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Item A Novel Perioperative Multidose Methadone-Based Multimodal Analgesic Strategy in Children Achieved Safe and Low Analgesic Blood Methadone Levels Enabling Opioid-Sparing Sustained Analgesia With Minimal Adverse Effects(Wolters Kluwer, 2021) Sadhasivam, Senthilkumar; Aruldhas, Blessed W.; Packiasabapathy, Senthil; Overholser, Brian R.; Zhang, Pengyue; Zang, Yong; Renschler, Janelle S.; Fitzgerald, Ryan E.; Quinney, Sara K.; Anesthesia, School of MedicineBackground: Intraoperative methadone, a long-acting opioid, is increasingly used for postoperative analgesia, although the optimal methadone dosing strategy in children is still unknown. The use of a single large dose of intraoperative methadone is controversial due to inconsistent reductions in total opioid use in children and adverse effects. We recently demonstrated that small, repeated doses of methadone intraoperatively and postoperatively provided sustained analgesia and reduced opioid use without respiratory depression. The aim of this study was to characterize pharmacokinetics, efficacy, and safety of a multiple small-dose methadone strategy. Methods: Adolescents undergoing posterior spinal fusion (PSF) for idiopathic scoliosis or pectus excavatum (PE) repair received methadone intraoperatively (0.1 mg/kg, maximum 5 mg) and postoperatively every 12 hours for 3-5 doses in a multimodal analgesic protocol. Blood samples were collected up to 72 hours postoperatively and analyzed for R-methadone and S-methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP) metabolites, and alpha-1 acid glycoprotein (AAG), the primary methadone-binding protein. Peak and trough concentrations of enantiomers, total methadone, and AAG levels were correlated with clinical outcomes including pain scores, postoperative nausea and vomiting (PONV), respiratory depression, and QT interval prolongation. Results: The study population included 38 children (10.8-17.9 years): 25 PSF and 13 PE patients. Median total methadone peak plasma concentration was 24.7 (interquartile range [IQR], 19.2-40.8) ng/mL and the median trough was 4.09 (IQR, 2.74-6.4) ng/mL. AAG concentration almost doubled at 48 hours after surgery (median = 193.9, IQR = 86.3-279.5 µg/mL) from intraoperative levels (median = 87.4, IQR = 70.6-115.8 µg/mL; P < .001), and change of AAG from intraoperative period to 48 hours postoperatively correlated with R-EDDP (P < .001) levels, S-EDDP (P < .001) levels, and pain scores (P = .008). Median opioid usage was minimal, 0.66 (IQR, 0.59-0.75) mg/kg morphine equivalents/d. No respiratory depression (95% Wilson binomial confidence, 0-0.09) or clinically significant QT prolongation (median = 9, IQR = -10 to 28 milliseconds) occurred. PONV occurred in 12 patients and was correlated with morphine equivalent dose (P = .005). Conclusions: Novel multiple small perioperative methadone doses resulted in safe and lower blood methadone levels, <100 ng/mL, a threshold previously associated with respiratory depression. This methadone dosing in a multimodal regimen resulted in lower blood methadone analgesia concentrations than the historically described minimum analgesic concentrations of methadone from an era before multimodal postoperative analgesia without postoperative respiratory depression and prolonged corrected QT (QTc). Larger studies are needed to further study the safety and efficacy of this methadone dosing strategy.Item Characterizing Effects of Sphingosine-1-Phosphate Receptor 1 Activation in Subtypes of Central Amygdala Neurons and Effects of Prenatal Methadone Exposure on Motor Cortex Neurons in Mice(2021-04) Mork, Briana E.; Atwood, Brady K.; Sheets, Patrick L.; Cummins, Theodore R.; Fehrenbacher, Jill C.; McKinzie, David L.Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a wide spectrum of biological processes including apoptosis, immune response and inflammation. S1P receptor (S1PR) ligands have been utilized as an effective immunosuppressant, treatment in multiple sclerosis and studied as a treatment for pain. The primary cellular response to S1P is thought to be elicited through S1PR type 1 (S1PR1). My first goal was to understand how S1PR1 signaling affects neuronal excitability in the central amygdala (CeA), a supraspinal node of the descending pain pathway. The CeA is made up of a heterogenous population of neurons which form complex local and long-range circuits. The central lateral amygdala (CeL) consists of two major populations of inhibitory neurons identified by expression of the peptides somatostatin (Sst) and protein kinase Cδ (PKCδ). Sst neurons have been shown to maintain control over local circuits within the CeL and play a critical role in pain modulation. I utilized transgenic breeding strategies to fluorescently label Sst-expressing CeL neurons for whole-cell electrophysiology in acute brain slice. This strategy allowed me to study the effects of S1PR1 agonist SEW2871 and S1PR1 antagonist NIBR on the cellular physiology of CeL Sst neurons. My findings reveal intrinsically distinct subtypes of CeL Sst neurons that are uniquely affected by S1PR1 activation, which may have implications for how S1P alters supraspinal pain pathways. My second goal was to assess the physiology of motor cortex neurons in mice exposed to prenatal methadone. Methadone is a synthetic μ-opioid agonist used for opioid maintenance therapy and chronic pain management. Methadone treatment for opioid use disorder in pregnant women can result in structural changes within the brain of their offspring causing and developmental delays to their children, including poorer motor performance. Using a mouse model of prenatal methadone exposure (PME), whole-cell electrophysiology, and analyses of cellular morphology, I elucidated the effects of PME on primary motor cortex (M1) output layer 5 (L5) neurons, which encompass the major cortical output pathway for motor control. My findings provide the first evidence that PME disrupts neuronal firing, subthreshold properties, and strength of local inputs onto M1 L5 neurons in prepubescent mice.Item The Enduring Consequences of Prenatal Opioid Exposure(2022-02) Grecco, Gregory Giovanni; Sheets, Patrick; Atwood, Brady; Yamamoto, Bryan; McKinzie, David; Yoder, KarmenThe opioid crisis has resulted in an unprecedented number of neonates born with prenatal opioid exposure; however, the long-term effects of opioid exposure on offspring behavior and neurodevelopment remain relatively unknown. I developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. PME produced substantial impairments in offspring growth, sensorimotor milestone acquisition, and activity in an open field. Furthermore, these behavioral alterations were associated with significant disruptions in the primary motor cortex (M1). Notably, layer 5 pyramidal neurons of the M1 displayed significantly increased voltage sag which is primarily mediated by HCN1 channels. Interestingly, the α2-adrenergic receptor, a known modulator of HCN1 channels, displayed significantly increased expression in the M1 of PME animals. The locomotor activity in an open field was significantly reduced following in vivo pharmacological activation of the α2-adrenergic receptor with clonidine in PME offspring suggesting this may be therapeutic target for the hyperactivity associated with prenatal exposure to opioids. Previous work has also described an association between prenatal opioid exposure and alterations in opioid reward-related behavior; however, the effect of PME on alcohol reward remains undetermined. Given the widespread accessibility and usage, alcohol represents the most likely addictive substance the growing population of opioid exposed neonates will encounter as they age. I discovered that PME disrupts conditioned preference for alcohol, enhances the locomotor stimulating effects of alcohol, and increases alcohol consumption in a sex-dependent manner. This alcohol-reward phenotype in PME offspring was associated with altered excitatory neurotransmission and disrupted cannabinoid-mediated long-term depression (CB-LTD) in the dorsolateral striatum, an important substrate involved in compulsive drug use. Further work is required to determine the specific inputs at which CB-LTD is disrupted and if restoring this form of plasticity in PME animals prevents the enhanced alcohol addiction phenotype.Item Medication for Adolescents and Young Adults with Opioid Use Disorder(Elsevier, 2021) Hadland, Scott E.; Aalsma, Matthew C.; Akgül, Sinem; Alinsky, Rachel H.; Bruner, Ann; Chadi, Nicholas; Galagali, Preeti M.; Kreida, Ellen C.; Robinson, Camille A.; Wilson, J. Deanna; Pediatrics, School of MedicineOpioid-related morbidity and mortality have risen in many settings globally. It is critical that practitioners who work with adolescents and young adults (AYAs) provide timely, evidence-based