Olbrecht, VA; Ding, L; Spruance, K; Hossain, M; Sadhasivam, S; Chidambaran, V. Intravenous Acetaminophen Reduces Length of Stay Via Mediation of Postoperative Opioid Consumption After Posterior Spinal Fusion in a Pediatric Cohort. Clinical Journal of Pain. 2018; 34(7):593-599.
Intravenous acetaminophen (IV APAP) is commonly used at many institutions to optimize pain management, including in pediatric settings. Since the United States Food and Drug Administration approved IV acetaminophen (IV APAP) in 2010 its use has become quite common in pediatrics without strong positive evidence. The key advantage of IV APAP is that it results in greater central nervous system penetration with corresponding superior analgesic efficacy in the surgical setting as compared to the oral version. To date, the only evidence supporting cost-effectiveness of IV APAP use comes from a study of single dose IV APAP for outpatient pediatric tonsillectomy. Thus, routine use of IV APAP may be questionable in the absence of evidence of clear positive effects on clinical outcomes, especially given its rapid increase in cost over time. The goal of this study was to determine the effect of IV APAP on hospital length of stay (LOS) via mediation of opioid-related side effects in pediatric patients.

Importantly, this study found that the use of IV APAP hastens oral intake in an adolescent surgery population and is associated with a reduction in the length of hospital stay after posterior spinal fusion likely through a decrease in IV opioid consumption. The authors present evidence for a strategy that can result in decreased LOS, an important outcome, given recent trends indicating a transition from traditional “fee-for-service” models to “bundled payments” whereby health care providers are encouraged to deliver care more efficiently while improving quality, cost and outcomes. Their results spur the need for a cost-effectiveness analysis to further inform pain management practices after major surgeries. Based on these findings, the authors recommend the use of IV APAP every 6 hours in weight and age appropriate doses for children undergoing posterior spinal fusion.
Ross, JL; Queme, LF; Lamb, JE; Green, KJ; Jankowski, MP. Sex differences in primary muscle afferent sensitization following ischemia and reperfusion injury. Biology of Sex Differences. 2018; 9(1).
Chronic pain conditions are more prevalent in women, but most preclinical studies into mechanisms of pain generation are performed using male animals. Until recently, these studies have been performed primarily in male rodents, which is translationally counterintuitive as many chronic musculoskeletal pain conditions, including CRPS and fibromyalgia, are more prevalent in women. There are sex-dependent effects on disease severity and patient outcomes in ischemic myalgia-associated conditions. Because of the lack of effective therapies for ischemic myalgia, understanding how deficits in peripheral perfusion generate this type of muscle pain is crucial.

Females and males show differing pain tolerance and prevalence of pain conditions in clinical reports. Sex-dependent pain mechanisms have also been described in rodent models. However, the physiological effects of sex-dependent primary afferent sensitization have yet to be understood, particularly in regard to muscle nociceptors. In this study, the authors first compared the response properties and phenotypes of individual group III and IV muscle afferents in age-matched uninjured males and females, which yielded basal sex difference. Whereas group III and IV nociceptive muscle afferents provoke central sensitization more effectively than their cutaneous counterparts, less is known about this critical population of muscle nociceptors. This study compared the physiology of individual muscle afferents in uninjured males and females and characterizes the molecular, physiological, and behavioral effects of transient ischemia and reperfusion injury (I/R). Using natural mechanical, thermal, and metabolite stimuli in our novel ex vivo electrophysiology preparation allowed the researchers to phenotype individual group III and IV primary muscle afferents, and thus, analyze injury-induced changes in distinct subpopulations.

This research illustrates a unique phenomenon wherein discrete, sex-dependent mechanisms of primary muscle afferent sensitization after ischemic injury to the periphery may underlie similar behavioral changes between the sexes. Furthermore, although the group III and IV muscle afferents are fully developed functionally, the differential mechanisms of sensitization manifest prior to sexual maturity. Hence, this study illustrates the pressing need for further exploration of sex differences in afferent function throughout the lifespan for use in developing appropriately targeted pain therapies.
Jankowski, MP; Miller, L; Koerber, HR. Increased Expression of Transcription Factor SRY-box-Containing Gene 11 Sox11 Enhances Neurite Growth by Regulating Neurotrophic Factor Responsiveness. Neuroscience. 2018; 382:93-104.
Peripheral axons of sensory neurons regenerate after injury significantly better than their central projections, due to several discrepancies including Wallerian Degeneration, changes in gene expression and neurotrophic factor production in the injured nerve and periphery. Among these, dorsal root ganglion (DRG) neurons display significant inconsistencies in transcriptional output of pro-regeneration genes between peripheral and central axon injury.The peripherally projecting axons of dorsal root ganglion (DRG) neurons readily regenerate after damage while their centrally projecting branches do not regenerate to the same degree after injury. One important reason for this inconsistency is the lack of pro-regeneration gene expression that occurs in DRG neurons after central injury relative to peripheral damage.

