A Series of 8 Illicit Fentanyl Intoxication Deaths in Infants and Toddlers.

ABSTRACT: We report 8 children younger than 2 years who died from acute illicit fentanyl intoxications in Connecticut between 2020 and 2022.The Connecticut Office of the Chief Medical Examiner (CT OCME) investigates all unexpected, violent, and suspicious deaths in Connecticut. The CT OCME's electronic database was searched for fentanyl deaths by age. All underwent autopsies and toxicology testing.The ages ranged from 28 days to 2 years (mean age, 12 months). The causes of death involved acute fentanyl intoxications with 1 having xylazine, 1 having para-fluorofentanyl, and 1 having cocaine and morphine. All the manners of death were certified as homicide. The postmortem fentanyl blood concentrations ranged from 0.40 to 46 ng/mL. Most of the children were found unresponsive after being put to sleep. Three were co-sleeping with adults (2 in bed; 1 on a recliner). There was a known history of parental/caregiver drug abuse in 7 of 8 of the fatalities.We summarize the key investigative, autopsy, and toxicological findings. As illicit fentanyl use increases, there is a potential for infant exposure and death. The investigation and certification of these deaths and the role of intentional administration versus inadvertent exposure due to caregiver neglect in the context of the certification of the manner of death are described.

Quantifying the Pharmacodynamics of Morphine in the Treatment of Postoperative Pain in Preverbal Children.

While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration-effect relationship of morphine for postoperative pain in preverbal children between 0 and 3 years of age. For this, we applied item response theory modeling in the pharmacokinetic/pharmacodynamic analysis of COMFORT-Behavior (COMFORT-B) scale data from 2 previous clinical studies. In the model, we identified a sigmoid maximal efficacy model for the effect of morphine and found that in 26% of children, increasing morphine concentrations were not associated with lower pain scores (nonresponders to morphine up-titration). In responders to morphine up-titration, the COMFORT-B score slowly decreases with increasing morphine concentrations at morphine concentrations >20 ng/mL. In nonresponding children, no decrease in COMFORT-B score is expected. In general, lower baseline COMFORT-B scores (2.1 points on average) in younger children (postnatal age <10.3 days) were found. Based on the model, we conclude that the percentage of children at a desirable COMFORT-B score is maximized at a morphine concentration between 5 and 30 ng/mL for children aged <10 days, and between 5 and 40 ng/mL for children >10 days. These findings support a dosing regimen previously suggested by Krekels et al, which would put >95% of patients within this morphine target concentration range at steady state. Our modeling approach provides a promising platform for pharmacodynamic research of analgesics and sedatives in children.

Involvement of the Peripheral µ-Opioid Receptor in Tramadol-Induced Constipation in Rodents.

Tramadol is a weak opioid that produces analgesic effect via both the µ-opioid receptor (MOR) and non-opioid targets. Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear. Therefore, we used naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3-100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01-10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01-0.3 mg/kg, and complete recovery was observed at 0.3-10 m/kg. Additionally, tramadol (30 and 100 mg/kg, subcutaneously (s.c.)) inhibited small intestinal transit in wild-type mice but not in MOR-knockout mice. These results suggest that peripheral MOR participates in tramadol-induced constipation.

Pharmacological and metabolic characterization of the novel synthetic opioid brorphine and its detection in routine casework.

After their first emergence in 2009, Novel synthetic opioids (NSO) have become an emerging class of New Psychoactive Substances (NPS) on the market for these new drugs. So far, 67 NSO have been reported to the Early Warning system of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). It is presumed that NSO mainly target the four known opioid receptors, i.e. the µ-opioid (MOR), the δ-opioid (DOR), the κ-opioid (KOR) and nociceptin receptors and that their consumption can result in serious adverse effects such as massive respiratory depression or death. In the present study we investigated the in vivo and in vitro metabolism of brorphine, a NSO that was first identified on the NPS market in August 2019 in the United States, using both a pooled human liver microsome assay and real forensic case samples. For the detection of metabolites LC-HR-MS/MS was used and quantification of brorphine was performed using an LC-MS/MS method. Additionally, we pharmacologically characterized brorphine regarding its activation of the MOR and KOR via G protein recruitment using the [35S]-GTPγS assay. In forensic urine samples, 14 distinct metabolites were identified, whereas in blood only four metabolites could be found. The pooled human liver microsome assay generated six distinct in vitro phase I metabolites. The most prominent in vivo metabolite was formed by N-oxydation, whereas the main in vitro metabolite was formed by hydroxylation. The pharmacological characterization at the MOR and KOR revealed brorphine to be a potent MOR agonist and a weak, partial KOR agonist in the [35S]-GTPγS assay.

