and pain sensitivity in red-haired individuals.
Learn More >Observing others' aversive experiences is central to know what is dangerous for ourselves. Hence, observation often elicits behavioral and physiological responses comparable to first-hand aversive experiences and engages overlapping brain activation. While brain activation to first-hand aversive experiences relies on connections to the spinal cord, it is unresolved whether merely observing aversive stimulation also involves responses in the spinal cord. Here, we show that observation of others receiving painful heat stimulation involves neural responses in the spinal cord, located in the same cervical segment as first-hand heat pain. However, while first-hand painful experiences are coded within dorsolateral regions of the spinal cord, observation of others' painful heat stimulation involves medial regions. Dorsolateral areas that process first-hand pain exhibit negative responses when observing pain in others. Our results suggest a distinct processing between self and others' pain in the spinal cord when integrating social information.
Learn More >The objective of this study was to review and synthesize qualitative research studies exploring the experiences of individuals living with shoulder pain to enhance understanding of the experiences of these individuals as well as facilitate health care developments.
Learn More >Nalfurafine has been used clinically in Japan for treatment of itch in kidney dialysis patients and in patients with chronic liver diseases. A one-year post-marketing study showed nalfurafine to be safe and efficacious without producing side effects of typical KOR agonists such as anhedonia and psychotomimesis. In this chapter, we summarize in vitro characterization and in vivo preclinical studies on nalfurafine. In vitro, nalfurafine is a highly potent and moderately selective KOR full agonist; however, whether it is a biased KOR agonist is a matter of debate. In animals, nalfurafine produced anti-pruritic effects in a dose range lower than that caused side effects, including conditioned place aversion (CPA), hypolocomotion, motor incoordination, consistent with the human data. In addition, nalfurafine showed antinociceptive effects in several pain models at doses that did not cause the side effects mentioned above. It appears to be effective against inflammatory pain and mechanical pain, but less so against thermal pain, particularly high-intensity thermal pain. U50,488H and nalfurafine differentially modulated several signaling pathways in a brain region-specific manners. Notably, U50,488H, but not nalfurafine, activated the mTOR pathway, which contributed to U50,488H-induced CPA. Because of its lack of side effects associated with typical KOR agonists, nalfurafine has been investigated as a combination therapy with an MOR ligand for pain treatment and for its effects on opioid use disorder and alcohol use disorder, and results indicate potential usefulness for these indications. Thus, although in vitro data regarding uniqueness of nalfurafine in terms of signaling at the KOR are somewhat equivocal, in vivo results support the assertion that nalfurafine is an atypical KOR agonist with a significantly improved side-effect profile relative to typical KOR agonists.
Learn More >Osteoarthritis (OA) is a chronic condition often associated with pain, affecting approximately fourteen percent of the population, and increasing in prevalence. A globally aging population have made treating OA-associated pain as well as maintaining mobility and activity a public health priority. OA affects all mammals, and the use of spontaneous animal models is one promising approach for improving translational pain research and the development of effective treatment strategies. Accelerometers are a common tool for collecting high-frequency activity data on animals to study the effects of treatment on pain related activity patterns. There has recently been increasing interest in their use to understand treatment effects in human pain conditions. However, activity patterns vary widely across subjects; furthermore, the effects of treatment may manifest in higher or lower activity counts or in subtler ways like changes in the frequency of certain types of activities. We use a zero inflated Poisson hidden semi-Markov model to characterize activity patterns and subsequently derive estimators of the treatment effect in terms of changes in activity levels or frequency of activity type. We demonstrate the application of our model, and its advance over traditional analysis methods, using data from a naturally occurring feline OA-associated pain model.
Learn More >The main objective of this pilot clinical trial was to evaluate outcome measures for the assessment of the nonsteroidal anti-inflammatory drug (NSAID) robenacoxib in cats with degenerative joint disease-associated pain (DJD-pain). Otherwise healthy cats (n = 109) with DJD-pain entered a parallel group, randomized, blinded clinical trial. Cats received placebo (P) or robenacoxib (R) for two consecutive 3-week periods. Treatment groups were PP, RR, and RP. Actimetry and owner-assessment data were collected. Data were analyzed using mixed-effects and generalized mixed-effects linear models. Activity data showed high within-cat and between-cat variability, and 82.4% of the values were zero. Compared to placebo, mean total activity was higher (5.7%) in robenacoxib-treated cats (p = 0.24); for the 80th percentile of activity, more robenacoxib-treated cats had a > 10% increase in activity after 3 (p = 0.046) and 6 weeks (p = 0.026). Robenacoxib treatment significantly decreased owner-assessed disability, (p = 0.01; 49% reduction in disability; effect size ~ 0.3), and improved temperament (p = 0.0039) and happiness (p = 0.021) after 6 weeks. More robenacoxib-treated cats were successes at 6 weeks (p = 0.018; NNT: 3.8). Adverse effect frequencies were similar across groups. Results identified suitable endpoints for confirmatory studies, while also indicating efficacy of robenacoxib in cats with DJD-pain.
