Search

1000 SNPs with greatest statistical association with cumulative docetaxel dose at grade 3+ neuropathy in CALGB 90401 discovery GWAS.

Peripheral neuronal cells (Peri.4U) treated with docetaxel were found to have a significant decrease in sensitivity for A) mean process lengths but not for B) mean outgrowth intensity or C) relative straightness as measured after 24 hours post-drug treatment. For paclitaxel treatment at the same time point, the cells were also found to have significantly decreased sensitivity for D) relative mean process length and E) mean outgrowth intensity but not for F) relative straightness. Neurite parameters measured with MetaXPress® software were averaged from 3 independent experiments. Error bars represent the standard error of the mean from three independent transfection experiments. NTC = non-targeting control, UT= untransfected control.

Number of patients who experienced neuropathy, completed treatment without neuropathy and discontinued treatment early without having neuropathy while on study and within each range of cumulative treatment.

Sensitivity to mechanical stimuli with Von Frey filaments for C57BL/6J mice and litter-mates heterozygous for VAC14 prior to docetaxel treatment. The figure displays the estimate of the proportion of mice without a hind-paw withdrawal response to stimulation by each Von Frey fiber weight, e.g., no mice respond to fibers {less than or equal to}0.2 g and all mice respond to fibers{greater than or equal to}1.4 g. The VAC14 heterozygous mice (hatched line) are more likely than wild-type mice (solid line) to respond, meaning they are more sensitive to nociceptive stimuli (p=0.0012). Gray lines denote 95% confidence intervals.

CONSORT diagram illustrating patient flow from enrollment on parent study to population included in pharmacogenetic discovery analysis and quality control filtering of SNPs from the Illumina HumanHap610-Quad into the pharmacogenetic analysis.

Most Highly Enriched Canonical Pathways

Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy.Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy.Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001).Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most frequent side effects of antineoplastic treatment, particularly of lung, breast, prostate, gastrointestinal, and germinal cancers, as well as of different forms of leukemia, lymphoma, and multiple myeloma. Currently, no effective therapies are available for CIPN prevention, and symptomatic treatment is frequently ineffective; thus, several clinical trials are addressing this unmet clinical need. Among possible pharmacological treatments of CIPN, modulation of the endocannabinoid system might be particularly promising, especially in those CIPN types where analgesia and neuroinflammation modulation might be beneficial. In fact, several clinical trials are ongoing with the specific aim to better investigate the changes in endocannabinoid levels induced by systemic chemotherapy and the possible role of endocannabinoid system modulation to provide relief from CIPN symptoms, a hypothesis supported by preclinical evidence but never consistently demonstrated in patients. Interestingly, endocannabinoid system modulation might be one of the mechanisms at the basis of the reported efficacy of exercise and physical therapy in CIPN patients. This possible virtuous interplay will be discussed in this review. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01127-1.

Emergent work suggests that sleep is a robust biobehavioral predictor of pain; however, it remains unclear how sleep is prospectively linked to pain on a day-to-day basis among older adults. The current prospective study examined how sleep duration (total sleep time), quality (sleep efficiency, wake after sleep onset), and late and irregular sleep timing influenced next-day pain perception among community-dwelling older adults ( N = 10; 65 matched observations) with lower extremity chronic pain over 1 week. Multilevel modeling estimated the association between sleep (Actigraph GT9X Link) and pain perception (Brief Pain Inventory Short Form). Increased wake after sleep onset (B = 0.19, p = 0.04), sleep variability (B = 0.02, p = 0.01), and later midsleep time (B = 0.40, p < 0.05) were associated with increased pain interference the following day. Findings support the idea that timely sleep interventions may reduce the effect of poor sleep on next-day pain in older adults. [ Research in Gerontological Nursing, 14 (4), 173–179.]

Background Precision health considers individual lifestyle, genetics, behaviors, and environment context and facilitates interventions aimed at helping individuals achieve well-being and optimal health. Purpose To present the Nursing Science Precision Health (NSPH) Model and describe the integration of precision health concepts within the domains of symptom and self-management science as reflected in the National Institute of Nursing Research P30 Centers of Excellence and P20 Exploratory Centers. Methods Center members developed the NSPH Model and the manuscript based on presentations and discussions at the annual NINR Center Directors Meeting and in follow-up telephone meetings. Discussion The NSPH Model comprises four precision components (measurement; characterization of phenotype including lifestyle and environment; characterization of genotype and other biomarkers; and intervention target discovery, design, and delivery) that are underpinned by an information and data science infrastructure. Conclusion Nurse scientist leadership is necessary to realize the vision of precision health as reflected in the NSPH Model.

Fatigue affects nearly half of all adults with osteoarthritis. Affected individuals report difficulty with daily functioning, requiring more time and rest during activities, feeling easily exhausted, and having to give up on social and volunteer activities known to improve quality of life. Because its etiology is poorly understood, clinical practice guidelines are unable to address management of fatigue in osteoarthritis. Elucidating a mechanism of osteoarthritis fatigue is a high priority, but few studies have identified key factors associated with fatigue in osteoarthritis. Thus, the purpose of this narrative literature review is to present the current evidence of known and potential correlates of fatigue in osteoarthritis, and synthesize our findings into a conceptual framework. The overarching goal of this work is to provide insight into areas of needed research and guide future work toward mechanistic insight of osteoarthritis fatigue. This knowledge could lead to novel nursing interventions for prevention, management, and treatment of fatigue among adults with osteoarthritis.