Positive Toxicology Results Are Not Associated with Emergency Physicians' Opioid Prescribing Behavior.

INTRODUCTION: Given the general lack of literature on opioid and naloxone prescribing guidelines for patients with substance use disorder, we aimed to explore how a physician's behavior and prescribing habits are altered by knowledge of the patient's concomitant use of psychotropic compounds as evident on urine and serum toxicology screens. METHODS: We conducted a retrospective chart review study at a tertiary, academic, Level I trauma center between November 2017-October 2018 that included 358 patients who were discharged from the emergency department (ED) with a diagnosis of fracture, dislocation, or amputation and received an opioid prescription upon discharge. We extracted urine and serum toxicology results, number and amount of prescription opioids upon discharge, and the presence of a naloxone script. RESULTS: The study population was divided into five subgroups that included the following: negative urine and serum toxicology screen; depressants; stimulants; mixed; and no toxicology screens. When comparing the 103 patients in which toxicology screens were obtained to the 255 patients without toxicology screens, we found no statistically significant differences in the total prescribed morphine milligram equivalent (75.0 and 75.0, respectively) or in the number of pills prescribed (15.0 and 13.5, respectively). Notably, none of the 103 patients who had toxicology screens were prescribed naloxone upon discharge. CONCLUSION: Our study found no association between positive urine toxicology results for psychotropically active substances and the rates of opioid prescribing within a single-center, academic ED. Notably, none of the 103 patients who had toxicology screens were prescribed naloxone upon discharge. More research on the associations between illicit drug use, opioids, and naloxone prescriptions is necessary to help establish guidelines for high-risk patients.

Effects of different plasma target concentrations of remifentanil on the MACBAR of sevoflurane in children with laparoscopic surgery.

BACKGROUND: To investigate the effects of different plasma target concentrations of remifentanil on the minimum alveolar concentration (MAC) for blocking adrenergic response (BAR) of sevoflurane in children with laparoscopic herniorrhaphy. METHODS: Seventy-five children with 3-7 years old scheduled for laparoscopic herniorrhaphy were randomly divided into group R0, group R1, and group R2 according to different remifentanil plasma target concentration (0, 1, and 2 ngml-1), respectively. The MACBAR of sevoflurane was determined by the up-and-down and sequential method in each group. The concentrations of epinephrine and noradrenaline were also determined at corresponding time points. RESULTS: A total of 52 child patients were used among the anticipated 75 patients. In groups R0, R1, and R2, the MACBAR of sevoflurane was (3.29 ± 0.17) %, (2.12 ± 0.10) % and (1.29 ± 0.11) %, respectively, and a significant difference was found among the three groups (P<0.05). The changes of epinephrine and noradrenaline concentrations in each group before and after insufflation of carbon dioxide pneumoperitoneum showed no significant differences. CONCLUSION: Remifentanil by target-controlled infusion can effectively reduce the MACBAR of sevoflurane during laparoscopic surgery in children. At a similar effect of MACBAR, both the changes of epinephrine and noradrenaline concentrations are not affected by the infusion of different remifentanil target concentrations. TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn ( ChiCTR1800019393 , 8, Nov, 2018).

Lipemia in the Plasma Sample Affects Fentanyl Measurements by Means of HPLC-MS2 after Liquid-Liquid Extraction.