Learn More >Beta 2 adrenergic receptor (β2 AR) activation in the central and peripheral nervous system has been implicated in nociceptive processing in acute and chronic pain settings with anti-inflammatory and anti-allodynic effects of β2-AR mimetics reported in several pain states. In the current study, we examined the therapeutic efficacy of the β2-AR agonist clenbuterol in a rat model of persistent postsurgical hypersensitivity induced by disruption of descending noradrenergic signaling in rats with plantar incision. We used growth curve modeling of ipsilateral mechanical paw withdrawal thresholds following incision to examine effects of treatment on postoperative trajectories. Depletion of spinal noradrenergic neurons delayed recovery of hypersensitivity following incision evident as a flattened slope compared to non-depleted rats (-1.8 g/day with 95% CI -2.4 to -1.085, p < 0.0001). Chronic administration of clenbuterol reduced mechanical hypersensitivity evident as a greater initial intercept in noradrenergic depleted (6.2 g with 95% CI 1.6 to 10.8, p = 0.013) and non-depleted rats (5.4 g with 95% CI 1.2 to 9.6, p = 0.018) with plantar incision compared to vehicle treated rats. Despite a persistent reduction in mechanical hypersensitivity, clenbuterol did not alter the slope of recovery when modeled over several days (p = 0.053) or five weeks in depleted rats (p = 0.64). Systemic clenbuterol suppressed the enhanced microglial activation in depleted rats and reduced the density of macrophage at the site of incision. Direct spinal infusion of clenbuterol failed to reduce mechanical hypersensitivity in depleted rats with incision suggesting that beneficial effects of β2-AR stimulation in this model are largely peripherally mediated. Lastly, we examined β2-AR distribution in the spinal cord and skin using hybridization and IHC. These data add to our understanding of the role of β2-ARs in the nervous system on hypersensitivity after surgical incision and extend previously observed anti-inflammatory actions of β2-AR agonists to models of surgical injury.
Learn More >Opioid use disorder (OUD) is a debilitating disorder that affects millions of people. Neutral cues can acquire motivational properties when paired with the positive emotional effects of drug intoxication to stimulate relapse. However, much less research has been devoted to cues that become conditioned to the aversive effects of opioid withdrawal. We argue that environmental stimuli promote motivation for opioids when cues are paired with withdrawal (conditioned withdrawal) and generate opioid consumption to terminate conditioned withdrawal (conditioned negative reinforcement). We review evidence that cues associated with pain drive opioid consumption, as patients with chronic pain may misuse opioids to escape physical and emotional pain. We highlight sex differences in withdrawal-induced stress reactivity and withdrawal cue processing and discuss neurocircuitry that may underlie withdrawal cue processing in dependent individuals. These studies highlight the importance of studying cues associated with withdrawal in dependent individuals and point to areas for exploration in OUD research.
Learn More >C-C chemokine receptor 2 (CCR2) signaling plays a key role in pain associated with experimental murine osteoarthritis (OA) after destabilization of the medial meniscus (DMM). Here, we aimed to assess if CCR2 expressed by intra-articular sensory neurons contributes to knee hyperalgesia in the early stages of the model.
Learn More >ObjectiveTo determine whether the intravenous infusion of adrenomedullin, a potent vasodilator belonging to calcitonin family of peptides, provokes attacks of migraine in patients.MethodsTwenty migraine without aura patients participated in a placebo-controlled and double-blinded clinical study. In a randomized and crossover design the patients received an intravenous infusion of human adrenomedullin (19.9 picomole/kg/min) or placebo (saline) administrated via an automated intravenous pump (20 minutes). The patients participated in two study days with washout period of minimum of seven days. The primary outcome of the study was predefined as a difference in migraine incidence (0-12 h) and the secondary outcome were the headache intensity score's area under curve (AUC) and the (AUC ) for MAP, flushing and HR.ResultsEleven migraine without aura patients (55%) fulfilled migraine attacks criteria after adrenomedullin infusion in comparison to only three patients reported attack (15%) after placebo ( 0.039). We found that patients reported in a period of (0-12 hours) stronger headache intensity after adrenomedullin in comparison to placebo infusion ( 0.035). AUC for HR and, flushing ( < 0.05) were significant and MAP ( = 0.502) remain unchanged. Common adverse events reported were facial flushing, heat sensation and palpitation ( <0.001)ConclusionOur data implicate adrenomedullin in migraine pathogenesis. This suggests that adrenomedullin and/or its receptors are novel therapeutic targets for the treatment of migraine. However, we cannot discount for the possibility that adrenomedullin may be acting through the canonical CGRP receptor.
