Managing Chronic Regional Pain Syndrome: The Potential Impact of the Food and Drug Omnibus Reform Act.

Complex regional pain syndrome (CRPS) is a neurological disorder characterized by persistent limb symptoms. With there being no definitive tests, diagnosis can be challenging. The Budapest criteria are the standard for diagnosis. The underlying mechanisms of CRPS involve changes in skin innervation, sensitization of the nervous system, inflammatory cytokines, and genetic and psychological factors. Treatment typically involves a multidisciplinary approach. We present a case of a 71-year-old male with CRPS involving the right upper extremity and a complex history of management including physical therapy, oxycodone, muscle relaxers, non-steroidal anti-inflammatory drugs, and multiple stellate ganglion blocks. The patient manages his pain with off-label medications, including methadone, duloxetine, and pregabalin. In the United States, the management of chronic pain may be affected by potential usage restrictions imposed by the Food and Drug Omnibus Reform Act (FDORA). Under this new act, physicians may face limitations in prescribing off-label medications for specific diagnoses. We aim to highlight the need for prioritizing patient care and individualized treatment in healthcare policy decision-making.

Mechanisms of improved erythroid progenitor growth with removal of chronic stress after trauma.

BACKGROUND: Erythropoietic dysfunction after trauma and critical illness is associated with anemia, persistent inflammation, increased hematopoietic progenitor cell mobilization from the bone marrow, and reduced erythroid progenitor growth. Yet the duration and reversibility of these postinjury bone marrow changes remain unknown. This study sought to determine whether removal of chronic postinjury stress could induce improvements in erythroid progenitor growth. METHODS: Sprague-Dawley rats (n = 8-11/group) were assigned to the following: naïve, lung contusion and hemorrhagic shock, lung contusion and hemorrhagic shock plus daily chronic stress for 7 days followed by 7 days of routine handling to allow recovery (lung contusion and hemorrhagic shock + chronic stress 7), or lung contusion and hemorrhagic shock plus chronic stress for 14 days (lung contusion and hemorrhagic shock + chronic stress 14). Circulating CD117+CD71+ erythroid progenitors were detected by flow cytometry. Rodents were killed on day 14, and bone marrow erythroid progenitor growth and erythroid transcription factors were assessed. Differences were assessed by analysis of variance (P < .05). RESULTS: Compared to lung contusion and hemorrhagic shock + chronic stress 14, lung contusion and hemorrhagic shock + chronic stress 7 rodents had improved hemoglobin (8% ± 10% increase vs 6% ± 10% decrease) with fewer mobilized erythroid progenitors (898 × vs 1,524 cells), lower granulocyte-colony stimulating factor levels (3.1 ± 1.1 × pg/mL vs 5.9 ± 1.8 pg/mL), and improved erythroid progenitor growth. Cessation of stress had no impact on erythroid transcription factors GATA-1, GATA-2, LMO2, or KLF1. CONCLUSION: Improvements in erythroid progenitor growth and reduced hematopoietic progenitor cell mobilization were seen 7 days after cessation of chronic stress and were associated with an improvement in hemoglobin. Early bone marrow erythropoietic functional recovery may result from resolution of hematopoietic progenitor mobilization rather than upregulation of pro-erythroid transcription factors. This study suggests that postinjury anemia is reversible and has the potential to improve with the cessation of stress.

Stress-related changes in the gut microbiome after trauma.

BACKGROUND: The gut microbiome protects the host from infection by promoting epithelial integrity and providing basal immunologic stimulation. Disruption of this delicate ecosystem is linked to morbidity and mortality among critically ill patients, but the impact of traumatic injury on the gut microbiome is poorly understood. This study sought to identify alterations in gut microbiota following trauma and persistent stress in rodents without confounding antibiotics. METHODS: Male Sprague-Dawley rats aged 9 weeks to 11 weeks were randomized to naive, lung contusion with hemorrhagic shock (LCHS), and LCHS plus either 7 (LCHS/CS 7/7) or 14 days (LCHS/CS 14) of restraint cylinder stress for 2 hours daily. Stool was collected on Days 0, 3, 7, and 14 for bacterial whole genome DNA isolation. Alpha diversity, or the number and relative abundance of unique bacterial species within each cohort, was assessed using Chao1 indices. Beta diversity, or the measure of differences in biodiversity across cohorts, was assessed by principle coordinate analysis. False discovery rate correction was applied to all statistical analyses and corrected for cohousing effects. RESULTS: Rodent groups subject to restraint stress demonstrated a progressive increase in alpha diversity over time. These microbiota changes resolved after cessation of stress (LCHS/CS 7/7) but continued to increase among rats subjected to ongoing stress (LCHS/CS 14). The LCHS/CS 7/7 also demonstrated reductions in class Actinobacteria and increased abundance of the genus Bacteroides by Day 7, which resolved by Day 14. Increased abundance of Bacteroides was also noted in the LCHS/CS 14 cohort, suggesting the role of chronic stress in its destabilization. CONCLUSION: This study points to persistent stress as a potential source of the destabilization of microbial diversity seen after trauma. This lack of microbiota stability could be associated with worse long-term outcomes in critically ill trauma patients. Further studies are warranted to elucidate mechanistic pathways and potential therapeutic modalities.

Effect of Beta-Blockade on the Expression of Regulatory MicroRNA after Severe Trauma and Chronic Stress.

BACKGROUND: Beta-blockade administration after lung contusion, hemorrhagic shock, and chronic stress has been shown to improve bone marrow function, decrease hypercatecholaminemia, and reduce inflammation. MicroRNAs (miR) are critical biologic regulators that can downregulate gene expression by causing messenger RNA degradation or inhibition of translation. This study sought to expand our understanding of the molecular mechanisms underlying the reduced inflammatory response after the administration of beta-blockade (BB) in our rodent trauma model. STUDY DESIGN: Male Sprague-Dawley rats aged 8 to 9 weeks were randomized to lung contusion, hemorrhagic shock with daily restraint stress (LCHS/CS) or LCHS/CS plus propranolol (LCHS/CS+BB). Restraint stress occurred 2 hours daily after LCHS. Propranolol (10 mg/kg) was given daily until day 7. Total RNA and miR were isolated from bone marrow and genome-wide miR expression patterns were assayed. Bone marrow cytokine expression was determined with quantitative polymerase chain reaction. RESULTS: LCHS/CS led to significantly increased bone marrow expression of interleukin (IL) 1ß, tumor necrosis factor-α, IL-6, nitric oxide, and plasma C-reactive protein. There were marked differences in expression of 45 miRs in the LCHS/CS+BB group compared with the LCHS/CS group when using a p value <0.001. Rno-miR-27a and miR-25 were upregulated 7- to 8-fold in the rodents who underwent LCHS/CS+BB compared with LCHS/CS alone, and this correlated with reduced bone marrow expression of IL-1ß, tumor necrosis factor-α, IL-6, nitric oxide, and reduced plasma C-reactive protein in the LCHS/CS+BB group. CONCLUSIONS: The genomic and miR expression patterns in bone marrow after LCHS/CS differed significantly compared with rodents that received propranolol after LCHS/CS. The use of BB after severe trauma can help mitigate persistent inflammation by upregulating Rno-miR-27a and miR-25 and reducing inflammatory cytokines in those who remain critically ill.