Chronic Pathological Pain Research Articles

Design, Synthesis, and Biological Evaluations of 5-aryl-pyrazole-3-carboxamide Derivatives as Selective CB2 Receptor Agonists for the Treatment of Colitis

Synthetic CB2 receptor agonists exhibit great potential in the treatment of neurodegenerative diseases, chronic and neuropathic pain, cancer, and inflammation-associated pathologies while avoiding adverse psychoactive effects caused by interactions with CB1 receptors. Herein, a class of 5-aryl-pyrazole-3-carboxamide derivatives was thus designed, synthesized, and biologically evaluated. Among the compounds tested, compound 33, one of the most potent leads, showed a remarkably high potency and selectivity at the CB2 receptor (EC50, CB2 = 16.2 nM, EC50, CB1 > 105 nM). Furthermore, 33 treatment significantly attenuate colon inflammation in a dextran sodium sulfate (DSS)-induced mouse model of colitis, supporting that CB2 receptor agonists might serve as potential therapeutics for treating colitis.

Radiofrequency Ablation: Honoring the Pioneers of Modern Therapeutic Innovations.

Radiofrequency ablation (RFA) is a minimally invasive technique used to alleviate chronic pain by destroying pain-signaling nerve fibers. This procedure offers precise and focused pain relief, serving as an alternative to surgical and pharmacological treatments for chronic conditions such as arthritis, back pain, neck pain, and nerve pain. RFA has evolved over a long period, beginning with early work on electrical currents. Significant progress has been made in its application to pain management with continual technological improvements enhancing its safety and effectiveness. As technology and research continue to progress, RFA promises even greater efficacy and safety, enhancing the quality of life for patients with chronic pain. Additionally, as the understanding of pain mechanisms advances, RFA can be utilized as a procedure to treat a wider lexicon of chronic pain pathologies. This historical narrative outlines the history and clinical origins of RFA, the pioneers that pushed the development of the field, and the treatment's path to modern implications in chronic pain relief.

Cortical kappa opioid receptors integrate negative affect and sleep disturbance

Sleep disruption and negative affect are attendant features of many psychiatric and neurological conditions that are often co-morbid including major depressive disorder, generalized anxiety disorder and chronic pain. Whether there is a causal relationship between negative affect and sleep disruption remains unclear. We therefore asked if mechanisms promoting negative affect can disrupt sleep and whether inhibition of pathological negative affect can normalize disrupted sleep. Signaling at the kappa opioid receptor (KOR) elicits dysphoria in humans and aversive conditioning in animals. We tested the possibility that (a) increased KOR signaling in the anterior cingulate cortex (ACC), a brain region associated with negative emotions, would be sufficient to promote both aversiveness and sleep disruption and (b) inhibition of KOR signaling would normalize pathological negative affect and sleep disruption induced by chronic pain. Chemogenetic Gi-mediated inhibition of KOR-expressing ACC neurons produced conditioned place aversion (CPA) as well as sleep fragmentation in naïve mice. CRISPR/Cas9 editing of ACC KOR normalized both the negative affect and sleep disruption elicited by pathological chronic pain while maintaining the physiologically critical sensory features of pain. These findings suggest therapeutic utility of KOR antagonists for treatment of disease conditions that are associated with both negative affect and sleep disturbances.

Abstract LB419: Neuroinflammation and aromatase inhibitor associated musculoskeletal syndrome (AIMSS) in breast cancer: Initial insights from [11C]PBR28 PET/MR imaging