Learn More >More than hurt feelings: The wear and tear of day-to-day discrimination in adults with chronic pain.
To examine the extent to which self-reported experiences of discrimination are associated with pain interference among men and women with chronic non-cancer pain.
Learn More >Chronic pain is nowadays used as an umbrella term referring to a wide range of clinical conditions, such as fibromyalgia, migraine, or long-standing pain states without actual known causes. However, labeling a patient's clinical condition with the term "chronic pain", when dealing with pain lasting longer than 3 months, might be misleading. This paper aims at analyzing the possible pitfalls related to the use of the term "chronic pain" in the clinical field. It appears, indeed, that the term "chronic pain" shows a semantic inaccuracy on the basis of emerging scientific evidences on the pathogenesis of different long-standing pain states. The major pitfalls in using this label emerge in clinical settings, especially with patients having a biomedical perspective on pain or from different cultures, or with healthcare providers of other medical specialties or different disciplines. A label solely emphasizing temporal features does not help to discern the multifaceted complexity of long-standing pain states, whose onset, maintenance and exacerbation are influenced by a complex and interdependent set of bio-psycho-social factors. Thus, finding a more meaningful name might be important. We call upon the necessity of bringing awareness and implementing educational activities for healthcare providers, as well as for the public, on the biopsychosocial approach to assess, prevent and care of chronic pain. Further research on the etiopathogenetic processes of chronic pain states is also required, together with examinative diagnostic methods, to individuate the most appropriate label(s) representing the complex long-standing pain states and to avoid adopting the term "chronic pain" inappropriately.
Learn More >Up to 80% of patients with head and neck cancer undergoing ablative surgery and neck dissection develop postoperative pain with detrimental effects on quality of life that also contributes to neuropathic and chronic postoperative pain.
Learn More >Altered balance in nociception in response to noxious stimuli is commonly reported in chronic low back pain (LBP). However, it is unclear whether an improvement in the clinical presentation is contingent on a reduction in pain sensitivity. This study investigated whether the quantitative sensory testing (QST) profile changes in people undergoing rehabilitation for LBP.
Learn More >Adverse childhood experiences (ACEs) are commonly reported by individuals with chronic pain. However, little is known about how ACE exposure influences treatment outcomes. The goal of the current study was to evaluate group and treatment-related differences among adults with varying levels of ACE exposure participating in a pain rehabilitation treatment program.
Learn More >This journal recently published a paper by Wager and colleagues, entitled "Long-term outcomes of children with severe chronic pain: Comparison of former patients with a community sample" (Wager et al., in press). This paper demonstrates the lasting positive effects of intensive interdisciplinary pain treatment (IIPT) in children, and adds confidence in the duration of treatment effects through its unprecedented, controlled, 7-year follow-up design. Youth treated in IIPT are those with the most impairing pain; thus, these results are particularly encouraging, with almost 60% of the clinical sample no longer experiencing chronic pain.
Learn More >This study aims to evaluate the efficacy of 10-kHz high-frequency (HF10) devices as a rescue treatment in patients with failure of conventional spinal cord stimulation (SCS) therapy for chronic pain without the need to change the spinal hardware.
