Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids.

Opioid-induced respiratory depression (OIRD) deaths are ~80,000 a year in the US and are a major public health issue. Approximately 90% of fatal opioid-related deaths are due to synthetic opioids such as fentanyl, most of which is illicitly manufactured and distributed either on its own or as an adulterant to other drugs of abuse such as cocaine or methamphetamine. Other potent opioids such as nitazenes are also increasingly present in the illicit drug supply, and xylazine, a veterinary tranquilizer, is a prevalent additive to opioids and other drugs of abuse. Naloxone is the main treatment used to reverse OIRD and is available as nasal sprays, prefilled naloxone injection devices, and generic naloxone for injection. An overdose needs to be treated as soon as possible to avoid death, and synthetic opioids such as fentanyl are up to 50 times more potent than heroin, so the availability of new, higher-dose, 5-mg prefilled injection or 8-mg intranasal spray naloxone preparations are important additions for emergency treatment of OIRDs, especially by lay people in the community. Higher naloxone doses are expected to reverse a synthetic overdose more rapidly and the current formulations are ideal for use by untrained lay people in the community. There are potential concerns about severe withdrawal symptoms, or pulmonary edema from treatment with high-dose naloxone. However, from the perspective of first responders, the balance of risks would point to administration of naloxone at the dose required to combat the overdose where the risk of death is very high. The presence of xylazines as an adulterant complicates the treatment of OIRDs, as naloxone is probably ineffective, although it will reverse the respiratory depression due to the opioid. For these patients, hospitalization is particularly vital. Education about the benefits of naloxone remains important not only in informing people about how to treat emergency OIRDs but also how to obtain naloxone. A call to emergency services is also essential after administering naloxone because, although the patient may revive, they may overdose again later because of the short half-life of naloxone and the long-lasting potency of fentanyl and its analogs.

Multicenter Population Pharmacokinetics of Fentanyl in Neonatal Surgical Patients Using Dried Blood Spot Specimen Collection Demonstrates Maturation of Elimination Clearance.

BACKGROUND: Fentanyl is widely used for analgesia and sedation in neonates, but pharmacokinetic (PK) analysis in this population has been limited by the relatively large sample volumes required for plasma-based assays. METHODS: In this multicenter observational study of fentanyl kinetics in neonates up to 42 weeks of postmenstrual age (PMA) who received fentanyl boluses and continuous infusions, dried blood spots were used for small-volume sampling. A population PK analysis was used to describe fentanyl disposition in term and preterm neonates. Covariates for the model parameters, including body weight, PMA, birth status (preterm or term), and presence of congenital cardiac disease, were assessed in a stepwise manner. RESULTS: Clearance was estimated to be greater than adult clearance of fentanyl and varied with weight. Covariate selection did not yield a significant relationship for age as a continuous or dichotomous variable (term or preterm, the latter defined as birth with PMA of <37 weeks) and clearance. CONCLUSIONS: A supra-allometric effect on clearance was determined during covariate analyses (exponential scaling factor for body weight >0.75), as has been described in population PK models that account for maturation of intrinsic clearance (here, predominantly hepatic microsomal activity) in addition to scaling for weight, both of which impact clearance in this age group.

Population Pharmacokinetics of Single Bolus Dose Fentanyl in Obese Children.