Abstract Introduction: While 5-10 years of aromatase inhibitor (AI) treatment clearly improves survival rates of postmenopausal women with hormone-sensitive breast cancer, up to 85% of AI users report aromatase inhibitor associated musculoskeletal syndrome (AIMSS, including arthralgias, myalgias, and muscle stiffness). The biological mechanisms underlying AIMSS are not well understood, but accumulating preclinical and clinical evidence implicate an important role for neuroinflammation in the development and maintenance of other types of chronic musculoskeletal pain (e.g., low back pain, fibromyalgia etc.). The purpose of this pilot study was to investigate the role of neuroinflammation in breast cancer patients with AIMSS. Methods: This cross-sectional case control study used Siemens 3 T integrated positron emission tomography-magnetic resonance imaging (PET/MRI) with the radioligand [11C]PBR28, which binds to the neuroinflammation marker 18kDa translocator protein (TSPO), to assess neuroinflammation in two cohorts (chronic AIMSS, no-AIMSS) of breast cancer patients undergoing AI therapy, and age-, sex- and TSPO genotype-matched healthy controls. Static [11C]PBR28 PET images were reconstructed from 60-90 minutes post-injection. Standardized uptake value (SUV) maps were obtained voxel-wise by normalizing radioactivity by injected dose/body weight. SUV maps were normalized to whole brain to obtain SUV ratio (SUVR) maps. SUVR images spatially normalized to MNI template and then spatially smoothed (FWHM=8mm). Results: Two breast cancer patients (1 AIMSS, 1 no-AIMSS) and 2 matched healthy controls were included in this analysis. Compared to their individual matched healthy controls, both breast cancer patients showed increased [11C]PBR28 signal uptake in the thalamus/midbrain and pons. This elevated signal was more prominent in the breast cancer patient with AIMSS. Conclusions: These preliminary findings suggest an elevated signal of neuroinflammation in the thalamus and brainstem in AI-treatment and AIMSS, aligning with existing literature emphasizing their pivotal role in chronic pain pathology. While it is imperative to acknowledge the limitation of a small sample size, these promising findings suggest a potential role of neuroinflammation for the first time in AIMSS. Future focused Region of Interest (ROI) analysis in thalamus and brainstem with a larger sample size may confirm. Citation Format: Yehui Zhu, Natalie Swanson, Jennifer Murphy, Minhae Kim, Ann Partridge, Robert Edwards, Kristin Schreiber, Marco Loggia. Neuroinflammation and aromatase inhibitor associated musculoskeletal syndrome (AIMSS) in breast cancer: Initial insights from [11C]PBR28 PET/MR imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB419.

Applications of Cryoneurolysis in Chronic Pain Management: a Review of the Current Literature.

The purpose of this review is to evaluate and summarize the literature investigating cryoneurolysis in the treatment of various chronic pain pathologies. There is an increasing amount of interest in the use of cryoneurolysis in chronic pain, and various studies have investigated its use in lumbar facet joint pain, SI joint pain, post-thoracotomy syndrome, temporomandibular joint pain, chronic knee pain, phantom limb pain, neuropathic pain, and abdominal pain. Numerous retrospective studies and a more limited number of prospective, sham-controlled prospective studies suggest the efficacy of cryoneurolysis in managing these chronic pain pathologies with a low complication rate. However, more blinded, controlled, prospective studies comparing cryoneurolysis to other techniques are needed to clarify its relative risks and advantages.

Silencing of secreted phosphoprotein 1 attenuates sciatic nerve injury-induced neuropathic pain: Regulating extracellular signal-regulated kinase and neuroinflammatory signaling pathways.

Neuropathic pain (NP) is a chronic pathological pain that affects the quality of life and is a huge medical burden for affected patients. In this study, we aimed to explore the effects of secreted phosphoprotein 1 (SPP1) on NP. We established a chronic constriction injury (CCI) rat model, knocked down SPP1 via an intrathecal injection, and/or activated the extracellular signal-regulated kinase (ERK) pathway with insulin-like growth factor 1 (IGF-1) treatment. Pain behaviors, including paw withdrawal threshold (PWT), paw withdrawal latency (PWL), lifting number, and frequency, were assessed. After sacrificing rats, the L4-L5 dorsal root ganglion was collected. Then, SPP1 levels were determined using quantitative polymerase chain reaction (qPCR) and western blot analysis. The levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, IL-10, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-β were determined using qPCR and enzyme-linked immunosorbent assay. The levels of ERK pathway factors were determined via western blot analysis. We found that CCI decreased PWT and PWL, increased the lifting number and frequency, and upregulated SPP1 levels. The loss of SPP1 reversed these CCI-induced effects. Additionally, CCI upregulated IL-1β, TNF-α, IL-6, EGF, and VEGF levels, downregulated TGF-β levels, and activated the ERK pathway, while silencing of SPP1 abrogated these CCI-induced effects. Moreover, IGF-1 treatment reversed the effects of SPP1 loss. The data indicate that silencing SPP1 attenuates NP via inactivation of the ERK pathway, suggesting that SPP1 may be a promising target for NP treatment.