Examination of fentanyl levels is frequently performed in certain scientific evaluations and forensic toxicology. It often involves the collection of very variable blood samples, including lipemic plasma or serum. To date, many works have reported the methods for fentanyl detection, but none of them have provided information about the impact on the assay performance caused by an excessive amount of lipids. This aspect may be, however, very important for highly lipophilic drugs like fentanyl. To address this issue, we developed the liquid chromatography method with mass spectrometry detection and utilized it to investigate the impact of lipids presence in rabbit plasma on the analytical method performance and validation. The validation procedure, conducted for normal plasma and lipemic plasma separately, resulted in good selectivity, sensitivity and linearity. The limits of detection and quantification were comparable between the two matrices, being slightly lower in normal plasma (0.005 and 0.015 µg/L) than in lipemic plasma (0.008 and 0.020 µg/L). Liquid-liquid extraction provided a low matrix effect regardless of the lipid levels in the samples (<10%), but pronounced differences were found in the recovery and accuracy. In the normal plasma, this parameter was stable and high (around 100%), but in the lipemic matrix, much more variable and less efficient results were obtained. Nevertheless, this difference had no impact on repeatability and reproducibility. In the present work, we provided reliable, convenient and sensitive method for fentanyl detection in the normal and lipemic rabbit plasma. However, construction of two separate validation curves was necessary to provide adequate results since the liquid-liquid extraction was utilized. Therefore, special attention should be paid during fentanyl quantification that involves lipemic plasma samples purified by this technique.

The role of QT-prolonging medications in a forensic autopsy study from Western Denmark.

Medication-induced prolongation of the QT-interval (miQTP) can lead to cardiac arrhythmia. Our aim was to investigate the prevalence of forensic autopsy cases where fatal cardiac arrhythmia related to treatment with QT-prolonging medications (QT-PMs) could be suspected. We performed a cross-sectional study of 741 forensic autopsies undertaken at our institution in non-drug addicts aged 15 years or above from 2017 to 2019. We defined a high risk of miQTP by one detected QT-PM in a concentration above therapeutic level, or two or more detected QT-PMs in post mortem blood. We reviewed the autopsy reports from cases with a high miQTP-risk to identify cases with no other apparent cause of death. We discarded suicides and cases with lethal levels of QT-PMs. We identified 167 cases (22.5%) with high risk of miQTP, and discarded 36 suicides (4.9%) and 7 (0.9%) with lethal levels of QT-PMs. Apart from a high risk of miQTP, no other apparent explanation of the cause of death was present in seven (0.9%). In 18 cases (2.4%) with high miQTP-risk, the cause of death was primarily attributed to cardiac changes other than acute cardiovascular events. In conclusion, 22.5% had a high risk of miQTP, and fatal cardiac arrhythmia related to treatment with QT-PMs could be suspected in 0.9%. However, a genetic pro-arrhythmic background could not be excluded in our study. Furthermore, it is possible that QT-PMs could have played a role in some of the 2.4% of cases where the cause of death was mainly attributed to cardiac changes and the risk of miQTP was high.

Simultaneous trace-level monitoring of seven opioid analgesic drugs in biological samples by pipette-tip micro solid phase extraction based on PVA-PAA/CNT-CNC composite nanofibers followed by HPLC-UV analysis.

Electrospun poly(vinyl alcohol)-(PVA)-poly(acrylic acid) (PAA)/carbon nanotubes(CNTs)-cellulose nanocrystal (CNC) (PVA-PAA/CNT-CNC) composite nanofibers were prepared and characterized using Fourier transform-infrared spectroscopy and field emission scanning electron microscopy. The resultant composite was used as an effective and novel sorbent for pipette-tip micro-solid phase extraction (PT-µSPE) of seven opioid analgesics (OAs) in biological samples followed by HPLC-UV analysis. Addition of CNT-CNC with the high specific surface area and plenty of OH-functional groups endows the nanofibers with considerable extraction efficiency. Under the optimum conditions, the linearity was obtained in the range 1.5 to 700.0 ng mL-1 for morphine, codeine, oxycodone, and tramadol, and 0.5 to 1000.0 ng mL-1 for nalbuphine, thebaine, and noscapine with coefficient of determination (r2) ≥ 0.9990. Detection limits (LODs) based on S/N = 3 were in the range of 0.15-0.50 ng mL-1. The relative standard deviations (RSDs) of 4.1-5.4% (intra-day, n = 5) and 5.2-6.4% (inter-day, n = 3) for three consecutive days were achieved. Finally, the efficiency of the PT-µSPE-HPLC-UV method was evaluated for the determination of OAs in human plasma and urine samples with good recoveries (87.3 to 97.8%). A: Schematic illustration for the preparation of PVA-PAA/CNT-CNC composite nanofibers. B: Schematic presentation of applying PVA-PAA/CNT-CNC composite nanofibers as the sorbent in pipette-tip micro solid-phase extraction (PT-µSPE) for the preconcentration of seven opioid analgesic drugs in biological samples before HPLC-UV analysis.