treatment for opioid use disorder (OUD). Such treatment should include medications for opioid use disorder (MOUD), including buprenorphine, naltrexone, and methadone. Medication treatment is associated with reduced mortality, fewer relapses to opioid use, and enhanced recovery and retention in addiction care, among other positive health outcomes. Unfortunately, the vast majority of AYAs with OUD do not receive medication. The Society for Adolescent Health and Medicine recommends that AYAs be offered MOUD as a critical component of an integrated treatment approach. Barriers to receipt of medications are widespread; many are common to high-, middle-, and low-income countries alike, whereas others differ. Such barriers should be minimized to ensure equitable access to youth-friendly, affirming, and confidential addiction treatment that includes MOUD. Robust education on OUD and medication treatment should be provided to all practitioners who work with AYAs. Strategies to reduce stigma surrounding medication-and stigma experienced by individuals with substance use disorders more generally-should be widely implemented. A broad research agenda is proposed with the goal of expanding the evidence base for the use and delivery of MOUD for AYAs.Item Methadone-based Multimodal Analgesia Provides the Best-in-class Acute Surgical Pain Control and Functional Outcomes With Lower Opioid Use Following Major Posterior Fusion Surgery in Adolescents With Idiopathic Scoliosis(Wolters Kluwer, 2020-07-27) Ye, Jian; Myung, Karen; Packiasabapathy, Senthil; Yu, Jeffrey S.; Jacobson, Joseph E.; Whittaker, Stephanie C.; Castelluccio, Peter; Drayton Jackson, Meghan; Sadhasivam, Senthilkumar; Anesthesia, School of MedicineIntroduction: Posterior spinal fusion for idiopathic scoliosis is extremely painful, with no superior single analgesic modality. We introduced a methadone-based multimodal analgesia protocol, aiming to decrease the length of hospital stay (LOS), improve pain control, and decrease the need for additional opioids. Methods: We analyzed 122 idiopathic scoliosis patients with posterior instrumented spinal fusion. They were matched by age, sex, surgeon, and the number of levels fused before and after the implementation of the new protocol. This analysis included 61 controls (intrathecal morphine, gabapentin, intravenous opioids, and adjuncts) and 61 patients on the new protocol (scheduled methadone, methocarbamol, ketorolac/ibuprofen, acetaminophen, and oxycodone with intravenous opioids as needed). The primary outcome was LOS. Secondary outcomes included pain scores, total opioid use (morphine milligram equivalents), time to a first bowel movement, and postdischarge phone calls. Results: New protocol patients were discharged earlier (median LOS, 2 days) compared with control patients (3 days; P < 0.001). Total inpatient morphine consumption was lower in the protocol group (P < 0.001). Pain scores were higher in the protocol group on the day of surgery, similar on postoperative day (POD) 1, and lower by POD 2 (P = 0.01). The new protocol also reduced the median time to first bowel movement (P < 0.001), and the number of postdischarge pain-related phone calls (P < 0.006). Conclusion: Methadone-based multimodal analgesia resulted in significantly lower LOS compared with the conventional regimen. It also provided improved pain control, reduced total opioid consumption, and early bowel movement compared with the control group.Item Novel associations between CYP2B6 polymorphisms, perioperative methadone metabolism and clinical outcomes in children(Future Medicine, 2021-07) Packiasabapathy, Senthil; Aruldhas, Blessed W.; Zhang, Pengyue; Overholser, Brian R.; Quinney, Sara K.; Sadhasivam, Senthilkumar; Anesthesia, School of MedicineAim: Methadone exhibits significant variability in clinical response. This study explores the genetic influence of variable methadone pharmacokinetics. Methods: This is a prospective study of methadone in children undergoing major surgery. CYP2B6 genotyping, plasma methadone and metabolite levels were obtained. Clinical outcomes include pain scores and postoperative nausea and vomiting (PONV). Results:CYP2B6 poor metabolizers (*6/*6) had >twofold lower methadone metabolism compared with normal/rapid metabolizers. The incidence of PONV was 4.7× greater with CYP2B6 rs1038376 variant. AG/GG variants of rs2279343 SNP had 2.86-fold higher incidence of PONV compared