Efficacy and tolerability of full spectrum hemp oil in dogs living with pain in common household settings.

Lameness and restricted mobility are a significant concern in companion animals experiencing chronic pain, inflammation, or age-related pathologies. The growing awareness of health risks and side effects associated with the long-term use of prescription analgesics requires different management strategies to address these issues. In this study, we conducted a crossover evaluation of the effect of full spectrum hemp oil dosed orally at 2 mg/kg BID phytocannabinoids for 8 weeks in dogs (n = 37) living with pain in common household settings. Owner-reported canine pain, home activity, accelerometer-based activity, walkway-based gait, and tolerability were assessed at each phase of the study. Secondary endpoints included changes in blood biochemistry, liver enzymes, inflammatory biomarkers, and plasma metabolites. The intervention was positively associated with a decrease in pain scores (-46.2%, p = 0.0016), increased ability to walk up and down the stairs (10.6-14.7%, p < 0.05), and improved daily activity (25.9%, p = 0.0038). Decreases in plasma levels of proinflammatory cytokines TNF-α, IL-6, and IL-8 were also observed. Taken together, these findings suggest that the benefits of nutritional supplementation with hemp oil could include control of pain, greater mobility, and an overall improvement in the animal wellbeing.

Chronic Pain and Bone-Related Pathologies: A Narrative Review.

Pain related to bone may occur as a result of trauma, bone fracture, genetic disease, arthritis, benign or malignant primary bone tumors and bone cancer metastases. We discuss the pathophysiology of chronic bone-related pain, treatment options and therapeutic perspectives. Using predefined terms, we searched PubMed, MEDLINE, and Google Scholar for meta-analyses, evidence-based reviews, and clinical practice guidelines. This narrative article reviews pathologies linked to chronic bone pain and discusses the preventive and therapeutic strategies for better bone pain management. Pathophysiology of bone-related pain is complex, especially in cancer conditions and missing gaps are underlined. Treatment of pain, after adequate evaluation, includes classical analgesics, adjuvants for neuropathic and refractory pain, specific bone drugs, surgery and non-pharmacological approaches. Prevention of chronic bone pain encompasses prevention of central sensitization and of causal diseases. Translational research, drug repurposing, an interdisciplinary approach and a person-centered assessment to evaluate, beyond pain, physical, social and functional abilities, are proposed future directions to improve chronic bone pain management and optimize independence and quality of life. Chronic bone-related pain is frequent and is associated with an impairment of quality of life. In this review, we summarize the pathophysiology of chronic bone pain, describe treatment approaches and envisage new avenues for pain alleviation. Our article will help doctors manage chronic bone pain and address unmet needs for future research to alleviate bone-related pain.

Autonomic nervous system function assessed by heart rate variability and the presence of symptoms affecting activities of daily living in community-dwelling residents with chronic pain: The Hisayama Study.

Autonomic nervous system dysfunction has been reported to be associated with impaired activities of daily living (ADL) among patients with chronic pain, but the association has not been fully addressed in general populations. This study cross-sectionally investigated the association between autonomic nervous system function and the presence of subjective symptoms affecting ADL in community-dwelling residents with chronic pain. A total of 888 residents with chronic pain, aged 40-79 years, who underwent a health examination in 2017-2018 were included. Based on heart rate variability measured by fingertip pulse wave, the standard deviation of normal-to-normal intervals (SDNN), root mean square of successive RR interval differences (RMSSD), low frequency (LF) power, and high frequency (HF) power were calculated. Symptoms affecting ADL were defined as those scoring ≥1 on the modified Rankin Scale. Odds ratios (ORs) and their 95% confidence intervals (CIs) for symptoms affecting ADL were estimated using a logistic regression analysis. The overall prevalence of symptoms affecting ADL was 39.4%. The ORs for symptoms affecting ADL increased significantly per 1-standard-deviation decrement in log-transformed SDNN (OR 1.23 [95% CI 1.06-1.44]), RMSSD (1.25 [1.08-1.45]), LF power (1.29 [1.11-1.52]), and HF power (1.29 [1.11-1.51]) after adjusting for age, sex, education, hypertension, diabetes, serum total cholesterol level, body mass index, past medical history, current smoking, current drinking, exercise, depressive symptoms, and pain intensity. Decreased heart rate variability was associated with the presence of symptoms affecting ADL among individuals with chronic pain in a Japanese community. Decrease in heart rate variability was associated with the presence of symptoms affecting ADL among individuals with chronic pain in a Japanese community. This article could help scientists understand the significance of autonomic nervous system dysfunction in the pathology of chronic pain. Approaches that target autonomic nervous system dysfunction may be an option to relieve or prevent symptoms affecting ADL for chronic pain sufferers.