BACKGROUND: Childhood obesity is a significant problem. Obesity may alter the pharmacokinetics (PKs) of medications. Fentanyl is commonly used for procedural sedation, but there is a paucity of bolus dose fentanyl PK data in obese children. Better understanding of fentanyl PK in obese children would facilitate dosing recommendations. We conducted a study involving children with and without obesity to assess the potential differences in bolus dose fentanyl PK between the 2 groups. METHODS: We enrolled children 2 to 12 years of age with and without obesity, defined as >95th percentile body mass index (BMI) for age and sex, undergoing elective tonsillectomy ± adenoidectomy. After induction, subjects had 2 intravenous (IV) lines placed in 2 different extremities: 1 for medications and IV fluids and 1 for obtaining blood aliquots for fentanyl concentration analysis. After administration of 1 mcg/kg of fentanyl based on total body weight (TBW), blood sample collections for fentanyl concentration analysis were attempted at 5, 15, 30, 60, 90, and 120 minutes. Five-minute fentanyl concentrations were compared between obese and nonobese cohorts. Population PK analysis to examine the differences between obese and nonobese children was performed and included various body size descriptors, such as TBW, BMI, and fat-free mass (FFM), to examine their influence on model parameters. RESULTS: Half of the 30 subjects were obese. Mean fentanyl concentrations at 5 minutes were 0.53 ng/mL for the nonobese group and 0.88 ng/mL for the obese group, difference 0.35 ng/mL (95% CI, 0.08-0.61 ng/mL; P = .01). Population PK analysis showed that FFM was a significant covariate for the central volume of distribution. The potential clinical effect of an IV bolus dose of fentanyl based on TBW versus FFM in an obese child was assessed in a simulation using our model. 1 mcg/kg fentanyl dose based on TBW resulted in an approximately 60% higher peak fentanyl effect site concentration than dosing based on FFM. CONCLUSIONS: Our data demonstrated higher peak plasma fentanyl concentrations in obese compared to nonobese subjects. Population PK analysis found that FFM was a significant covariate for the central volume of distribution. Model simulation showed dosing of fentanyl in obese children based on TBW resulted in significantly higher peak concentrations than dosing based on FFM. Based on this modeling and the known concentration-effect relationship between fentanyl and adverse effects, our results suggest that bolus dosing of fentanyl in obese children should be based on FFM rather than TBW, particularly for procedures of short duration.

Cannabis, e-cigarettes and anesthesia.

PURPOSE OF REVIEW: Both cannabis and e-cigarette use are increasing, particularly among adolescents. The use of cannabis products may impact patients' physiology under anesthesia. Understanding the effects of cannabis and vaping are critical to the provision of safe and effective anesthetic care. RECENT FINDINGS: E-cigarettes have recently been implicated in a severe presentation of acute lung injury, often in association with vaporization of the cannabinoid, THC. E-cigarette use appears to be associated with other less-acute pulmonary adverse effects that are yet to be fully understood. Cannabis affects many organ systems with alterations in cardiovascular, respiratory and neurological function. Specifically, there is emerging evidence that cannabis use may reduce the efficacy of sedative agents and postoperative pain management efforts. SUMMARY: There is a very wide variety of cannabis products currently available, with respect to both route of administration as well as cannabinoid content. Patients using cannabis products prior to anesthesia may present with altered physiology that place them at increased risk for cardiovascular and respiratory complications. They may also be tolerant to the effects of propofol and opioid for pain management, thus consideration should be given to use of a multimodal regimen.

A Sensitive LC-MS/MS Assay for the Quantification of Methadone and its Metabolites in Dried Blood Spots: Comparison With Plasma.

INTRODUCTION: Methadone, a synthetic narcotic, is widely used both in adults and children for pain control and as a replacement drug in opioid use disorder to prevent craving and withdrawal. To support clinical pharmacokinetic trials in neonates, infants, and children, the authors developed and validated a novel, automated, highly sensitive liquid chromatography-electrospray-tandem mass spectrometry ionization (LC-ESI-MS/MS) method for the quantification of methadone and its metabolites, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP), in samples collected as dried blood spots. METHODS: Blood was spiked with different concentrations of methadone, EDDP, and EMDP, and blood drops were applied to filter paper cards. Punches of 6.4 mm were removed from the cards, and 600 µL of protein precipitation solution (methanol/0.2M ZnSO4, 7:3, vol/vol) containing the internal standards (methadone-d9 and EDDP-d5) at a concentration of 1 mcg/L was added. The extracts were analyzed using LC-ESI-MS/MS in combination with online extraction. The mass spectrometer was run in the positive multiple reaction monitoring mode, and the total run time was 3.2 minutes. RESULTS: For the dried blood spots, the assay has a lower limit of quantification of 0.1 mcg/L for methadone, EDDP, and EMDP. The range of reliable response for methadone for the ion transition m/z = 310.2→265.1 was 0.1-100 mcg/L and for the ion transition m/z = 310.2→223.1 5-1000 mcg/L. For EDDP, on the range of reliable response for the ion transition, m/z = 278.2→234.3 was 0.1-100 mcg/L and for the ion transition m/z = 278.2→186.1 5-1000 mcg/L. The calibration range for EMDP was 0.1-100 mcg/L. Accuracy (85%-115%) and imprecision (<15%) met predefined acceptance criteria. DISCUSSION: This assay allows for the measurement of small volume blood samples without the need for an intravenous blood draw, and thus, it is suitable for pharmacokinetics studies and therapeutic drug monitoring in pediatric patients.

Preoperative Vancomycin Administration for Surgical Site Prophylaxis: Plasma and Soft-Tissue Concentrations in Pediatric Neurosurgical and Orthopedic Patients.