Learn More >Transdermal buprenorphine is indicated for chronic pain management, but as its role in the clinical management of acute pain is less clear, this narrative review examines studies of the patch for acute pain, mainly in the postoperative setting. Although perhaps better known for its role in opioid rehabilitation programs, buprenorphine is also an effective analgesic that is a Schedule III controlled substance. Although buprenorphine is a partial agonist at the μ-opioid receptor, it is erroneous to think of the agent as a partial analgesic; it has full analgesic efficacy and unique attributes among opioids, such as a ceiling for respiratory depression and low "drug likeability" among those who take opioids for recreational purposes. Transdermal buprenorphine has been most thoroughly studied for acute pain control in postoperative patients. Postoperative pain follows a distinct and predictable trajectory depending on the type of surgery and patient characteristics. Overall, when the patch is applied prior to surgery and left in place for the prescribed seven days, it was associated with reduced postoperative pain, lower consumption of other analgesics, and patient satisfaction. Transdermal buprenorphine has been evaluated in clinical studies of patients undergoing gynecological surgery, hip fracture surgery, knee or hip arthroscopy/arthroplasty, shoulder surgery, and spinal surgery. Transdermal buprenorphine may also be appropriate pain medication for controlling pain during postsurgical orthopedic rehabilitation programs. Transdermal buprenorphine may result in typical opioid-associated side effects but with less frequency than other opioids. Despite clinical reservations about transdermal buprenorphine and its potential role in acute pain management in the clinical setting, clinical acceptance may be hampered by the fact that it is off-label and buprenorphine is better known as an opioid maintenance agent rather than an analgesic.
Learn More >New therapeutic alternatives for pain relief include the use of phosphodiesterase-5 (PDE5) inhibitors, which could prevent the transmission of painful stimuli by neuron hyperpolarization via nitric oxide (NO)/cyclic 3',5'-guanosine monophosphate (cGMP) pathway. The present work investigated the antinociceptive activity of a new PDE5 inhibitor, lodenafil carbonate, in inflammatory and neuropathic pain models.
Learn More >Currently, there is no biologically based rationale for drug selection in migraine prophylactic treatment.
Learn More >This paper is the forty-second consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2019 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Learn More >Mechanical stress to the TMJ is an important factor in cartilage degeneration, with both clinical and pre-clinical studies suggesting that repeated TMJ overloading could contribute to pain, inflammation, and/or structural damage in the joint. However, the relationship between pain severity and early signs of cartilage matrix microstructural dysregulation is not understood, limiting advancement of diagnoses and treatments for TMJ-OA. Changes in the pericellular matrix (PCM) surrounding chondrocytes may be early indicators of osteoarthritis. A rat model of TMJ pain induced by repeated jaw loading (1 hr/day for 7 days) was used to compare the extent of PCM modulation for different loading magnitudes with distinct pain profiles (3.5N – persistent pain, 2N – resolving pain, or unloaded controls – no pain) and macrostructural changes previously indicated by Mankin scoring. Expression of PCM structural molecules, collagen VI and aggrecan NITEGE neo-epitope, were evaluated at day 15 by immunohistochemistry within TMJ fibrocartilage and compared between pain conditions. Pericellular collagen VI levels increased at day 15 in both the 2N (p=0.003) and 3.5N (p=0.042) conditions compared to unloaded controls. PCM width expanded to a similar extent for both loading conditions at day 15 (2N, p<0.001; 3.5N, p=0.002). Neo-epitope expression increased in the 3.5N group over levels in the 2N group (p=0.041), indicating pericellular changes that were not identified in the same groups by Mankin scoring of the pericellular region. Although remodeling occurs in both pain conditions, the presence of pericellular catabolic neo-epitopes may be involved in the macrostructural changes and behavioral sensitivity observed in persistent TMJ pain. This article is protected by copyright. All rights reserved.
Learn More >Determining long-term trends in chronic pain prevalence is critical for evaluating and shaping U.S. health policies, but little research has examined such trends. This study (1) provides estimates of pain trends among U.S. adults across major population groups; (2) tests whether sociodemographic disparities in pain have widened or narrowed over time; and (3) examines socioeconomic, behavioral, psychological, and medical correlates of pain trends. Regression and decomposition analyses of joint, low back, neck, facial/jaw pain, and headache/migraine using the 2002-2018 National Health Interview Survey for adults aged 25-84 (N = 441,707) assess the trends and their correlates. We find extensive escalation of pain prevalence in all population subgroups: overall, reports of pain in at least one site increased by 10%, representing an additional 10.5 million adults experiencing pain. Socioeconomic disparities in pain are widening over time, and psychological distress and health behaviors are among the salient correlates of the trends. This study thus comprehensively documents rising pain prevalence among Americans across the adult life span and highlights socioeconomic, behavioral, and psychological factors as important correlates of the trends. Chronic pain is an important dimension of population health, and demographic research should include it when studying health and health disparities.
Learn More >CGRP, a neuropeptide involved in migraine pathophysiology, is also known to play a role in the respiratory system and in immunological conditions such as sepsis. We analyzed the impact of the use of CGRP antagonists in patients with migraine during the COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus.