Background This study evaluated the association between age, sex, comorbidities, cognition, and administration of opioids with pain and the impact of all of these variables plus function, agitation, resistiveness to care, and depression on quality of life among residents in nursing home with severe dementia. Design This was a descriptive study using baseline data from the Evidence Integration Triangle for Behavioral and Psychological Symptoms of Dementia implementation study. Methods Model testing was done using structural equation modeling. The sample included 553 residents from 55 nursing homes with a mean age of 83.88 (standard deviation = 10.44) and mean Brief Interview of Mental Status of 4.30 (standard deviation = 3.50). Results There were significant associations showing those who were older, male, had fewer comorbidities, better cognition, and were black were more likely to have pain. Pain, in combination with the demographic and descriptive variables, explained 32% of the variance in function, 75% of the variance in depression, 88% of the variance in agitation, 98% of the variance in resistiveness to care, and 92% of the variance in quality of life. The model however did not show a good fit to the data. Setting The study was done in 55 nursing homes in Maryland and Pennsylvania. Participants/Subjects A total of 553 residents were included in the study. Conclusions The model did not have a good fit with the data which likely was due to the lack of variance in outcomes. The hypothesized paths, with the exception of opioid use, were significant.

Precision health considers individual lifestyle, genetics, behaviors, and environment context and facilitates interventions aimed at helping individuals achieve well-being and optimal health. The purposes of this manuscript are to present the Nursing Science Precision Health (NSPH) Model and describe the integration of precision health concepts within the domains of symptom and self-management science as reflected in the National Institute of Nursing Research P30 Centers of Excellence and P20 Exploratory Centers. Center members developed the NSPH Model and the manuscript based on presentations and discussions at the annual NINR Center Directors Meeting and in follow-up telephone meetings. The NSPH Model comprises four precision components (measurement; characterization of phenotype including lifestyle and environment; characterization of genotype and other biomarkers; and intervention target discovery, design, and delivery) that are underpinned by an information and data science infrastructure. Nurse scientist leadership is necessary to realize the vision of precision health.

Background Traumatic injury is a major source of chronic pain, particularly for individuals with traumatic fracture of the fibula and/or tibia (lower extremity fracture [LEFx]). Although several factors (e.g., older age, being female, high pain intensity at time of initial injury) have been identified as risk factors for chronic pain associated with LEFx. Comprehensive biopsychosical models to predict the odds of transitioning from acute to chronic pain after LEFx are needed to better understand the underlying processes, predict risk for chronic pain, and develop personalized therapies for individuals at higher risk for developing chronic pain. Objective The aim of the study was to outline the study design that will be used to examine the physiological, psychological, and genetic/genomic variables-models that predict the transition from acute to chronic pain after LEFx. Method This prospective descriptive cohort study will enroll 240 participants with a fibula and/or tibia fracture and 40 controls with no LEFx. Data will be collected during an in-hospital baseline visit, five in-person clinic visits (6 weeks, 12 weeks, 24 weeks, 52 weeks, and 24 months), and seven online between-visit surveys (2 weeks, 4 weeks, 8 weeks, 10 weeks, 16 weeks, 20 weeks, and 18 months) from participants with LEFx and at concordant intervals from controls. Measures will consist of 19 questionnaires characterizing pain and psychological status, neurophysiological testing for peripheral sensory nerve function, and peripheral blood samples collections for RNA sequencing. Illumina standard protocols will be used to sequence RNA, and read counts will be used to measure gene expression. Analysis Direct-entry, multiple logistic regression will be used to produce odds ratios expressing the relative risk on each explanatory variable when controlling for other predictors/covariates in the model. Conclusion This study is one of the first to longitudinally characterize the biopsychosocial variables associated with a clinically relevant problem of the transition from acute to chronic posttraumatic fracture pain in individuals with LEFx. Results from this study will be used to construct predictive risk models of physiological, psychological, and genetic/genomic variables associated with increased risk for transitioning from acute to chronic pain status after LEFx. This work will lead to a better understanding of the trajectory of pain and relevant variables over time; initiate a better understanding of variables associated with risk for transitioning from acute to chronic pain; and, in the future, could provide a foundation for the identification of novel therapeutic targets to improve the outcomes of individuals with LEFx.

Millions of Americans suffer from both acute and chronic pain conditions. While our understanding of the physiological mechanisms underlying pain has increased, pain remains a major healthcare problem in the USA that costs more than $100 million annually for management and due to lost work productivity. The magnitude of the pain problem necessitates that new treatment strategies be discovered, which requires ongoing in-depth research into pain mechanisms, discovery of new therapeutic targets, and the development of new analgesic modalities, both pharmacological and non-pharmacological. This chapter provides a brief overview of pain physiology to help understand where in the pain process new therapeutic targets might be found.

Animal models of pain serve as a way to study the mechanisms in vivo and from the cell to systems level. Distinct pathologies can be mimicked to represent the pathophysiologic context of pain and interrogate the underlying mechanisms through both cellular and behavioral measures. This chapter will describe the various animal models used to study different types of pain, the challenges in translating animal models to humans, and advances that have been facilitated through animal research.

Chapter 2 describes the molecular events associated with pain signaling. The mechanisms associated with chemical, thermal, and mechanical pain signaling in the peripheral nerve endings are detailed. Molecular signaling mechanisms occurring in the spinal dorsal horn, including the primary afferent nociceptor, the inhibitory interneurons, and the descending on-cells and off-cells projecting from the nucleus raphe magnocellularis are described. Persistent increases in pain signaling resulting from inflammatory mediators are explained with reference to specific molecules. Signaling events at supraspinal levels, such as the thalamus, cortex, periaqueductal gray, and nucleus raphe magnus, including cannabinoids, opioids, and noradrenergic and serotonergic neurotransmitter events, are described as critical to pain pathways with relevance to potential pain therapies.

