Perioperative and Periprocedural anesthetic management of opioid tolerant patients and patients with active and medically treated opioid use disorder.

PURPOSE OF REVIEW: The increasing prevalence of opioid tolerant individuals, in combination with the expanding scope and utilization of nonoperating room anesthesia (NORA) necessitates ongoing investigation into best clinical practice for managing surgical/procedural pain in this population. The purpose of this article is to review recent guidelines, identify specific challenges, and offer considerations for managing pain in patients who are opioid tolerant secondary to opioid use disorder (OUD), with or without medications for the treatment of OUD. RECENT FINDINGS: A comprehensive preoperative evaluation in conjunction with a multidisciplinary, multimodal pain approach is optimal. NORA adds unique situational and environmental challenges for optimizing acute on chronic pain control in tolerant individuals while maintaining safety. Direct and partial/mixed mu-agonists should typically be continued throughout the perioperative period, while mu-antagonists (naltrexone) should be held 72 h. Postprocedural discharge instructions and follow-up must be carefully arranged and ensured. SUMMARY: Clinical recommendations continue to evolve as new consensus guidelines are published, although institution-specific guidelines are most often followed. This review focuses on most recent best practices, within NORA and operating room settings, for managing opioid tolerant patients, patients with OUD and those on medications for the treatment of OUD.

Behavioral and pharmacological evaluation of a selectively bred mouse model of home cage hyperactivity.

Daily levels of physical activity vary greatly across individuals and are strongly influenced by genetic background. While moderate levels of physical activity are associated with improved physical and mental health, extremely high levels of physical activity are associated with behavioral disorders such as attention deficit hyperactivity disorder (ADHD). However, the genetic and neurobiological mechanisms relating hyperactivity to ADHD or other behavioral disorders remain unclear. Therefore, we conducted a selective breeding experiment for increased home cage activity starting with a highly genetically variable population of house mice and evaluated the line for correlated responses in other relevant phenotypes. Here we report results through Generation 10. Relative to the Control line, the High-Active line traveled approximately 4 times as far in the home cage (on days 5 and 6 of a 6-day test), displayed reduced body mass at maturity, reduced reproductive success, increased wheel running and open field behavior, decreased performance on the rotarod, decreased performance on the Morris water maze that was not rescued by acute administration of d-amphetamine, reduced hyperactivity from chronically administered low clinical doses of d-amphetamine, and increased numbers of new cells and neuronal activation of the dentate gyrus. Standardized phenotypic differences between the lines were compared to estimates expected from genetic drift to evaluate whether the line differences could have resulted from random effects as opposed to correlated responses to selection. Results indicated line differences in body mass and locomotor responses to low doses of amphetamine were more likely due to selection than drift. The efficacy of low doses of d-amphetamine in ameliorating hyperactivity support the High-Active line as a useful model for exploring the etiology of hyperactivity-associated comorbid behavioral disorders.

Dorsal root ganglion stimulation for patients with chronic pelvic pain: A retrospective review of patient experiences and long-term outcomes.

Introduction: Chronic pelvic pain (CPP) is a refractory condition that has physical, emotional, and financial impacts on patients. Dorsal root ganglion stimulation (DRGS) is a promising interventional modality for patients with refractory CPP, however studies of long-term outcomes are limited. We aim to present the results from a retrospective review of 31 patients with CPP treated using DRGS. Materials and methods: IRB approval was obtained. A retrospective chart review was conducted, including 31 patients who underwent a DRGS trial between 2017 and 2022 at two academic centers. Pain history, trial/implant lead configuration, complications/revisions, pain scores, functional goals, and medication use were recorded. Results: Thirty-one patients with CPP underwent a 7-10 day DRGS trial between 2017 and 2022. Of the 31 patients, 21 (68%, CI 50-81%) had a successful trial, defined as >50% reported pain relief. Twenty patients underwent DRGS implantation. Average follow-up was 28.2 ± 17.3 months. Nine patients (45%) required revision surgery for lead migration or fracture. Thirteen patients remain implanted with an average reported percent relief of 55 ± 15%. Seven patients were explanted (35%), with an average time to explant of 12.5 ± 3 months. Conclusions: This study presents one of the largest groups of patients with DRGS for the treatment of CPP. The results highlight the variable experiences of patients after DRGS trial/implant. We report on the incidence of lead migration and fracture, sparingly described in the literature. Larger, prospective studies are needed to elucidate which patients with CPP may benefit most from DRGS, and to better understand the incidence and implications of complications.

Intracranial Hypertension following Acute Mesenteric Ischemia: A Case Study on the Multiple Compartment Syndrome.