IL-33/ST2 Signaling in the Pathogenesis of Chronic Pain and Itch.

Interleukin-33 (IL-33) is an inflammatory factor with an extensive range of biological effects and pleiotropic roles in diseases. Evidence suggests that IL-33 and its receptor ST2 play a pivotal role in chronic pain and itch at the level of primary sensory neurons, the spinal cord, and the brain. In this review, we outline an evolving understanding of the roles and mechanisms of IL-33 in chronic pathological pain, including inflammatory, neuropathic, and cancer, and chronic pruritus, such as allergic contact dermatitis, atopic dermatitis, and dry skin. Understanding the key roles of IL-33/ST2 signaling may provide exciting insights into the mechanisms of chronic pain and itch and lead to new clues for therapeutic approaches to the resolution of chronic pain and itch.

Posterior chain and core training improves pelvic posture, hamstrings-to-quadriceps ratio, and vertical jump performance.

Poor pelvic posture demonstrated through anterior pelvic tilt (APT) have been known to produce musculoskeletal imbalances involving weakness of the abdominal and pelvic musculature. While stretching and massage techniques have been reported to be effective in alleviating APT, it remains unclear if similar improvements can be elicited by posterior chain and core strength training. Therefore, the aim of this study was to examine the effect of an 8-week posterior and core strengthening program on APT, hamstrings-to-quadriceps (H:Q) strength ratio, and vertical jump performance in healthy individuals. Ten healthy males (age = 26±12 years; mass = 87±14 kg; height = 1.8±0.1 m) and nine healthy females (age = 22±4 years; mass = 70±14 kg; heigh t = 1.7±0.1 m) performed resistance training (2×/week; 40-45 mins) involving a combination of hip extensors and abdominal strengthening exercises for 8 weeks. APT (°), vertical jump power (W), vertical jump height (m), and H:Q ratio at 60, 180, and 300°/s were assessed prior to and following the resistance training program. APT, vertical jump power, vertical jump height, and H:Q ratio at 60 and 180°/s, were significantly improved following 8 weeks of resistance training (all Ps<0.05). Our main finding was that 8 weeks of resistance training emphasizing posterior chain and core strengthening was effective in reducing APT, improving vertical jump performance and H:Q ratio in healthy individuals. Our findings have potential implications for clinicians prescribing resistance training exercises to improve pelvic posture in healthy asymptomatic individuals at risk of developing chronic low back pain and lumbar-spinal pathologies due to excessive anterior pelvic tilt.

Role of magnesium-L-Threonate in alleviating skin/muscle incision and retraction induced mechanical allodynia and anxiodepressive-like behaviors in male rats

Chronic postsurgical pain (CPSP) and its emotional comorbidities poses health burden to patients who have received the surgical treatment. However, its underlying mechanism remains unclear. Emerging studies indicate that magnesium deficiency is associated with neurological diseases, and magnesium supplement confers protection under these disease conditions. In this study, we examined the role and mechanism of magnesium deficiency in the pathology of surgery-induced allodynia and negative emotion using a rat model of skin/muscle incision and retraction (SMIR) and investigated the therapeutic effects of magnesium supplementation by oral magnesium-L-Threonate (L-TAMS) in SMIR-injured rats. In the SMIR model, rats developed mechanical allodynia and anxiodepressive-like behaviors. Further, SMIR caused microglia and astrocyte activation and enhanced expression of pro-inflammatory cytokine (TNF-α, IL-1β and IL-6) in the anterior cingulate cortex (ACC). Importantly, magnesium ion (Mg2+) levels decreased in the serum and cerebrospinal fluid (CSF) of SMIR-injured rats, which exhibited high correlation with pain and emotion behavioral phenotypes in these rats. Repeated oral administration of L-TAMS increased serum and CSF levels of Mg2+ in SMIR-injured rats. Notably, L-TAMS administration reversed SMIR-induced mechanical allodynia and anxiodepressive-like behaviors but did not affect pain and emotional behaviors in sham rats. Moreover, L-TAMS administration suppressed SMIR-caused glial activation and proinflammatory cytokine expression in the ACC but had no such effect in sham rats. Together, our study demonstrates the contributing role of magnesium deficiency in the pathology of surgery-induced chronic pain and negative emotion. Moreover, we suggest that L-TAMS might be a novel approach to treat CPSP and its emotional comorbidities.