PURPOSE Biomarkers as common data elements (CDEs) are important for the characterization of biobehavioral symptoms given that once a biologic moderator or mediator is identified, biologically based strategies can be investigated for treatment efforts. Just as a symptom inventory reflects a symptom experience, a biomarker is an indicator of the symptom, though not the symptom per se. The purposes of this position paper are to (a) identify a "minimum set" of biomarkers for consideration as CDEs in symptom and self-management science, specifically biochemical biomarkers; (b) evaluate the benefits and limitations of such a limited array of biomarkers with implications for symptom science; (c) propose a strategy for the collection of the endorsed minimum set of biologic samples to be employed as CDEs for symptom science; and (d) conceptualize this minimum set of biomarkers consistent with National Institute of Nursing Research (NINR) symptoms of fatigue, depression, cognition, pain, and sleep disturbance. DESIGN AND METHODS From May 2016 through January 2017, a working group consisting of a subset of the Directors of the NINR Centers of Excellence funded by P20 or P30 mechanisms and NINR staff met bimonthly via telephone to develop this position paper suggesting the addition of biomarkers as CDEs. The full group of Directors reviewed drafts, provided critiques and suggestions, recommended the minimum set of biomarkers, and approved the completed document. Best practices for selecting, identifying, and using biological CDEs as well as challenges to the use of biological CDEs for symptom and self-management science are described. Current platforms for sample outcome sharing are presented. Finally, biological CDEs for symptom and self-management science are proposed along with implications for future research and use of CDEs in these areas. FINDINGS The recommended minimum set of biomarker CDEs include pro- and anti-inflammatory cytokines, a hypothalamic-pituitary-adrenal axis marker, cortisol, the neuropeptide brain-derived neurotrophic factor, and DNA polymorphisms. CONCLUSIONS It is anticipated that this minimum set of biomarker CDEs will be refined as knowledge regarding biologic mechanisms underlying symptom and self-management science further develop. The incorporation of biological CDEs may provide insights into mechanisms of symptoms, effectiveness of proposed interventions, and applicability of chosen theoretical frameworks. Similarly, as for the previously suggested NINR CDEs for behavioral symptoms and self-management of chronic conditions, biological CDEs offer the potential for collaborative efforts that will strengthen symptom and self-management science. CLINICAL RELEVANCE The use of biomarker CDEs in biobehavioral symptoms research will facilitate the reproducibility and generalizability of research findings and benefit symptom and self-management science.

Background: Chronic pain is a significant problem for patients with lower extremity injuries. While pain hypersensitivity has been identified in many chronic pain conditions, it is not known whether patients with chronic pain following lower extremity fracture report pain hypersensitivity in the injured leg. Purpose: To quantify and compare peripheral somatosensory function and sensory nerve activation thresholds in persons with chronic pain following lower extremity fractures with a cohort of persons with no history of lower extremity fractures. Method: This was a cross-sectional study where quantitative sensory testing and current perception threshold testing were conducted on the injured and noninjured legs of cases and both legs of controls. Results: A total of 14 cases and 28 controls participated in the study. Mean time since injury at the time of testing for cases was 22.3 (standard deviation = 12.1) months. The warmth detection threshold ( p = .024) and nerve activation thresholds at 2,000 Hz ( p < .001) and 250 Hz ( p = .002), respectively, were significantly higher in cases compared to controls. Conclusion: This study suggests that patients with chronic pain following lower extremity fractures may experience hypoesthesia in the injured leg, which contrasts with the finding of hyperesthesia previously observed in other chronic pain conditions but is in accord with patients with nerve injuries and surgeries. This is the first study to examine peripheral sensory nerve function at the site of injury in patients with chronic pain following lower extremity fractures using quantitative sensory testing and current perception threshold testing.

Following spinal cord injury (SCI), astrocytes demonstrate long-lasting reactive changes, which are associated with the persistence of neuropathic pain and motor dysfunction. We previously demonstrated that upregulation of trkB.T1, a truncated isoform of the brain-derived neurotrophic factor receptor (BDNF), contributes to gliosis after SCI, but little is known about the effects of trkB.T1 on the function of astrocytes. As trkB.T1 is the sole isoform of trkB receptors expressed on astrocytes, we examined the function of trkB.T1-driven astrocytesin vitroandin vivo. Immunohistochemistry showed that trkB.T1+cells were significantly upregulated 7 d after injury, with sustained elevation in white matter through 8 weeks. The latter increase was predominantly found in astrocytes. TrkB.T1 was also highly expressed by neurons and microglia/macrophages at 7 d after injury and declined by 8 weeks. RNA sequencing of cultured astrocytes derived fromtrkB.T1+/+(WT) andtrkB.T1−/−(KO) mice revealed downregulation of migration and proliferation pathways in KO astrocytes. KO astrocytes also exhibited slower migration/proliferationin vitroin response to FBS or BDNF compared with WT astrocytes. Reduced proliferation of astrocytes was also confirmed after SCI in astrocyte-specifictrkB.T1KO mice; using mechanical allodynia and pain-related measurements on the CatWalk, these animals also showed reduced hyperpathic responses, along with improved motor coordination. Together, our data indicate that trkB.T1 in astrocytes contributes to neuropathic pain and neurological dysfunction following SCI, suggesting that trkB.T1 may provide a novel therapeutic target for SCI.SIGNIFICANCE STATEMENTNeuropathic pain after spinal cord injury (SCI) may in part be caused by upregulation of the brain-derived neurotrophic factor (BDNF) receptor trkB.T1, a truncated isoform of BDNF. TrkB.T1 is the only isoform of tropomyosin-related receptor kinase type B (trkB) receptors expressed on astrocytes. Here, we showed that trkB.T1 is significantly increased in the injured mouse spinal cord, where it is predominantly found in astrocytes. RNA sequencing of cultured astrocytes demonstrated downregulation of migration and proliferation pathways intrkB.T1KO astrocytes. This was validatedin vivo, where deletion oftrkB.T1in astrocytes reduced cell proliferation and migration. After SCI, astrocyte-specifictrkB.T1KO mice showed reduced hyperpathic responses and improved motor coordination. Therefore, the trkB.T1 receptor plays a significant pathophysiological role after SCI, and may provide a novel therapeutic target for SCI.

