Sarah D. Linnstaedt

Gender differences in acute and chronic pain in the emergency department: Results of the 2014 academic emergency medicine consensus conference pain section

Pain is a leading public health problem in the United States, with an annual economic burden of more than

μ-Opioid Receptor Gene A118 G Variants and Persistent Pain Symptoms Among Men and Women Experiencing Motor Vehicle Collision

630 billion, and is one of the most common reasons that individuals seek emergency department (ED) care. There is a paucity of data regarding sex differences in the assessment and treatment of acute and chronic pain conditions in the ED. The Academic Emergency Medicine consensus conference convened in Dallas, Texas, in May 2014 to develop a research agenda to address this issue among others related to sex differences in the ED. Prior to the conference, experts and stakeholders from emergency medicine and the pain research field reviewed the current literature and identified eight candidate priority areas. At the conference, these eight areas were reviewed and all eight were ratified using a nominal group technique to build consensus. These priority areas were: 1) gender differences in the pharmacological and nonpharmacological interventions for pain, including differences in opioid tolerance, side effects, or misuse; 2) gender differences in pain severity perceptions, clinically meaningful differences in acute pain, and pain treatment preferences; 3) gender differences in pain outcomes of ED patients across the life span; 4) gender differences in the relationship between acute pain and acute psychological responses; 5) the influence of physician-patient gender differences and characteristics on the assessment and treatment of pain; 6) gender differences in the influence of acute stress and chronic stress on acute pain responses; 7) gender differences in biological mechanisms and molecular pathways mediating acute pain in ED populations; and 8) gender differences in biological mechanisms and molecular pathways mediating chronic pain development after trauma, stress, or acute illness exposure. These areas represent priority areas for future scientific inquiry, and gaining understanding in these will be essential to improving our understanding of sex and gender differences in the assessment and treatment of pain conditions in emergency care settings.

CRHBP polymorphisms predict chronic pain development following motor vehicle collision

UNLABELLED The μ-opioid receptor 1 (OPRM1) binds endogenous opioids. Increasing evidence suggests that endogenous OPRM1 agonists released at the time of trauma may contribute to the development of posttraumatic musculoskeletal pain (MSP). In this prospective observational study, we evaluated the hypothesis that individuals with an AG or GG genotype at the OPRM1 A118 G allele, which results in a reduced response to opioids, would have less severe MSP 6 weeks after motor vehicle collision (MVC). Based on previous evidence, we hypothesized that this effect would be sex-dependent and most pronounced among women with substantial peritraumatic distress. European American men and women ≥ 18 years of age presenting to the emergency department after MVC and discharged to home after evaluation (N = 948) were enrolled. Assessments included genotyping and 6-week evaluation of overall MSP severity (0-10 numeric rating scale). In linear regression modeling, a significant A118 G Allele × Sex interaction was observed: an AG/GG genotype predicted reduced MSP severity among women with substantial peritraumatic distress (β = -.925, P = .014) but not among all women. In contrast, men with an AG/GG genotype experienced increased MSP severity at 6 weeks (β = .827, P = .019). Further studies are needed to understand the biologic mechanisms mediating observed sex differences in A118 G effects. PERSPECTIVE These results suggest a sex-dependent mechanism by which an emotional response to trauma (distress) contributes to a biologic mechanism (endogenous opioid release) that increases MSP in the weeks after stress exposure. These results also support the hypothesis that endogenous opioids influence pain outcomes differently in men and women.

Genetic variant rs3750625 in the 3'UTR of ADRA2A affects stress-dependent acute pain severity after trauma and alters a microRNA-34a regulatory site.

Abstract Musculoskeletal pain (MSP) is a common sequela of traumatic stress exposure. While biological factors contributing to chronic MSP after motor vehicle collision (MVC) have traditionally focused on tissue injury, increasing evidence suggests that neuro/stress/immune processes mediated by stress system activation may play a more dominant role. In a previous study, we found that genetic variants in the hypothalamic–pituitary–adrenal (HPA) axis–related gene FKBP5 influence vulnerability to persistent MSP 6 weeks after MVC. In the present cohort study (n = 855), we evaluated whether genetic variants in several other important HPA axis–related genes, including the glucocorticoid receptor (NR3C1), corticotropin-releasing hormone receptor R1 (CRHR1), and corticotropin-releasing hormone-binding protein (CRHBP), influence risk of chronic MSP over time after MVC. Genetic polymorphism rs7718461 in the CRHBP gene showed significant association (P = 0.0012) with overall pain severity during the year after MVC in regression models controlling for multiple comparisons. Two additional CRHBP alleles in high linkage disequilibrium with rs7718461 also showed trend-level significance. In secondary analyses, a significant interaction between this CRHBP locus (minor allele frequency = 0.33) and time was observed (P = 0.015), with increasing effect observed over time following trauma. A significant CRHBP × FKBP5 interaction was also observed, with substantially increased MSP after MVC in those with a risk allele in both genes compared with either gene alone. The results of this study indicate that genetic variants in 2 different HPA axis genes predict chronic MSP severity following MVC and support the hypothesis that the HPA axis is involved in chronic post-MVC MSP pathogenesis.