Chronic pain, chronic stress and substance use: overlapping mechanisms and implications.

Chronic pain is among the most common reasons adults in the U.S. seek medical care. Despite chronic pain's substantial impact on individuals' physical, emotional, and financial wellness, the biologic underpinnings of chronic pain remain incompletely understood. Such deleterious impact on an individuals' wellness is also manifested in the substantial co-occurrence of chronic stress with chronic pain. However, whether chronic stress and adversity and related alcohol and substance misuse increases risk of developing chronic pain, and, if so, what the overlapping psychobiological processes are, is not well understood. Individuals suffering with chronic pain find alleviation through prescription opioids as well as non-prescribed cannabis, alcohol, and other drugs to control pain, and use of these substances have grown significantly. Substance misuse also increases experience of chronic stress. Thus, given the evidence showing a strong correlation between chronic stress and chronic pain, we aim to review and identify overlapping factors and processes. We first explore the predisposing factors and psychologic features common to both conditions. This is followed by examining the overlapping neural circuitry of pain and stress in order to trace a common pathophysiologic processes for the development of chronic pain and its link to substance use. Based on the previous literature and our own findings, we propose a critical role for ventromedial prefrontal cortex dysfunction, an overlapping brain area associated with the regulation of both pain and stress that is also affected by substance use, as key in the risk of developing chronic pain. Finally, we identify the need for future research in exploring the role of medial prefrontal circuits in chronic pain pathology. Critically, in order to alleviate the enormous burden of chronic pain without exacerbating the co-occurring substance misuse crisis, we emphasize the need to find better approaches to treat and prevent chronic pain.

ID: 201967 Post Dural Puncture Headache After Removal of Trail Spinal Cord Stimulator Leads: A Case Report

Spinal cord stimulators (SCS) have been invaluable resource in treating chronic pain pathologies stemming from failed back surgery syndrome, complex regional pain syndrome, neuropathic pain and leg ischemia.1The incidence of complications with SCS has been reported in 30-40% of cases, including hardware complications, lead migration, and infection.2 Post dural puncture headaches (PDPH) are a common phenomenon that can be seen in neuroaxial procedures due to dural compromise.3 Studies assessing this phenomenon is overall lacking in SCS procedures. This case describes a unique presentation of a patient who presents with symptoms of PDPH after removal of SCS leads.

Post-injury pain and behaviour: a control theory perspective.

Injuries of various types occur commonly in the lives of humans and other animals and lead to a pattern of persistent pain and recuperative behaviour that allows safe and effective recovery. In this Perspective, we propose a control-theoretic framework to explain the adaptive processes in the brain that drive physiological post-injury behaviour. We set out an evolutionary and ethological view on how animals respond to injury, illustrating how the behavioural state associated with persistent pain and recuperation may be just as important as phasic pain in ensuring survival. Adopting a normative approach, we suggest that the brain implements a continuous optimal inference of the current state of injury from diverse sensory and physiological signals. This drives the various effector control mechanisms of behavioural homeostasis, which span the modulation of ongoing motivation and perception to drive rest and hyper-protective behaviours. However, an inherent problem with this is that these protective behaviours may partially obscure information about whether injury has resolved. Such information restriction may seed a tendency to aberrantly or persistently infer injury, and may thus promote the transition to pathological chronic pain states.

Regulatory T-cells and IL-5 mediate pain outcomes in a preclinical model of chronic muscle pain.