The mechanisms underlying the transition from acute to chronic pain remain unclear. Here, we sought to characterize the transcriptome associated with chronic low back pain as well as the transcriptome of the transition from acute to chronic low back pain. For the analysis, we compared the whole blood transcriptome of: (a) patients at the onset of low back pain who no longer had pain within 6 weeks after onset (acute) with patients who developed chronic low back pain at 6 months (chronic T5); and, (b) patients at the onset of low back pain (chronic T1) who developed chronic pain at 6 months with healthy pain-free (normal) controls. The majority of differentially expressed genes were protein coding. We illustrate a unique chronic low back pain transcriptome characterized by significant enrichment for known pain genes, extracellular matrix genes, and genes from the extended major histocompatibility complex (MHC) genomic locus. The transcriptome of the transition from acute to chronic low back pain was characterized by significant upregulation of antigen presentation pathway (MHC class I and II) genes and downregulation of mitochondrial genes associated with oxidative phosphorylation, suggesting a unique genomic signature of vulnerability to low back pain chronicity.

Background Multiple cell signaling pathways are implicated in the development, progression, and persistence of cisplatin-induced peripheral neuropathy. Although advances have been made in terms of understanding specific neurotoxic mechanisms, there are few predictive factors identified that can help inform the clinician approach to symptom prevention or management. Objective We investigate the differential sensitivity to cisplatin-induced peripheral neuropathy and examine the contribution of dorsal root ganglion (DRG) transcriptional profiles across two inbred strains of mice. Methods Cisplatin (4 mg/kg intraperitoneal or vehicle control) was administered twice a week for 4 weeks to adult female C57BL/6J and A/J mice-the C57BL/6J strain of mice characterized by a robust mechanical allodynia and the A/J with a mild largely resistant allodynia phenotype. Peripheral nerve conduction velocities (NCVs), electrophysiological evaluation of wide dynamic range (WDR) neurons, morphological examination of DRG neurons, and microarray analysis of spinal cord tissues were compared across the 4 weeks. Results The A/J strain presents with an early, mild nocifensive response to cisplatin with reduced neuronal activity in WDR neurons and small changes in cross-sectional nucleus size in DRG neurons at 4 weeks. The more nocifensive-sensitive C57BL/6J strain presents with no early changes in WDR neuron responsiveness; however, there were significant changes in DRG size. Both strains demonstrate a drop in NCV after 4 weeks of treatment, with the greatest reduction present in the A/J strain. Transcriptome data implicate neuroimmune modulation in the differential response to cisplatin in the DRGs of A/J and C57BL/6J mice. Discussion Nocifensive responses in both strains implicate involvement of small myelinated and unmyelinated fibers in neurotoxic cisplatin response, whereas reductions in NCV reflect involvement of the largest myelinated fibers in the peripheral nerves. Microarray data analysis identifies neuropathy-relevant gene sets with differential activation of pathways, suggesting a role for antigen presentation in the differential neurotoxic response to cisplatin across strains. Further research is indicated to determine the relative contributions of each of these potential pathological mechanisms to both the neurotoxic response to cisplatin and to the potential for targeted therapy.

PURPOSE The purpose of this article was to discuss barriers and potential solutions for strengthening inter- and intraprofessional collaborations that will advance biobehavioral symptom science. ORGANIZING CONSTRUCT General and team-based barriers and solutions for advancing biobehavioral symptom science are reviewed with an exemplar discussion that is guided by Carper's patterns of knowing. CONCLUSIONS Strategic partnerships across nursing associations and organization can help to build collaborations that are focused on symptom science in a specific population, disease, or setting. Additional strategies to build collaborations include supporting interprofessional workgroups, data sharing, and dissemination of research findings across associations. Prioritization of funding opportunities and resources devoted to building inter- and intraprofessional collaborations focused on advancing biobehavioral symptom science will benefit nursing science, the membership, and patients and families. CLINICAL RELEVANCE Nursing associations and organizations can play an integral role in building inter- and intraprofessional teams dedicated to advancing biobehavioral symptom science via multiple ways of knowing that nurses use to generate new knowledge, develop innovations, and apply them in practice.