Gender Differences in Pain Experience and Treatment after Motor Vehicle Collisions: A Secondary Analysis of the CRASH Injury Study

Abstract &agr;2A adrenergic receptor (&agr;2A-AR) activation has been shown in animal models to play an important role in regulating the balance of acute pain inhibition vs facilitation after both physical and psychological stress. To our knowledge, the influence of genetic variants in the gene encoding &agr;2A-AR, ADRA2A, on acute pain outcomes in humans experiencing traumatic stress has not been assessed. In this study, we tested whether a genetic variant in the 3′UTR of ADRA2A, rs3750625, is associated with acute musculoskeletal pain (MSP) severity following motor vehicle collision (MVC, n = 948) and sexual assault (n = 84), and whether this influence was affected by stress severity. We evaluated rs3750625 because it is located in the seed binding region of miR-34a, a microRNA (miRNA) known to regulate pain and stress responses. In both cohorts, the minor allele at rs3750625 was associated with increased musculoskeletal pain in distressed individuals (stress*rs3750625 P = 0.043 for MVC cohort and P = 0.007 for sexual assault cohort). We further found that (1) miR-34a binds the 3′UTR of ADRA2A, (2) the amount of repression is greater when the minor (risk) allele is present, (3) miR-34a in the IMR-32 adrenergic neuroblastoma cell line affects ADRA2A expression, (4) miR-34a and ADRA2A are expressed in tissues known to play a role in pain and stress, (5) following forced swim stress exposure, rat peripheral nerve tissue expression changes are consistent with miR-34a regulation of ADRA2A. Together, these results suggest that ADRA2A rs3750625 contributes to poststress musculoskeletal pain severity by modulating miR-34a regulation.

Methodology of AA CRASH: a prospective observational study evaluating the incidence and pathogenesis of adverse post-traumatic sequelae in African-Americans experiencing motor vehicle collision

PURPOSE Little is known about gender differences in the treatment of pain after motor vehicle collisions (MVCs) in an emergency department (ED). We aimed to describe gender differences in pain experiences and treatment, specifically the use of opioids and benzodiazepines after ED discharge, for MVC-related pain. METHODS This was a secondary analysis of previously collected data from the CRASH Injury studies. We included patients who were seen and discharged from an ED after an MVC and who were enrolled in 1 of 2 multicenter longitudinal prospective cohort studies (1 black/non-Hispanic and 1 white/non-Hispanic). First, we compared the experience of pain as defined by self-reported moderate-to-severe axial pain, widespread pain, number of somatic symptoms, pain catastrophizing, and peritraumatic distress between women and men using bivariate analyses. We then determined whether there were gender differences in the receipt of prescription medications for post-MVC pain symptoms (opioids and benzodiazepines) using multivariate logistic regression adjusting for demographic characteristics, pain, and collision characteristics. FINDINGS In total, 1878 patients were included: 61.4% were women. More women reported severe symptoms on the pain catastrophizing scale (36.8% vs 31.0%; P = 0.032) and peritraumatic distress following the MVC (59.7% vs 42.5%; P < 0.001), and women reported more somatic symptoms than men (median, 3.9; interquartile range, 3.7-4.0 vs median, 3.3; interquartile range, 3.1-3.5; P < 0.001). Unadjusted, similar proportions of women and men were given opioids (29.2% vs 29.7%; P = 0.84). After adjusting for covariates, women and men remained equally likely to receive a prescription for opioids (relative risk = 0.83; 95% confidence interval, 0.58-1.19). Women were less likely than men to receive a benzodiazepine at discharge from an ED (relative risk = 0.53; 95% confidence interval, 0.32-0.88). IMPLICATIONS In a large, multicenter study of ED patients treated for MVC, there were gender differences in the acute psychological response to MVC with women reporting more psychological and somatic symptoms. Women and men were equally likely to receive opioid prescriptions at discharge. Future research should investigate potential gender-specific interventions to reduce both posttraumatic distress and the risk of developing negative long-term outcomes like chronic pain.