In this case study, we describe a 25-year-old male who was admitted due to a severe traumatic brain injury, requiring invasive intracranial pressure monitoring. At 48 hours posttrauma, he developed intracranial hypertension refractory to medical treatment without tomographic changes in the brain. Subsequently, intra-abdominal hypertension and tomographic signs of abdominal surgical pathology were observed. An exploratory laparotomy was performed with an intraoperative diagnosis of acute mesenteric ischemia. After surgical intervention for the abdominal pathology, intracranial pressure was restored to physiological values with a favorable recovery of the patient. In this report, the relationship between intracranial pressure and intra-abdominal pressure is discussed, highlighting the delicate association between the brain, abdomen, and thorax. Measures should be taken to avoid increases in intra-abdominal pressure in neurocritical patients. When treating intracranial hypertension refractory to conventional measures, abdominal causes and multiple compartment syndrome must be considered. The cranial compartment has physiological interdependence with other body compartments, where one can be modified by variations from another, giving rise to the concept of multiple compartment syndrome. Understanding this relationship is fundamental for a comprehensive approach of the neurocritical patient. To the best of our knowledge, this is the first report of a comatose patient post-traumatic brain injury, who developed medically unresponsive intracranial hypertension secondary to acute mesenteric ischemia, in which surgical resolution of intra-abdominal pathology resulted in intracranial pressure normalization and restitutio ad integrum of neurological status.

Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling.

Despite the prevalence and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), genetic etiology remains elusive. Clinical evidence points in part to reduced function of the striatum, but which specific genes are differentially expressed and how they sculpt striatal physiology to predispose ADHD are not well understood. As an exploratory tool, a polygenic mouse model of ADHD was recently developed through selective breeding for high home cage activity. Relative to the Control line, the High-Active line displays hyperactivity and motor impulsivity which are ameliorated with amphetamine. This study compared gene expression in the striatum between Control and High-Active mice to develop a coherent hypothesis for how genes might affect striatal physiology and predispose ADHD-like symptoms. To this end, striatal transcriptomes of High-Active and Control mice were analyzed after mice were treated with saline or amphetamines. The pseudogene Gm6180 for n-cofilin (Cfl1) displayed 20-fold higher expression in High-Active mice corresponding with reduced Cfl1 expression suggesting synaptic actin dysregulation. Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice. Multiple genes were altered in High-Active mice in a manner predicted to downregulate the canonical Wnt pathway. A smaller and different set of genes including glyoxalase (Glo1) were differentially regulated in High-Active as compared to Control in response to amphetamine. Together, results suggest genes involved in excitatory synapse regulation and maintenance are downregulated in ADHD-like mice. Consistent with the molecular prediction, stereological analysis of the striatum from a separate set of mice processed for imunohistochemical detection of synaptophysin revealed approximately a 46% reduction in synaptophysin immunoreactivity in High-Active relative to Control. Results provide a new set of molecular targets related to synapse maintenance for the next generation of ADHD medicines.

The impact of maternal neglect on genetic hyperactivity.

Early environmental conditions are increasingly appreciated as critical in shaping behavior and cognition. Evidence suggests that stressful rearing environments can have an enduring impact on behaviors in adulthood, but few studies have explored the possibility that rearing environment could exacerbate genetic hyperactivity disorders. Uncovering a strong environmental influence on the transmission of hyperactivity could provide novel avenues for translational research. Recently we developed a selectively bred High-Active line of mice to model ADHD, providing a unique resource to address the question of environmental transmission. The High-Active line demonstrates transgenerational hyperactivity, but the influence of the postnatal environment (i.e. maternal care provided by dams) on hyperactivity had not been systemically quantified. This study employed a cross-fostering method to simultaneously address 1) whether High-Active and Control pups are provided with similar levels of care in the early environment, and 2) whether any differences in rearing environment influence hyperactive behavior. High-Active dams demonstrated impairment in all measures of maternal competence relative to Controls, which reduced survival rates and significantly reduced the body mass of offspring in early life and at weaning. While the deteriorated postnatal environment provided by High-Active dams was ultimately sufficient to depress Control activity, the hyperactivity of High-Active offspring remained unaffected by fostering condition. These data not only confirm the power of genetics to influence hyperactivity across generations, but also provide evidence that early rearing environments may not have a significant impact on the extreme end of hyperactive phenotypes.

A new mouse model of ADHD for medication development.

ADHD is a major societal problem with increasing incidence and a stagnant track record for treatment advances. A lack of appropriate animal models has partly contributed to the incremental advance of this field. Hence, our goal was to generate a novel mouse model that could be useful for ADHD medication development. We reasoned that hyperactivity is a core feature of ADHD that could easily be bred into a population, but to what extent other hallmark features of ADHD would appear as correlated responses was unknown. Hence, starting from a heterogeneous population, we applied within-family selection over 16 generations to produce a High-Active line, while simultaneously maintaining an unselected line to serve as the Control. We discovered that the High-Active line demonstrated motor impulsivity in two different versions of the Go/No-go test, which was ameliorated with a low dose of amphetamine, and further displayed hypoactivation of the prefrontal cortex and dysregulated cerebellar vermal activation as indexed by c-Fos immunohistochemical staining. We conclude that the High-Active line represents a valid model for the Hyperactive-Impulsive subtype of ADHD and therefore may be used in future studies to advance our understanding of the etiology of ADHD and screen novel compounds for its treatment.