Pain has a significant effect on physical and psychological outcomes for older adults post orthopedic trauma. The purpose of this study was to describe the management of pain among older trauma patients and consider differences between those who received 3 or more dosages daily of opioids versus those who did not. This was a secondary data analysis using data from an intervention study testing the effect of Function Focused Care among older orthopedic trauma patients (FFC-AC). The FFC-AC study was done on trauma units in two acute care settings designated as Level I or II trauma centers from September 2014 to September 2015. All participants from the parent FFC-AC study were included. Data collection for the parent study was done within 24 hours of admission and within 24 hours of discharge and included demographics, medications, assessment of function, physical activity, mood, physical resilience, and whether the patient had pain and their pain intensity. Patient records included all 89 individuals from the parent study, 59 (66%) of whom were female and 82 (92%) were white. Records indicated that those who received more than three dosages per day of opioids had a shorter length of stay, were younger, had more intense pain, and were more resilient compared with those who received less than three dosages per day. This secondary data analysis provides support for the importance of considering pain and pain management among older adults post trauma.

Brain-derived neurotrophic factor (BDNF), a major focus for regenerative therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, studies of tyrosine receptor kinase B (TrkB), a major receptor for BDNF, indicate that certain effects of the TrkB receptor in response to disease or injury may be maladaptive. More specifically, imbalance among TrkB receptor isoforms appears to contribute to aberrant signaling and hyperpathic pain. A truncated isoform of the receptor, TrkB.T1, lacks the intracellular kinase domain of the full length receptor and is up-regulated in multiple CNS injury models. Such up-regulation is associated with hyperpathic pain, and TrkB.T1 inhibition reduces neuropathic pain in various experimental paradigms. Deletion of TrkB.T1 also limits astrocyte changes in vitro, including proliferation, migration, and activation. Mechanistically, TrkB.T1 is believed to act through release of intracellular calcium in astrocytes, as well as through interactions with neurotrophins, leading to cell cycle activation. Together, these studies support a potential role for astrocytic TrkB.T1 in hyperpathic pain and suggest that targeted strategies directed at this receptor may have therapeutic potential.

Background Effective acute pain management following injury is critical to improve short-and long-term patient outcomes. Analgesics can effectively reduce pain intensity, yet half of injury patients report moderate to severe pain during hospitalization. Purpose The primary aim of this study was to identify the analgesic, different analgesic combinations, or analgesic and adjuvant analgesic combination that generated the largest percent change from pre- to post-analgesic pain score. Design This was a descriptive retrospective cohort study of 129 adults admitted with lower extremity fractures to a trauma center. Methods Name, dose, and frequency of analgesics and adjuvant analgesics administered from admission to discharge were collected from medical records. Percent change was calculated from pain scores documented on the 0-10 numeric rating scale. Results The analgesic with largest percent change from pre- to post-administration pain score was hydromorphone 2 mg IV (53%) for the emergency department and morphine 4 mg IV (54%) for the in-patient unit. All analgesics administered in the emergency department and ∼50% administered on the in-patient unit produced a minimal (15%) decrease in pain score. Conclusions This study revealed that few analgesics administered in the emergency department and the in-patient unit to patients with lower extremity fractures provide adequate pain relief. In the emergency department, all analgesics administered resulted in at least minimal improvement of pain. On the in-patient unit 13 analgesic doses resulted at least minimal improvement in pain while nine doses did not even reach 20% change in pain. Findings from this study can be used guide the treatment of fracture pain in the hospital.

Chronic pain has become a public health epidemic based on the number of Americans affected and its associated health care costs. Unfortunately, there are few efficacious treatments to manage chronic pain and as the population of older adults and centenarians who are at high risk for chronic pain continues to grow, the chronic pain epidemic will continue to worsen unless new therapeutic strategies are discovered. In the current era of precision medicine, there is a major emphasis being placed on the use of self-management and omics to discover new therapeutic targets and design treatment strategies that are tailored to the individual patient. This commentary discusses the current state of the science related to omics and self-management of chronic pain in older adults, the role of gerontological nurses in this process, and future directions. [Res Gerontol Nurs. 2018; 11(1):7–13.]

Context Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity of oxaliplatin and affects most colorectal cancer patients. OIPN is commonly evaluated by patient symptom report, using scales to reflect impairment. They do not discriminate between unique grouping of symptoms and signs, which impedes prompt identification of OIPN. Objective The objective of this study was to identify clusters of symptoms and signs that differentiated underlying clinical severity and segregated patients within our population into OIPN subgroups. Methods Chemotherapy-naive colorectal cancer patients ( N = 148) receiving oxaliplatin were administered the Total Neuropathy Score clinical (TNSc © ), which includes symptom report (sensory, motor, autonomic) and sensory examination (pin sense, vibration, reflexes). The TNSc was administered before chemotherapy initiation (T0) and after cumulative doses of oxaliplatin 510–520 mg/m 2 (T1) and 1020–1040 mg/m 2 of oxaliplatin (T2). Using mean T2 TNSc scores, latent class analysis grouped patients into OIPN severity cohorts. Results Latent class analysis categorized patients into four distinct OIPN groups: low symptoms and low signs ( n = 54); low symptoms and intermediate signs ( n = 44); low symptoms and high signs ( n = 21); and high symptoms and high signs ( n = 29). No differences were noted among OIPN groups on age, sex, chemotherapy regimen, or cumulative oxaliplatin dose. Conclusion We identified OIPN patient groups with distinct symptoms/signs, demonstrating variability of OIPN presentation regardless of cumulative oxaliplatin dose. Over half of the sample had positive findings on OIPN examination despite little or no symptoms. Sensory examination of all patients receiving oxaliplatin is indicated for timely identification of OIPN, which will allow earlier symptom management.