Fibromyalgia (FM) is a chronic musculoskeletal pain disorder primarily diagnosed in women. Historically, clinical literature focusing on cytokines and immune cells has been inconsistent. However, recent key studies show several layers of immune system dysfunction in FM. Preclinically, studies of the immune system have focused on monocytes with little focus on other immune cells. Importantly, T-cells are implicated in the development and resolution of chronic pain states, particularly in females. Our previous work showed that monocytes from women with FM produced more interleukin 5 (IL-5) and systemic treatment of IL-5 reversed mechanical hypersensitivity in a preclinical model of FM. Typically, IL-5 is produced by TH2-cells, so in this study we assessed T-cell populations and cytokine production in female mice using the acid-induced chronic muscle pain model of FM before and after treatment with IL-5. Two unilateral injections of pH4.0 saline, five days apart, into the gastrocnemius muscle induce long-lasting widespread pain. We found that peripheral (blood) regulatory Thelper-cells (CD4+ FOXP3+) are downregulated in pH4.0-injected mice, with no differences in tissue (lymph nodes) or CD8+ T-cell populations. We tested the analgesic properties of IL-5 using a battery of spontaneous and evoked pain measures. Interestingly, IL-5 treatment induced place preference in mice previously injected with pH4.0 saline. Mice treated with IL-5 show limited changes in T-cell populations compared to controls, with a rescue in regulatory T-cells which positively correlates with improved mechanical hypersensitivity. The experiments in this study provide novel evidence that downregulation of regulatory T-cells play a role in chronic muscle pain pathology in the acidic saline model of FM and that IL-5 signaling is a promising target for future development of therapeutics.

The psychological taking charge of the oncological patient: a 3 years study on the activities of psychologists of the Piedmont and Aosta Valley Oncology Network.

Tumor pathology is a bio-psycho-social event that has consequences for a person's life from all points of view, physical, psychological, relational and social. The mental discomfort that chronic pain and neoplastic pathology brings with it is present in 25-40% of cases, but the request for help to a psychologist, where not provided for by a specific diagnostic therapeutic assistance path, is in the case of medical pathologies less than 3%. The Piedmont and Valle d'Aosta Oncology Network has the role of coordinating the network of services that deal with the care of the cancer patient, including those relating to psycho-oncology. The article presents data relating to the activities of psycho-oncologists of the Network in the years 2017, 2018 and 2019. A shared tool is used to collect the data, a database, made up of various variables deemed necessary to be able to photograph the activities carried out by the psycho-oncologists belonging to the Network. The database has been the subject of comparison between psychologists and has led to continuous revisions of the tool from 2017 to 2019, more accurate version. The 3-year study involved 2188 (2017), 3341 (2018) and 3457 (2019) adult patients or their families treated by psycho-oncologists. Patients are predominantly female with breast cancer, married/cohabiting, whose pre-eminent discomfort is anxiety, combined with the depressive component. The psychological intervention is mainly psychological support (level 2). Psychological management is an important intervention in the path of the cancer patient. The systematic collection of data made it possible to detect an increase in patients who accessed the psycho-oncology service, from an estimate of 1/3% in 2009 to 4.6% in 2018/2019.

Young female participants show blunted placebo effects associated with blunted responses to a cue predicting a safe stimulus in the right dorsolateral prefrontal cortex.

Discrimination of cues predicting non-nociceptive/nociceptive stimuli is essential for predicting whether a non-painful or painful stimulus will be administered and for eliciting placebo/nocebo (pain reduction/pain enhancement) effects. Dysfunction of the neural system involved in placebo effects has been implicated in the pathology of chronic pain, while female sex is one of the important risk factors for development of chronic pain in young adults. The dorsolateral prefrontal cortex (dl-PFC) is suggested to be involved in placebo effects and is sensitive to sex and age. In this study, to examine the neural mechanisms by which sex and age alter placebo and nocebo effects, we analyzed cerebral hemodynamic activities in the dl-PFC in different sex and age groups during a differential conditioning task. During the training session, two different sounds were followed by low- and high-intensity electrical shocks. In the following recording session, electrical shocks, the intensity of which was mismatched to the sounds, were occasionally administered to elicit placebo and nocebo effects. In young female participants, both placebo effects and hemodynamic responses to the conditioned sounds in the right dl-PFC were significantly lower than those in elderly female participants, while there were no age differences in male participants. The hemodynamic responses to the sound paired with the safe stimulus in the right dl-PFC were significantly correlated with placebo effects, except in the young female group. These results suggest that blunted placebo effects in the young female participants are ascribed to blunted responses to the sound associated with the safe stimulus in the right dl-PFC, and that sex- and age-related factors may alter the responsiveness of the right dl-PFC to associative cues predicting a safe stimulus.