Although several genes could play a role in this difference in regenerative ability, the changes in gene expression in the transcription factor SRY-box containing gene 11 (Sox11) after axon damage may contribute to this inconsistency and subsequent differences in regenerative capacity of peripherally and centrally projecting DRG axons. Previous evidence has shown that it is highly upregulated after peripheral axon damage but not after central injury. Studies have also shown that overexpression or inhibition of Sox11 after peripheral nerve damage can promote or block axon regeneration, respectively.

Recent evidence suggested that manipulation of Sox11 regulates neurite growth and axon regeneration. Here, the authors sought to determine possible mechanisms of how enhanced levels of Sox11 could facilitate neurite growth in sensory neurons. To further understand the mechanisms of how Sox11 regulates axon growth, researchers artificially overexpressed Sox11 in DRG neurons in vitro to determine if increased levels of this transcription factor could enhance neurite growth. They found that Sox11 overexpression significantly enhanced neurite branching in vitro, and specifically induced the expression of glial cell line-derived neurotrophic factor (GDNF) family receptors, GFRα1 and GFRα3. The upregulation of these receptors by Sox11 overproduction altered the neurite growth patterns of DRG neurons alone and in response to growth factors GDNF and artemin; ligands for GFRα1 and GFRα3, respectively. These data support the role of Sox11 to promote neurite growth by altering responsiveness of neurotrophic factors and may provide mechanistic insight as to why peripheral axons of sensory neurons readily regenerate after injury, but the central projections do not have an extensive regenerative capacity.

These important results suggest that enhanced levels of Sox11 may alter neurite growth by regulating GDNF family neurotrophic factor responsiveness. They provide a better understanding of the possible actions of Sox11 and its potential promotion of axon regeneration. These results may provide insight into the feasibility of enhancing Sox11 in order to promote axon regeneration in vivo for patients that experience central nerve lesions.
Arafa, SR; LaSarge, CL; Pun, RY K; Khademi, S; Danzer, SC. Self-reinforcing effects of mTOR hyperactive neurons on dendritic growth. Experimental Neurology. 2019; 311:125-134.
Mechanistic target of rapamycin (mTOR) a serine/threonine kinase that plays central roles in various biological processes, regulates long-term synaptic plasticity, learning, and memory by controlling dendritic protein synthesis. The loss of the mTOR pathway negative regulator PTEN from hippocampal dentate granule cells leads to neuronal hypertrophy, increased dendritic branching and aberrant basal dendrite formation in animal models. Similar changes are evident in humans with mTOR pathway mutations. These genetic conditions are associated with autism, cognitive dysfunction and epilepsy.

Interestingly, humans with mTOR pathway mutations often present with mosaic disruptions of gene function, producing lesions that range from focal cortical dysplasia to hemimegalanecephaly. Whether mTOR-mediated neuronal dysmorphogenesis is impacted by the number of affected cells, however, is not known. mTOR mutations can produce secondary comorbidities, including brain hypertrophy and seizures, which could exacerbate dysmorphogenesis among mutant cells.

To determine whether the percentage or "load" of PTEN knockout granule cells impacts the morphological development of these same cells, the authors generated two groups of PTEN knockout mice. In the first, PTEN deletion rates were held constant, at about 5%, and knockout cell growth over time was assessed. Knockout cells exhibited significant dendritic growth between 7 and 18 weeks, demonstrating that aberrant dendritic growth continues even after the cells reach maturity. In the second group of mice, PTEN was deleted from 2 to 37% of granule cells to determine whether deletion rate was a factor in driving this continued growth. Multivariate analysis revealed that both age and knockout cell load contributed to knockout cell dendritic growth. Although the mechanism remains to be determined, these findings demonstrate that large numbers of mutant neurons can produce self-reinforcing effects on their own growth.
Parikh, JM; Amolenda, P; Rutledge, J; Szabova, A; Chidambaran, V. An update on the safety of prescribing opioids in pediatrics. Expert Opinion on Drug Safety. 2019; 18(2):127-143.
‘One size does not fit all’ describes the need for public policies focused on pediatric pain and opioid use, as children are not ‘little adults.’ Opioid prescribing rates, opioid misuse, and mortality from opioid abuse are on the rise in adolescents, which makes careful prescribing of opioids an important responsibility of all health-care providers. The opioid abuse epidemic and its toll on the adolescent population have heightened awareness for safer opioid prescribing practices in pediatric pain management. Clinical trials to evaluate pharmacokinetics–pharmacodynamics of opioids are currently lacking. Development of novel biased opioid agonists, clinical integration of genetics in informed decision-making, and emphasis on top-down approaches to pain management will be key to decrease opioid reliance.

In this timely update, the authors present information on parenteral/oral opioids commonly used in pediatrics. Recommendations for opioid use in special circumstances including neonates and developmental pharmacokinetic concerns are discussed. A summary of adverse effects and opioid safety data, and the role of regulations, risk assessment, Centers for Disease Control and Prevention guidelines, follow-up, and monitoring for compliance in opioid prescribing, are detailed. The authors review the importance of pharmacogenomics on opioid selection and dosing, with a special emphasis on CYP2D6 implications for opioid dosing, and warnings against use of codeine in the pediatric population