This study evaluated the contributions of psychological status and cardiovascular responsiveness to racial/ethnic differences in experimental pain sensitivity. The baseline measures of 3,159 healthy individuals-non-Hispanic white (NHW): 1,637, African-American (AA): 1,012, Asian: 299, and Hispanic: 211-from the OPPERA prospective cohort study were used. Cardiovascular responsiveness measures and psychological status were included in structural equation modeling based mediation analyses. Pain catastrophizing was a significant mediator for the associations between race/ethnicity and heat pain tolerance, heat pain ratings, heat pain aftersensations, mechanical cutaneous pain ratings and aftersensations, and mechanical cutaneous pain temporal summation for both Asians and AAs compared to NHWs. HR/MAP index showed a significant inconsistent (mitigating) mediating effect on the association between race/ethnicity (AAs vs. NHWs) and heat pain tolerance. Similarly, coping inconsistently mediated the association between race/ethnicity and mechanical cutaneous pain temporal summation in both AAs and Asians, compared to NHWs. The factor encompassing depression, anxiety, and stress was a significant mediator for the associations between race/ethnicity (Asians vs. NHWs) and heat pain aftersensations. Thus, while pain catastrophizing mediated racial/ethnic differences in many of the QST measures, the psychological and cardiovascular mediators were distinctly restrictive, signifying multiple independent mechanisms in racial/ethnic differences in pain.

Spinal cord injury (SCI) frequently causes severe, persistent central neuropathic pain that responds poorly to conventional pain treatments. Brain-derived neurotrophic factor (BDNF) signaling appears to contribute to central sensitization and nocifensive behaviors in certain animal models of chronic pain through effects mediated in part by the alternatively spliced truncated isoform of the BDNF receptor tropomyosin-related kinase B.T1 (trkB.T1). Mechanisms linking trkB.T1 to SCI-induced chronic central pain are unknown. Here, we examined the role of trkB.T1 in central neuropathic pain after spinal cord contusion. Genetic deletion of trkB.T1 in mice significantly reduced post-SCI mechanical hyperesthesia, locomotor dysfunction, lesion volumes, and white matter loss. Whole genome analysis, confirmed at the protein level, revealed that cell cycle genes were upregulated in trkB.T1(+/+) but not trkB.T1(-/-) spinal cord after SCI. TGFβ-induced reactive astrocytes from WT mice showed increased cell cycle protein expression that was significantly reduced in astrocytes from trkB.T1(-/-) mice that express neither full-length trkB nor trkB.T1. Administration of CR8, which selectively inhibits cyclin-dependent kinases, reduced hyperesthesia, locomotor deficits, and dorsal horn (SDH) glial changes after SCI, similar to trkB.T1 deletion, without altering trkB.T1 protein expression. In trkB.T1(-/-) mice, CR8 had no effect. These data indicate that trkB.T1 contributes to the pathobiology of SCI and SCI pain through modulation of cell cycle pathways and suggest new therapeutic targets.

Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy. Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy. Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001). Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.

Our objective was to describe the racial and ethnic differences in experimental pain sensitivity. Four databases (PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and PsycINFO) were searched for studies examining racial/ethnic differences in experimental pain sensitivity. Thermal-heat, cold-pressor, pressure, ischemic, mechanical cutaneous, electrical, and chemical experimental pain modalities were assessed. Risk of bias was assessed using the Agency for Healthcare Research and Quality guideline. Meta-analysis was used to calculate standardized mean differences (SMDs) by pain sensitivity measures. Studies comparing African Americans (AAs) and non-Hispanic whites (NHWs) were included for meta-analyses because of high heterogeneity in other racial/ethnic group comparisons. Statistical heterogeneity was assessed by subgroup analyses by sex, sample size, sample characteristics, and pain modalities. A total of 41 studies met the review criteria. Overall, AAs, Asians, and Hispanics had higher pain sensitivity compared with NHWs, particularly lower pain tolerance, higher pain ratings, and greater temporal summation of pain. Meta-analyses revealed that AAs had lower pain tolerance (SMD: -0.90, 95% confidence intervals [CIs]: -1.10 to -0.70) and higher pain ratings (SMD: 0.50, 95% CI: 0.30-0.69) but no significant differences in pain threshold (SMD: -0.06, 95% CI: -0.23 to 0.10) compared with NHWs. Estimates did not vary by pain modalities, nor by other demographic factors; however, SMDs were significantly different based on the sample size. Racial/ethnic differences in experimental pain sensitivity were more pronounced with suprathreshold than with threshold stimuli, which is important in clinical pain treatment. Additional studies examining mechanisms to explain such differences in pain tolerance and pain ratings are needed.

Many patients with injuries to lower extremities report chronic pain. High pain intensity at time of admission for injury is a risk factor for chronic pain, but it is not clear whether specific acute pain patterns following injury influence the development of chronic pain. To examine the relationship between the pain trajectory, the mean pain score, and the frequency of pain documentation during the immediate hospitalization following injury, with the report of chronic pain. This was a descriptive, retrospective cohort study of adults admitted with lower extremity fractures to an academic urban trauma center. Participants, 6-45 months postinjury, rated their current pain, worst pain, and average pain over the last 3 months. Pain scores from hospitalization associated with the injury were obtained through a retrospective chart review. The pain trajectory, mean pain score, and frequency of pain documentation was compared between patients with and without chronic pain. A total of 129 patients were enrolled in this study and 78% reported chronic pain at the site of injury. The mean pain score (5.1 vs. 4.2) and first pain score (5.6 vs. 3.4) were higher for patients with chronic pain compared to patients with no chronic pain. Consistent with other studies, high pain intensity at time of injury was associated with chronic pain. The findings contribute valuable information about acute pain characteristics associated with chronic pain and provide insight into the importance of early and adequate acute pain treatment.