A Review of Genetics in Chronic Pain

Chronic pain impacts up to 50 million Americans yearly, where hundreds of billions of dollars are spent annually treating pain. The burden on health care systems and patients emphasizes our need to further investigate chronic pain. In recent years, the advent of advanced genome sequencing technologies has enabled us to identify variations in genomic regions which might contribute to susceptibility to pain as well as individuals’ response to treatment. The purpose of this review is to better understand the complex and multifactorial pathophysiology of chronic pain. A deeper understanding of the genetics of chronic pain could have wide implications in the diagnosis of pain pathologies as well as pain management therapy. Methods: This review conducted a literature analysis on the genetics of chronic pain. The PubMed® search engine was used to research key words “chronic pain”, “pain management”, “pharmacogenomics”, “gene therapy”, and “individualized medicine”. This paper’s research focused on investigating studies that conducted hypothesis-free genetic studies and genome-wide association studies (GWAS). Data from our literature search was compiled into this review and analyzed to discuss strengths and weaknesses of the current literature, and to discuss future avenues of research. Results: Many gene loci and mutations were identified as being associated with chronic pain pathologies. Results from pertinent genetic studies as well as online gene databases were compared to one another to isolate significant associations between genetics, pharmacogenomics, and pain management therapy. Discussion: When reviewing the literature searches, we found that although individual studies found significant associations between specific genes and chronic pain pathologies, the results from these studies were unable to be replicated on a larger scale. The genetic data associated with chronic pain has yet to be replicated consistently in different studies on subjects of different ethnicities, geographical distributions, and socioeconomic statuses. Further research into the genetics of chronic pain is needed to make generalizable conclusions and implement them in clinical practice.

Percutaneous electric nerve field stimulation alters cortical thickness in a pilot study of veterans with fibromyalgia

ObjectiveTo evaluate changes in cortical thickness and right posterior insula (r-pIns) gamma-aminobutyric acid (GABA) concentrations in veterans with fibromyalgia treated with auricular percutaneous electric nerve field stimulation (PENFS). Materials & methodsThis was a randomized, controlled, open label investigation conducted in a government hospital. Twenty-oneveterans with fibromyalgia wererandomized to receive either standard therapy (ST; i.e., 4 weekly visits with a pain practitioner) or ST withauricular PENFS (ST + PENFS). Neuroimaging data was collected at baseline (i.e. before the first treatment session) and again within 2 weeks post-treatment.​ Clinical pain and physical function were also assessed atthese timepoints. Single-voxel magnetic resonance spectroscopy was carried out in r-pIns to assess changes in r-pIns GABA concentrations and high-resolution T1-weighted images were collected to assess changes in regional gray matter volume using cortical thickness. ResultsBoth the ST + PENFS and ST groups reported a decrease in pain with treatment. Volumetric: Cortical thickness significantly decreased in the left middle posterior cingulate (p = 0.018) and increased in the left cuneus (p = 0.014) following ST + PENFS treatment. These findings were significant following FDR correction for multiple comparisons. ST group right hemisphere insula cortical thickness increased post-treatment and was significantly (p = 0.02) inversely correlated with pain scores. ST + PENFS group right hemisphere posterior dorsal cingulate size significantly (p = 0.044) positively correlated with pain scores. GABA: There were no significant correlations with GABA, though a trend was noted towards increased GABA following treatment in both groups (p = 0.083) using a linear mixed effects model. ConclusionsResults suggest a novel effect of PENFS reflected by differential volumetric changes compared to ST. The changes in GABA that occur in both groups are more likely related to ST. Insular GABA and cortical thickness in key regions of interest may be developed as potential biomarkers for evaluating chronic pain pathology and treatment outcomes.