Longitudinal Opioid Surveillance Project Involving Toxicologic Analysis of Postmortem Specimens from 9 Counties in Michigan Suggests the Discovery of New High-Intensity Drug Trafficking Areas.

ABSTRACT: Acetyl fentanyl (AF) is a Schedule I fentanyl analog that has been increasingly seen in heroin and fentanyl polydrug toxicity overdoses in Michigan (MI). Drug users are often unaware of the presence of AF in their drugs because it is often sold mixed into or disguised as heroin. High levels of AF in heroin drug products can cause increased incidence of overdose. This article describes data from a longitudinal opioid surveillance program and details 102 decedents in MI who were found to have evidence of heroin in their postmortem blood. A large portion of these decedents were also found to have evidence of fentanyl and AF. Our data further show significant overlap in incidence rates of AF and heroin-related overdose deaths in several MI counties, suggesting that AF is becoming enmeshed in heroin trafficking. Furthermore, we report unprecedented high incidence rates of AF and heroin-related overdose deaths in Calhoun county, and we propose that it is a high-intensity drug trafficking area. Highways US-131 and US-31 are likely used to transport these drugs. More study is needed into the drug trafficking trends in MI to ascertain drug sources and monitor the ever developing and dangerous polydrug heroin combinations.

Oxycodone findings and CYP2D6 function in postmortem cases.

Genetic disposition can cause variation in oxycodone pharmacokinetic characteristics and decrease or increase the expected clinical response. In forensic medicine, determination of cause of death or assessing time between drug intake and death can be facilitated by knowledge of parent and metabolite concentrations. In this study, the aim was to investigate if CYP2D6 genotyping can facilitate interpretation by investigating the frequency of the four CYP2D6 phenotypes, poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultra-rapid metabolizer in postmortem cases, and to study if the CYP2D6 activity was associated with a certain cause of death, concentration, or metabolic ratio. Cases positive for oxycodone in femoral blood (n = 174) were genotyped by pyrosequencing for CYP2D6*3, *4, and *6 and concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined by LC-MS/MS (LLOQ 0.005 µg/g). Digital droplet PCR was used to determine the copy number variation for CYP2D6*5. Cases were categorized by cause of death. It was found that poor and intermediate CYP2D6 metabolizers had significantly higher oxycodone and noroxycodone concentrations compared to extensive and ultra-rapid metabolizers. CYP2D6 phenotype were equally distributed between cause of death groups, showing that no phenotype was overrepresented in any of the cause of death groups. We also found that the concentration ratio between oxymorphone and oxycodone depended on the CYP2D6 activity when death was unrelated to intoxication. In general, a low metabolite to parent ratio indicate an acute intake. By using receiver operating characteristic (ROC) analysis, we conclude that an oxymorphone/oxycodone ratio lower than 0.075 has a high sensitivity for separating intoxications with oxycodone from other intoxications and non-intoxications. However, the phenotype needs to be known to reach a high specificity. Therefore, the ratio should not be used as a biomarker on its own to distinguish between different causes of death but needs to be complemented by genotyping.

Maternal continuous oral oxycodone self-administration alters pup affective/social communication but not spatial learning or sensory-motor function.

BACKGROUND: The broad use/misuse of prescription opioids during pregnancy has resulted in a surge of infants with Neonatal Opioid Withdrawal Syndrome (NOWS). Short-term irritability and neurological complications are its hallmarks, but the long-term consequences are unknown. METHODS: A newly-developed preclinical model of oxycodone self-administration enables adult female rats to drink oxycodone (∼10/mg/kg/day) before and during pregnancy, and after delivery, and to maintain normal liquid intake, titrate dosing, and avoid withdrawal. RESULTS: Oxycodone was detected in the serum of mothers and pups. Growth parameters in dams and pups and litter mass and size were similar to controls. There were no differences in paw retraction latency to a thermal stimulus between Oxycodone and Control pups at postnatal (PN) 2 or PN14. Oxycodone and Control pups had similar motor coordination, cliff avoidance, righting time, pivoting, and olfactory spatial learning from PN3 through PN13. Separation-induced ultrasonic vocalizations at PN8 revealed higher call frequency in Oxycodone pups relative to Control pups (p<0.031; Cohen's d=1.026). Finally, Oxycodone pups displayed withdrawal behaviors (p's<0.029; Cohen's d's>0.806), and Oxycodone males only vocalized more than Control pups in the first minute of testing (p's<0.050; Cohen's d's>.866). Significant effects were corroborated by estimation plots. CONCLUSIONS: Our rat model of oral oxycodone self-administration in pregnancy shows exacerbated affect/social communication in pups in a sex-dependent manner but spared cognition and sensory-motor behaviors. This preclinical model reproduces selective aspects of human opioid use during pregnancy, enabling longitudinal analysis of how maternal oxycodone changes emotional behavior in the offspring.

Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children.

Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day- 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect.

Pharmacokinetic profile of injectable tramadol in the koala (Phascolarctos cinereus) and prediction of its analgesic efficacy.

Tramadol is used as an analgesic in humans and some animal species. When tramadol is administered to most species it undergoes metabolism to its main metabolites M1 or O-desmethyltramadol, and M2 or N-desmethyltramadol, and many other metabolites. This study describes the pharmacokinetic profile of tramadol when a single subcutaneous bolus of 2 mg/kg was initially administered to two koalas. Based on the results of these two koalas, subsequently 4 mg/kg as a single subcutaneous injection, was administered to an additional four koalas. M1 is recognised as an active metabolite and has greater analgesic activity than tramadol, while M2 is considered inactive. A liquid chromatography assay to quantify tramadol, M1 and M2 in koala plasma was developed and validated. Liquid chromatography-mass spectrometry confirmed that M1 had been identified. Additionally, the metabolite didesmethyltramadol was identified in chromatograms of two of the male koalas. When 4 mg/kg tramadol was administered, the median half-life of tramadol and M1 were 2.89 h and 24.69 h, respectively. The M1 plasma concentration remained well above the minimally effective M1 plasma concentration in humans (approximately 36 ng/mL) over 12 hours. The M1 plasma concentration, when tramadol was administered at 2 mg/kg, did not exceed 36 ng/mL at any time-point. When tramadol was administered at 2 mg/kg and 4 mg/kg the area under the curve M1: tramadol ratios were 0.33 and 0.50, respectively. Tramadol and M1 binding to plasma protein were determined using thawed, frozen koala plasma and the mean binding was 20% and 75%, respectively. It is concluded that when tramadol is administered at 4 mg/kg as a subcutaneous injection to the koala, it is predicted to have some analgesic activity.

Forensic pathological study of methadone-related deaths in the Genoa (Italy) district: A six-year study.

Methadone is a synthetic opioid, a pure agonist of the µ receptor. It is used for opioid maintenance therapy in heroin addiction. In recent years, Italian studies of incidence and prevalence have indicated an increase in the illegal sales of methadone and, consequently, an increase in deaths due to acute methadone intoxication as well. The present review is a prospective-observational study regarding epidemiological and toxicological analyses of methadone-related deaths recorded in the district of Genoa (Italy) from 2013 to 2018. The study includes a list of twenty-six people that have died from methadone toxicity: twenty-two males and four females. The concentration of methadone in the blood samples ranged from 181 to 4058.53 ng/mL, with an average of 964.29 ng/mL. Six subjects tested positive for methadone alone; twenty cases, however, presented drugs or substances in different concentrations in the blood samples. Illegal sales and consumption of methadone have a negative impact on the self-administration therapy of opioid addiction, inducing patients to increase their dosage or sell methadone in order to purchase illegal drugs. As shown in our study, this behaviour is associated with an increase in methadone-related deaths. Accordingly, careful monitoring of dosage administrated to patients is required in order to render the system safer.

Towards an untargeted mass spectrometric approach for improved screening in equine antidoping.

The emergence of novel doping agents is a continuous issue for analysts who aim to maintain the integrity of horseracing together with the well-being and safety of the animals and riders involved. Untargeted mass spectrometric analysis presents a potential improvement for antidoping as it enables the detection of compounds being indirectly affected by an administered drug. In this study, liquid chromatography-high-resolution mass spectrometry was used to investigate a 12-horse administration study of the synthetic opioid, butorphanol. A mass spectrometric workflow capable of detecting metabolic differences for an extended period of time was successfully developed. This proof-of-concept study demonstrates the potential of untargeted workflows to provide a list of biomarkers of exposure and effect that are indicative of drug administration which may be implemented into routine testing for improved doping control.