Background Aromatase inhibitors (AIs) have been established as successful adjuvant therapy for breast cancer survivors. Unfortunately, nearly half of women taking AIs report joint pain, AI-associated arthralgia (AIA). Aromatase inhibitor-associated arthralgia often results in noncompliance, which could lead to cancer recurrence. Objective The purpose of this study was to identify current pain management of AIA and to evaluate the study quality and effects of interventions. Methods Nineteen articles published from 2000 to August 2015 were identified using PubMed, CINAHL, PsycINFO, Web of Science, and additional records. Study quality was evaluated by the Quality Assessment Tool for Quantitative Studies. Meta-analysis was used to obtain effect sizes of interventions on pain and subgroups. Results Five types of interventions emerged: pharmacological approaches, acupuncture, nutritional supplementation, relaxation techniques, and physical exercise. Six studies were strong, 8 were moderate, and 5 were weak in quality. The overall effect size of the interventions on pain was large; pharmacological approaches, acupuncture, and relaxation techniques showed moderate to large effects on pain, whereas nutritional supplementation and physical exercise had no significant effects on it. Conclusion The evidence was based on a body of research with moderate study quality. Although the overall effect of interventions is large, further investigation into the influence of nutrition and physical exercise is needed to better discern their potential for pain management. Implication for practice Oncology nurses may be able to implement such validated interventions as pain management modalities to mitigate the symptoms so that breast cancer survivors remain compliant with AIA therapy.

Chronic pain after spinal cord injury (SCI) may present as hyperalgesia, allodynia, and/or spontaneous pain and is often resistant to conventional pain medications. Identifying more effective interventions to manage SCI pain requires improved understanding of the pathophysiological mechanisms involved. Cell cycle activation (CCA) has been implicated as a key pathophysiological event following SCI. We have shown that early central or systemic administration of a cell cycle inhibitor reduces CCA, prevents glial changes, and limits SCI-induced hyperesthesia. Here, we compared the effects of early vs late treatment with the pan-cyclin-dependent kinase inhibitor flavopiridol on allodynia as well as spontaneous pain. Adult C57BL/6 male mice subjected to moderate SCI were treated with intraperitoneal injections of flavopiridol (1 mg/kg), daily for 7 days beginning either 3 hours or 5 weeks after injury. Mechanical/thermal allodynia was evaluated, as well as spontaneous pain using the mouse grimace scale (MGS). We show that sensitivity to mechanical and thermal stimulation, and locomotor dysfunction were significantly reduced by early flavopiridol treatment compared with vehicle-treated controls. Spinal cord injury caused robust and extended increases of MGS up to 3 weeks after trauma. Early administration of flavopiridol significantly shortened duration of MGS changes. Late flavopiridol intervention significantly limited hyperesthesia at 7 days after treatment, associated with reduced glial changes, but without effect on locomotion. Thus, our data suggest that cell cycle modulation may provide an effective therapeutic strategy to reduce hyperesthesia after SCI, with a prolonged therapeutic window.

Neurotrophin-dependent activation of the tyrosine kinase receptor trkB.FL modulates neuromuscular synapse maintenance and function; however, it is unclear what role the alternative splice variant, truncated trkB ( trkB.T1), may have in the peripheral neuromuscular axis. We examined this question in trkB.T1 null mice and demonstrate that in vivo neuromuscular performance and nerve-evoked muscle tension are significantly increased. In vitro assays indicated that the gain-in-function in trkB.T1−/−animals resulted specifically from an increased muscle contractility, and increased electrically evoked calcium release. In the trkB.T1 null muscle, we identified an increase in Akt activation in resting muscle as well as a significant increase in trkB.FL and Akt activation in response to contractile activity. On the basis of these findings, we conclude that the trkB signaling pathway might represent a novel target for intervention across diseases characterized by deficits in neuromuscular function.

Up to 62% of patients report chronic pain at the injury site 6-12 months after blunt trauma, with pain from lower extremity fractures exceeding that from other sites. High pain intensity at time of injury is a risk factor for chronic pain, but it is not clear what patient characteristics influence the pain intensity level during the immediate hospitalization following injury. The purpose of this pilot study was to determine the feasibility of collecting pain scores from medical records to calculate pain trajectories and to determine whether it is possible to examine patient characteristics by classifying them into those whose pain improved and those whose pain did not improve. This descriptive study retrospectively reviewed medical records of 18 randomly chosen patients admitted to an academic trauma center. Patient characteristics and pain scores were collected form electronic and handwritten medical records. The pain trajectories calculated from routinely collected pain scores during the inpatient stay showed that for 44% of patients the pain improved during the hospitalization, for 39% the pain remained the same, and for 17% the pain worsened. The variables age, smoking, weight, abbreviated injury scores, length of hospital stay, mean pain score, and opioid equianalgesic dose differed based on pain trajectory. While patient characteristics differed based on pain trajectory, any significant effects seen from individual tests should be considered tentative, given the number of analyses conducted on this data set. However, feasibility and significance of conducting a larger study has been established.

Animal models are a critical component of biomedical and biobehavioral research and have contributed to the exponential expansion of our understanding of human disease. Now, as we move onward into the era of genetics and genomics research, the importance of animal models to the research process will become even more acute as we explore the significance of genetic differences that are found in the presence and absence of disease. The decision to use an animal model is not one that can be taken lightly; but, rather, requires careful thought and consideration. In this review, we will address (a) why we should consider using animal models, (b) several caveats that are associated with using animals for research, and (c) some of the common genetic tools that are used in animal research.