Learn More >Headache and facial pain are among the most common, disabling and costly diseases in Europe, which demands for high quality health care on all levels within the health system. The role of the Danish Headache Society is to educate and advocate for the needs of patients with headache and facial pain. Therefore, the Danish Headache Society has launched a third version of the guideline for the diagnosis, organization and treatment of the most common types of headaches and facial pain in Denmark. The second edition was published in Danish in 2010 and has been a great success, but as new knowledge and treatments have emerged it was timely to revise the guideline. The recommendations for the primary headaches and facial pain are largely in accordance with the European guidelines produced by the European Academy of Neurology. The guideline should be used a practical tool for use in daily clinical practice for primary care physicians, neurologists with a common interest in headache, as well as other health-care professionals treating headache patients. The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organized in Denmark. This description is followed by sections on the characteristics, diagnosis and treatment of each of the most common primary and secondary headache disorders and trigeminal neuralgia. The guideline includes many tables to facilitate a quick overview. Finally, the particular challenges regarding migraine and female hormones as well as headache in children are addressed.
Learn More >1) Compare pressure pain threshold (PPT) values between office workers with chronic neck pain and asymptomatic controls; 2) establish reference PPT values in chronic neck pain; 3) evaluate associations between PPTs, pain intensity and disability.
Learn More >Genetic knockout or knockdown of fat-mass and obesity-associated protein (FTO), a demethylase that participates in RNA N-methyladenosine modification in injured dorsal root ganglion (DRG), has been demonstrated to alleviate nerve trauma-induced nociceptive hypersensitivities. However, these genetic strategies are still impractical in clinical neuropathic pain management. The present study sought to examine the effect of intrathecal administration of two specific FTO inhibitors, meclofenamic acid (MA) and N-CDPCB, on the development and maintenance of nociceptive hypersensitivities caused by unilateral L5 spinal nerve ligation (SNL) in rats. Intrathecal injection of either MA or N-CDPCB diminished dose-dependently the SNL-induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia, and spontaneous ongoing nociceptive responses in both development and maintenance periods, without altering acute/basal pain and locomotor function. Intrathecal MA also reduced the SNL-induced neuronal and astrocyte hyperactivities in the ipsilateral L5 dorsal horn. Mechanistically, intrathecal injection of these two inhibitors blocked the SNL-induced increase in the histone methyltransferase G9a expression and rescued the G9a-controlled downregulation of mu opioid receptor and Kv1.2 proteins in the ipsilateral L5 DRG. These findings further indicate the role of DRG FTO in neuropathic pain and suggest potential clinical application of the FTO inhibitors for management of this disorder.
Learn More >Chronic low back pain (cLBP) rates among younger individuals are rising. Although pain and disability are often less severe, underlying changes in trunk behavior may be responsible for recurrence. We examine the biomarker capacity of a simple Trunk Compliance Index (TCI) to distinguish individuals with and without cLBP. A random subset (n = 49) of the RELIEF RCT were matched to healthy controls for sex, age, height and weight. We measured TCI (as displacement/ weight-normalized perturbation force) using anthropometrically-matched, suddenly-applied pulling perturbations to the trunk segment, randomized across three planes of motion (antero-posterior, medio-lateral, and rotational). Mean differences between cLBP, sex and perturbation direction were assessed with repeated-measures analysis of variance. Discriminatory accuracy of TCI was assessed using Receiver Operator Characteristic (ROC) analysis. Baseline characteristics between groups were equivalent (x̅ [range]): sex (57% female / group), age (23.0 [18-45], 22.8 [18-45]), height, cm (173.0 [156.5-205], 171.3 [121.2-197], weight, kg (71.8 [44.5-116.6], 71.7 [46.8-117.5]) with cLBP associated with significantly lower TCI for 5 of 6 directions (range mean difference, – 5.35: – 1.49, range 95% CI [- 6.46: – 2.18 to – 4.35: – 0.30]. Classification via ROC showed that composite TCI had high discriminatory potential (area under curve [95% CI], 0.90 [0.84-0.96]), driven by TCI from antero-posterior perturbations (area under curve [95% CI], 0.99 [0.97-1.00]). Consistent reductions in TCI suggests global changes in trunk mechanics that may go undetected in classic clinical examination. Evaluation of TCI in younger adults with mild pain and disability may serve as a biomarker for chronicity, leading to improved preventative measures in cLBP.Trial Registration and Funding RELIEF is registered with clinicaltrials.gov (NCT01854892) and funded by the NIH National Center for Complementary & Integrative Health (R01AT006978).
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