BACKGROUND: Vancomycin is used for antibiotic prophylaxis in pediatric surgical patients without a complete understanding of plasma and soft-tissue pharmacokinetics. Guidelines recommend incision within 60 minutes after administration; however, tissue vancomycin concentrations at that early time may not be therapeutic. We conducted a study of plasma and skin concentrations in pediatric neurosurgical and orthopedic patients to characterize intraoperative vancomycin pharmacokinetics. METHODS: Patients (0.1-18.8 years of age) undergoing posterior spinal fusion (n = 30) or ventriculoperitoneal shunt placement (n = 30) received intravenous vancomycin 15 mg/kg (maximum 1000 mg) over 1 hour. Skin was biopsied at incision and skin closure. Blood samples were collected at incision, at 2 and 4 hours intraoperatively, and at closure. Population pharmacokinetic analysis was performed to characterize pharmacokinetic parameter estimates and to develop a model of intraoperative plasma and skin vancomycin concentrations versus time. RESULTS: Pharmacokinetic analysis included data from 59 subjects, 130 plasma samples, and 107 skin samples. A 2-compartment model, volume of the central (Vc) and volume of the peripheral compartment (V2), proved to have the best fit. Stepwise covariate selection yielded a significant relationship for body surface area on elimination clearance and body weight on V2. Skin vancomycin concentrations rose continuously during surgery. Modeling predicted that equilibration of skin and plasma vancomycin concentrations took ≥5 hours. CONCLUSIONS: Skin vancomycin concentrations immediately after a preoperative dose are relatively low compared with concentrations at the end of surgery. It may be advisable to extend the time between dose and incision if higher skin concentrations are desired at the start of surgery.

Cannabinoids, Pain, and Opioid Use Reduction: The Importance of Distilling and Disseminating Existing Data.

The high prevalence of chronic pain conditions combined with an over-reliance on opioid prescriptions has resulted in an opioid epidemic and a desperate need for solutions. There is some debate about whether cannabis might play a role in addressing chronic pain conditions as well as the opioid epidemic. Recent surveys suggest that a large number of people are using cannabis as a treatment for pain and to reduce use of opioids, and cannabis-derived products demonstrate at least modest efficacy in the treatment of pain in randomized controlled trials. In addition, surveillance studies from countries that have approved the use of Sativex, which is a cannabis-based product, have demonstrated that a combination of Δ9-tetrahydrocannabinol and cannabidiol has low potential for harm, is well tolerated, and is helpful to patients. Given the number of people in the United States who are already using cannabis to manage pain and opioid use in state-regulated markets, it is imperative to conduct additional research in these areas, and to disseminate information on how to minimize harm and maximize any benefits of using cannabinoids to mitigate pain and reduce opioid use. The purpose of this article is to call attention to the fact that cannabis is being used in the management of chronic pain. Thus, this article also provides a set of guidelines on how to approach using cannabis to treat pain.

Prospective evaluation of oral cannabis extracts in children with epilepsy.

PURPOSE: Interest in the use of artisanal cannabinoids in pediatric epilepsy has increased but safety and utility data are lacking. Our aim was to prospectively characterize the use of oral cannabis extracts (OCE) in a refractory pediatric epilepsy population. METHODS: Families considering the use of an OCE were enrolled in a prospective observational study. Baseline seizure frequency was assessed over a period of 4 weeks. Seizure frequency, CBD and THC-COOH levels were assessed every 4 weeks during a 12-week treatment period. Response was defined as at least a 50% reduction in seizure frequency over the final 8 weeks of the study relative to baseline. RESULTS: Consent was obtained in 32 children; 11 were excluded from analysis (3 failed to complete baseline data, 3 started OCE before completing baseline period and 5 did not start OCE) leaving 21 to be included in subsequent analyses. Median age was 10.3 years (IQR 6.8-12.6), 13 (62%) were male and median seizure frequency was 2.7 seizures/day during the baseline period. The median of the high dose of CBD that was administered during the observation period was of 0.9 (0.6-2.2) mg/kg/day. Of the 21 subjects who were included in the analysis, 5 (24%) were responders. OCE was stopped early in 3 subjects (14%) due to a perceived increase in seizures. THC-COOH and CBD blood levels did not have a significant association with response status (p = 0.95 CBD, p = 0.53 THC-COOH, N = 14). CONCLUSION: The observed response rate in this study is similar to placebo rates in prospective randomized trials of pharmaceutical grade products and the withdrawal rate is greater than rates obtained with retrospective methods. Doses of OCE administered were lower than doses used in randomized trials.