A functional riboSNitch in the 3′UTR of FKBP5 alters microRNA-320a binding efficiency and mediates vulnerability to chronic posttraumatic pain

Introduction A motor vehicle collision (MVC) is one of the most common life-threatening events experienced by individuals living in the USA. While most individuals recover following MVC, a significant proportion of individuals develop adverse post-traumatic sequelae such as post-traumatic stress disorder or persistent musculoskeletal pain. Adverse post-traumatic sequelae are common, morbid and costly public health problems in the USA and other industrialised countries. The pathogenesis of these disorders following MVC remains poorly understood. In the USA, available data suggest that African-Americans experience an increased burden of adverse post-traumatic sequelae after MVC compared to European Americans, but to date no studies examining the pathogenesis of these disorders among African-Americans experiencing MVC have been performed. Methods and analysis The African-American CRASH (AA CRASH) study is an NIH-funded, multicentre, prospective study that enrols African-Americans (n=900) who present to the emergency department (ED) within 24 hours of MVC. Participants are enrolled at 13 ED sites in the USA. Individuals who are admitted to the hospital or who report a fracture or tissue injury are excluded. Participants complete a detailed ED interview that includes an assessment of crash history, current post-traumatic symptoms and health status prior to the MVC. Blood samples are also collected in the ED using PAXgene DNA and PAXgene RNA tubes. Serial mixed-mode assessments 6 weeks, 6 months and 1 year after MVC include an assessment of adverse sequelae, general health status and health service utilisation. The results from this study will provide insights into the incidence and pathogenesis of persistent pain and other post-traumatic sequelae in African-Americans experiencing MVC. Ethics and dissemination AA CRASH has ethics approval in the USA, and the results will be published in a peer-reviewed journal.

(282) Sex-dependent expression of microRNA -19b predicts chronic widespread pain and posttraumatic stress disorder development following trauma exposure

Previous studies have shown that common variants of the gene coding for FK506-binding protein 51 (FKBP5), a critical regulator of glucocorticoid sensitivity, affect vulnerability to stress-related disorders. In a previous report, FKBP5 rs1360780 was identified as a functional variant because of its effect on gene methylation. Here we report evidence for a novel functional FKBP5 allele, rs3800373. This study assessed the association between rs3800373 and post-traumatic chronic pain in 1607 women and men from two ethnically diverse human cohorts. The molecular mechanism through which rs3800373 affects adverse outcomes was established via in silico, in vivo, and in vitro analyses. The rs3800373 minor allele predicted worse adverse outcomes after trauma exposure, such that individuals with the minor (risk) allele developed more severe post-traumatic chronic musculoskeletal pain. Among these individuals, peritraumatic circulating FKBP5 expression levels increased as cortisol and glucocorticoid receptor (NR3C1) mRNA levels increased, consistent with increased glucocorticoid resistance. Bioinformatic, in vitro, and mutational analyses indicate that the rs3800373 minor allele reduces the binding of a stress- and pain-associated microRNA, miR-320a, to FKBP5 via altering the FKBP5 mRNA 3′UTR secondary structure (i.e., is a riboSNitch). This results in relatively greater FKBP5 translation, unchecked by miR-320a. Overall, these results identify an important gene–miRNA interaction influencing chronic pain risk in vulnerable individuals and suggest that exogenous methods to achieve targeted reduction in poststress FKBP5 mRNA expression may constitute useful therapeutic strategies. SIGNIFICANCE STATEMENT FKBP5 is a critical regulator of the stress response. Previous studies have shown that dysregulation of the expression of this gene plays a role in the pathogenesis of chronic pain development as well as a number of comorbid neuropsychiatric disorders. In the current study, we identified a functional allele (rs3800373) in the 3′UTR of FKBP5 that influences vulnerability to chronic post-traumatic pain in two ethnic cohorts. Using multiple complementary experimental approaches, we show that the FKBP5 rs3800373 minor allele alters the secondary structure of FKBP5 mRNA, decreasing the binding of a stress- and pain-associated microRNA, miR-320a. This results in relatively greater FKBP5 translation, unchecked by miR-320a, increasing glucocorticoid resistance and increasing vulnerability to post-traumatic pain.

μ-Opioid Receptor Gene A118G Polymorphism Predicts Pain Recovery After Sexual Assault

results suggest that the induction of CD163 via mPEI nanoparticles can shift the phenotype to an anti-inflammatory profile in human macrophages under different inflammatory conditions. This translational approach could be useful to specifically target macrophages in chronic inflammatory conditions such as invasive surgeries to prevent the development of chronic pain. Supported by Rita Allen Foundation & American Pain Society 2011 Pain grant (AR-S); National Institutes of Health, NIGMS, R15GM109333 (AR-S). PRSI program 2014 and 2015, Presbyterian College School of Pharmacy (AA, LB and DF).