Nucleoside reverse transcriptase inhibitors (NRTIs) are key components of HIV/AIDS treatment to reduce viral load. However, these drugs can induce chronic neuropathic pain, leading to increased morbidity in HIV patients. This study examines the role of brain-derived neurotrophic factor (BDNF) in the spinal dorsal horn (SDH) in development of mechanical allodynia in male C57BL/6J mice treated with the NRTI stavudine (d4T). After d4T administration, mice developed increased neuronal activity and BDNF expression in the SDH and hind paw mechanical allodynia that was exacerbated by intrathecal BDNF administration. Intrathecal BDNF alone also increased neuronal activity and caused mechanical allodynia. Because excess BDNF amplified d4T-induced mechanical allodynia and neuronal activity, the impact of decreasing BDNF in the SDH was investigated. After d4T, BDNF heterozygous mice were less allodynic than wild-type littermates, which was negated by intrathecal BDNF administration. Finally, pretreatment with intrathecal trkB-Fc chimera prior to d4T or administration of the tyrosine kinase inhibitor K252a 3 days after d4T blocked BDNF-mediated signaling, significantly attenuated the development of mechanical allodynia (trkB-Fc), and decreased neuronal activity (trkB-Fc and K252a). Taken together, these findings provide evidence that BDNF in the SDH contributes to the development of NRTI-induced painful peripheral neuropathy and may represent a new therapeutic opportunity.

Painful peripheral neuropathy is a debilitating complication of the treatment of HIV with nucleoside reverse transcriptase inhibitors (NRTIs). Patients are living longer with these drugs; however many develop excruciating, unremitting, and often treatment-limiting neuropathy that is resistant to conventional pain management therapies. Improving patient comfort and quality of life is paramount and depends on a clearer understanding of this devastating side effect. The mechanisms underlying the development of NRTI-induced neuropathy, however, remain unclear. Using a mouse model of NRTI-induced neuropathy, the authors conducted an unbiased whole-genome microarray screen to identify molecular targets in the spinal dorsal horn, which is the location where integration of ascending sensory transmission and descending modulatory effects occur. Analysis of the microarray data identified a change in the gene giant axonal neuropathy 1 (Gan1). Mutation of this gene has been linked to the development of giant axonal neuropathy (GAN), a rare autosomal recessive condition characterized by a progressive sensorimotor neuropathy. Gan1 has not been previously linked to nerve pathologies in other populations. In this study, downregulation of the Gan1 gene and the gene protein product, gigaxonin, was validated via quantitative polymerase chain reaction ([qPCR] gene expression) and Western blot analyses (protein level). Our report is the first to suggest that Gan1 might be a novel molecular target in the development of NRTI-induced peripheral neuropathy with implications for new therapeutic approaches to preventing or reducing a significant side effect of HIV treatment.

Brain-Derived Neurotrophic Factor (BDNF) is a central nervous system modulator of nociception. In animal models of chronic pain, BDNF exerts its effects on nociceptive processing by binding to the full-length receptor tropomyosin-related kinase B (trkB.FL) and transducing intracellular signaling to produce nocifensive behaviors. In addition to trkB.FL, the trkB locus also produces a widely-expressed alternatively-spliced truncated isoform, trkB.T1. TrkB.T1 binds BDNF with high affinity; however the unique 11 amino acid intracellular cytoplasmic tail lacks the kinase domain of trkB.FL. Recently, trkB.T1 was shown to be specifically up-regulated in a model of HIV-associated neuropathic pain, potentially implicating trkB.T1 as a modulator of nociception. Here, we report that trkB.T1 mRNA and protein is up-regulated in the spinal dorsal horn at times following antiretroviral drug treatment and hind paw inflammation in which nocifensive behaviors develop. While genetic depletion of trkB.T1 did not affect baseline mechanical and thermal thresholds, the absence of trkB.T1 resulted in significant attenuation of inflammation- and antiretroviral-induced nocifensive behaviors. Our results suggest that trkB.T1 up-regulation following antiretroviral treatment and tissue inflammation participates in the development and maintenance of nocifensive behavior and may represent a novel therapeutic target for pain treatment.

Background: Animal models in pain research have suggested that inclusion of both evoked and nonevoked behavioral measures is needed to better reflect the human pain experience. Individuals with chronic pain are known to experience spontaneous pain, in addition to pain after exposure to an external stimulus. Recently, the dynamic weight bearing (DWB) apparatus was developed to assess for nonevoked hyperalgesia by capturing weight bearing and surface distribution in the paws of mice after acute inflammation. Objectives: The aim of this study was to evaluate the DWB test as a measure of nonevoked hyperalgesia. Methods: The experimental group received an intraplantar injection in the left hind paw of the inflammatory agent—complete Freund’s adjuvant (CFA)—whereas the vehicle control group received a saline injection and the naive control group had no treatment. Calipers and a plethysmometer were used to verify inflammation and the hot-plate test was used as a measure for stimulus-evoked hyperalgesia. Data were collected at baseline; 3 hours; and 1, 3, and 7 days after injection. Results: Mice injected with CFA showed a statistically significant higher mean paw thickness and volume displacement compared with the vehicle and naive control groups. In the hot-plate testing, CFA-treated mice showed lower response temperature at 7 days compared with the other groups. On the DWB test, CFA-treated mice showed a reduction in the ipsilateral paw load and surface area compared with the contralateral paw load at Days 1, 3, and 7. Discussion: Mice with inflammation showed alterations in weight bearing as well as increased thermal hyperalgesia in comparison with control groups. These findings support the use of the DWB test as a tool for measuring nonevoked inflammatory hyperalgesia in a mouse model.