High-Performance Liquid Chromatography-Tandem Mass Spectrometry for Buprenorphine Evaluation in Plasma-Application to Pharmacokinetic Studies in Rabbits.

The precise and reliable determination of buprenorphine concentration is fundamental in certain medical or research applications, particularly in pharmacokinetic studies of this opioid. The main challenge is, however, the development of an analytical method that is sensitive enough, as the detected in vivo concentrations often fall in very low ranges. Thus, in this study we aimed at developing a sensitive, repeatable, cost-efficient, and easy HPLC analytical protocol for buprenorphine in rabbit plasma. In order to obtain this, the HPLC-MS2 system was used to elaborate and validate the method for samples purified with liquid-liquid extraction. Fragment ions 468.6→396.2 and 468.6→414.2 were monitored, and the method resulted in a high repeatability and reproducibility and a limit of quantification of 0.25 µg/L with a recovery of 98.7-109.0%. The method was linear in a range of 0.25-2000 µg/L. The suitability of the analytical procedure was tested in rabbits in a pilot pharmacokinetic study, and it was revealed that the method was suitable for comprehensively describing the pharmacokinetic profile after buprenorphine intravenous administration at a dose of 300 µg/kg. Thus, the method suitability for pharmacokinetic application was confirmed by both the good validation results of the method and successful in vivo tests in rabbits.

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.

BACKGROUND: 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.

Stereoselective Analysis of Methadone and EDDP in Laboring Women and Neonates in Plasma and Dried Blood Spots and Association with Neonatal Abstinence Syndrome.

OBJECTIVE: This pilot study evaluated the relationship between maternal and neonatal R- and S-methadone and R- and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) exposure and the severity of neonatal abstinence syndrome (NAS). The use of dried blood spots (DBS) as an alternative for plasma in assessing methadone and EDDP was also assessed. STUDY DESIGN: Women receiving methadone for medication assisted treatment of opioid use disorder during pregnancy were eligible for recruitment. Plasma and DBS samples were collected from mothers during labor, from cord blood, and from newborns during genetic screen. R-/S-methadone and EDDP were measured by high-performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS). Associations between methadone exposure, neonatal morphine requirements, and severity of NAS were examined. RESULTS: Twenty women and infants completed the study. Maternal methadone dose at delivery was 112 mg/day (range = 60-180 mg/day). Sixteen neonates experienced NAS requiring morphine; three also required phenobarbital. Higher cord blood concentrations of R-methadone, R- and S-EDDP were associated with higher maximum doses of morphine (p < 0.05). CONCLUSION: Maternal methadone and cord blood concentration at delivery are variable and may be potential markers of neonatal abstinence syndrome.

Sublingual Versus Swallowed Morphine: A Comparison.

BACKGROUND: The optimal route for immediate-release morphine administration is controversial. The known physical characteristics of morphine that allow absorption are counter to the unproven belief that sublingual morphine is absorbed more quickly. OBJECTIVE: The aim of this study was to compare swallowed and sublingual morphine for effects on plasma morphine concentrations (PMCs), pain relief, and taste. METHODS: Ten participants with cancer (mean age, 50 ± 12 years) received a 10-mg morphine tablet in a randomized crossover design with repeated premeasure and postmeasure for 60 minutes. Measures included PMC and visual analog scale (100 mm) scores for pain relief and taste. RESULTS: Interindividual variability in maximum PMC was 25-fold (2.2-55 ng/mL). At 60 minutes, sublingual and swallowed routes were not significantly different for mean area under the curve for PMC (swallowed, 329 ± 314 ng/mL; sublingual, 314 ± 299 ng/mL) or for mean pain relief scores (swallowed, 81 ± 32; sublingual, 78 ± 31). Taste scores at 5 (P < .05), 10 (P < .04), 15 (P < .02), and 20 (P < .04) minutes after swallowed doses were significantly less unpleasant than after sublingual doses. CONCLUSION: In this crossover design, between-group PMCs were similar for sublingual and swallowed morphine and resulted in a similar level of pain relief. Given the 25-fold across-participant differences in PMC after the same dose, additional research is warranted to identify the sources of this tremendous variability in PMC. IMPLICATIONS FOR PRACTICE: Because of unpleasant taste, which could influence adherence and subsequent analgesia, clinicians should encourage patients to swallow their morphine doses and restrict use of sublingual morphine to individuals who are unable to swallow.