with the wild variant (AA). Nominal associations between rs10500282, rs11882424, rs4803419 and pain scores were observed. Conclusion: We have described novel associations between CYP2B6 genetic variants and perioperative methadone metabolism, and associations with pain scores and PONV.Item Pharmacogenomics of methadone: a narrative review of the literature(Future Medicine, 2020-08) Packiasabapathy, Senthil; Aruldhas, Blessed W.; Horn, Nicole; Overholser, Brian R.; Quinney, Sara K.; Renschler, Janelle S.; Sadhasivam, Senthilkumar; Anesthesia, School of MedicineBackground: Methadone, a synthetic opioid with longer duration of action and lower abuse potential compared with morphine, is used to prevent opioid withdrawal, as well as to manage chronic and acute surgical pain. The variability in response to methadone has been widely recognized. The purpose of this article is to review the literature on the pharmacogenetic factors underlying this variability. Materials & methods: This is a narrative overview of the literature on the genetic variants affecting pharmacodynamics and pharmacokinetics of methadone, retrieved from searches of databases such as PubMed and google scholar. Discussion: Clinical responses to methadone may be affected by genetic variants in the opioidergic, dopaminergic and neurotrophic pathways. Polymorphisms in genes related to disposition and elimination of methadone alter the pharmacokinetics, and possibly pharmacodynamics of methadone. Cytochrome P450 enzymes and P-glycoprotein variants contribute to the interindividual variability in methadone pharmacokinetics. Evidence for single gene variants affecting methadone response remains weak. Multiple genetic variants must be considered in conjunction to improve predictive ability. Conclusion: Evidence remains scarce at this time, to recommend pharmacogenetic testing before methadone administration. Well-powered clinical studies are needed with population pharmacokinetic-pharmacodynamic modeling and multigenetic signature-based predictions to enable tailored use of methadone in clinical practice.Item Pharmacokinetic modeling of R and S-Methadone and their metabolites to study the effects of various covariates in post-operative children(Wiley, 2021-10) Aruldhas, Blessed W.; Quinney, Sara K.; Overholser, Brian R.; Heathman, Michael A.; Masters, Andrea R.; Ly, Reynold C.; Gao, Hongyu; Packiasabapathy, Senthil; Sadhasivam, Senthilkumar; Anesthesia, School of MedicineMethadone is a synthetic opioid used as an analgesic and for the treatment of opioid abuse disorder. The analgesic dose in the pediatric population is not well-defined. The pharmacokinetics (PKs) of methadone is highly variable due to the variability in alpha-1 acid glycoprotein (AAG) and genotypic differences in drug-metabolizing enzymes. Additionally, the R and S enantiomers of methadone have unique PK and pharmacodynamic properties. This study aims to describe the PKs of R and S methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in pediatric surgical patients and to identify sources of inter- and intra-individual variability. Children aged 8-17.9 years undergoing orthopedic surgeries received intravenous methadone 0.1 mg/kg intra-operatively followed by oral methadone 0.1 mg/kg postoperatively every 12 h. Pharmacokinetics of R and S methadone and EDDP were determined using liquid chromatography tandem mass spectrometry assays and the data were modeled using nonlinear mixed-effects modeling in NONMEM. R and S methadone PKs were well-described by two-compartment disposition models with first-order absorption and elimination. EDDP metabolites were described by one compartment disposition models with first order elimination. Clearance of both R and S methadone were allometrically scaled by bodyweight. CYP2B6 phenotype was a determinant of the clearance of both the enantiomers in an additive gene model. The intronic CYP3A4 single-nucleotide polymorphism (SNP) rs2246709 was associated with decreased clearance of R and S methadone. Concentrations of AAG and the SNP of AAG rs17650 independently increased the volume of distribution of both the enantiomers. The knowledge of these important covariates will aid in the optimal dosing of methadone in children.Item Prenatal methadone exposure selectively alters protein expression in primary motor cortex: Implications for synaptic function(Frontiers Media, 2023-02-01) Haggerty, David L.; Grecco, Gregory G.; Huang, Jui-Yen; Doud, Emma H.; Mosley, Amber L.; Lu, Hui-Chen; Atwood, Brady K.; Pharmacology and Toxicology, School of MedicineAs problematic opioid use has reached epidemic levels over the past 2 decades, the annual prevalence of opioid use disorder (OUD) in pregnant women has also increased 333%. Yet, how opioids affect the developing brain of offspring from mothers experiencing OUD remains understudied and not fully understood. Animal models of prenatal opioid exposure have discovered many deficits in the offspring of prenatal opioid exposed mothers, such as delays in the development of sensorimotor function and long-term locomotive hyperactivity. In attempt to further understand these deficits and link them with protein changes driven by prenatal opioid exposure, we used a mouse model of prenatal methadone exposure (PME) and preformed an unbiased multi-omic analysis across many sensoriomotor brain regions known to interact with opioid exposure. The effects of PME exposure on the primary motor cortex (M1), primary somatosensory cortex (S1), the dorsomedial striatum (DMS), and dorsolateral striatum (DLS) were assessed using quantitative proteomics and phosphoproteomics. PME drove many changes in protein and phosphopeptide abundance across all brain regions sampled. Gene and gene ontology enrichments were used to assess how protein and phosphopeptide changes in each brain region were altered. Our findings showed that M1 was uniquely affected by PME in comparison to other brain regions. PME uniquely drove changes in M1 glutamatergic synapses and synaptic function. Immunohistochemical analysis also identified anatomical differences in M1 for upregulating the density of glutamatergic and downregulating the density of GABAergic synapses due to PME. Lastly, comparisons between M1 and non-M1 multi-omics revealed conserved brain wide changes in phosphopeptides associated with synaptic activity and assembly, but only specific protein changes in synapse activity and assembly were represented in M1. Together, our studies show that lasting changes in synaptic function driven by PME are largely represented by protein and anatomical changes in M1, which may serve as a starting point for future experimental and translational interventions that aim to reverse the adverse effects of PME on offspring.Item Prenatal Opioid Administration Induces Shared Alterations to the Maternal and Offspring Gut Microbiome: A Preliminary Analysis(Elsevier, 2021) Grecco, Gregory G.; Gao, Yong; Gao, Hongyu; Liu, Yunlong; Atwood, Brady K.; Pharmacology and Toxicology, School of MedicineBackground: While many studies have described the impact of prenatal opioid exposure on development, possible mechanisms for how opioids exert developmental impairments remain elusive. Emerging evidence indicates disruptions in the maternal gut microbiome can alter offspring development; however, no studies to date have examined the impact of maternal opioid treatment on maternal-offspring microbiome dysbiosis. Methods: A mouse model of prenatal methadone exposure (PME) was employed to assess the impact of maternal opioid treatment on the microbiome of methadone-treated dams (MD) and their offspring. Fecal samples were collected from dams (n=8 per treatment), one male and one female offspring per dam (n=8 offspring per sex per treatment) for 16s rRNA sequencing. Results: Methadone treatment significantly increased the microbial diversity and led to an expansion in family level bacterial abundance. Correlational analysis revealed significant positive associations between dam and offspring measures of diversity indicating methadone-induced shifts in the microbial communities are shared between dam and offspring. Sixteen features in dams and 10 features in offspring were significantly differentially abundant between treatment groups with many features corresponding to the Lachnospiraceae NK4A136 genus. Of the six features identified as differentially abundant in both MD and PME offspring, all were assigned to the Lachnospiraceae NK4A136 group, and the abundances demonstrated strong positive correlations between dam and offspring. Conclusions: These preliminary findings indicate that maternal opioid treatment during pregnancy alters the composition of the maternal microbiome, and this opioid-induced shift is similarly observed in offspring which could contribute to the impaired developmental phenotypes previously described.