The Society for Pediatric Anesthesia recommendations for the use of opioids in children during the perioperative period.

Opioids have long held a prominent role in the management of perioperative pain in adults and children. Published reports concerning the appropriate, and inappropriate, use of these medications in pediatric patients have appeared in various publications over the last 50 years. For this document, the Society for Pediatric Anesthesia appointed a taskforce to evaluate the available literature and formulate recommendations with respect to the most salient aspects of perioperative opioid administration in children. The recommendations are graded based on the strength of the available evidence, with consensus of the experts applied for those issues where evidence is not available. The goal of the recommendations was to address the most important issues concerning opioid administration to children after surgery, including appropriate assessment of pain, monitoring of patients on opioid therapy, opioid dosing considerations, side effects of opioid treatment, strategies for opioid delivery, and assessment of analgesic efficacy. Regular updates are planned with a re-release of guidelines every 2 years.

Opioid Use Disorder in Children and Adolescents: Risk Factors, Detection, and Treatment.

Opioid medications are an important tool in the management of pain and have been used in clinical practice for centuries. However, due to the highly addictive nature of this class of medications coupled with the life-threatening side effect of respiratory depression, opioid misuse has become a significant public health crisis worldwide. Children and adolescents are at risk for opioid misuse, and early detection is imperative to facilitate treatment and improve outcomes. This review will address the current state of opioid misuse and treatment in children and adolescents in the United States.

Morphine Pharmacokinetics in Children With Down Syndrome Following Cardiac Surgery.

OBJECTIVES: To assess if morphine pharmacokinetics are different in children with Down syndrome when compared with children without Down syndrome. DESIGN: Prospective single-center study including subjects with Down syndrome undergoing cardiac surgery (neonate to 18 yr old) matched by age and cardiac lesion with non-Down syndrome controls. Subjects were placed on a postoperative morphine infusion that was adjusted as clinically necessary, and blood was sampled to measure morphine and its metabolites concentrations. Morphine bolus dosing was used as needed, and total dose was tracked. Infusions were continued for 24 hours or until patients were extubated, whichever came first. Postinfusion, blood samples were continued for 24 hours for further evaluation of kinetics. If patients continued to require opioid, a nonmorphine alternative was used. Morphine concentrations were determined using a unique validated liquid chromatography tandem-mass spectrometry assay using dried blood spotting as opposed to large whole blood samples. Morphine concentration versus time data was modeled using population pharmacokinetics. SETTING: A 16-bed cardiac ICU at an university-affiliated hospital. PATIENTS: Forty-two patients (20 Down syndrome, 22 controls) were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of morphine in pediatric patients with and without Down syndrome following cardiac surgery were analyzed. No significant difference was found in the patient characteristics or variables assessed including morphine total dose or time on infusion. Time mechanically ventilated was longer in children with Down syndrome, and regarding morphine pharmacokinetics, the covariates analyzed were age, weight, presence of Down syndrome, and gender. Only age was found to be significant. CONCLUSIONS: This study did not detect a significant difference in morphine pharmacokinetics between Down syndrome and non-Down syndrome children with congenital heart disease.

The pharmacokinetics of intravenous ketorolac in children aged 2 months to 16 years: A population analysis.

BACKGROUND: Intravenous ketorolac is commonly administered to children for the control of postoperative pain. An effect site EC50 for analgesia of 0.37 mg. L-1 is described in adults. AIMS: The aim of this study was to review age- and weight-related effects on ketorolac pharmacokinetic parameters in children and current dosing schedules. METHODS: Pooled intravenous ketorolac (0.5 mg. kg-1 ) concentration-time data in children aged 2 months to 16 years were analyzed using nonlinear mixed-effects models. Allometry was used to scale to a 70 kg person. RESULTS: There were 64 children aged 2 months to 16 years (641 plasma concentrations) available for analysis. A two-compartment mammillary model was used to describe pharmacokinetics. Clearance was 2.53 (CV 45.9%) L. h-1. 70 kg-1 and intercompartment clearance was 4.43 (CV 95.6%) L. h-1. 70 kg-1 . Both central (V1) and peripheral (V2) volumes of distribution decreased with age over the first few years of postnatal life to reach V1 6.89 (CV 30.3%) L. 70 kg-1 and V2 5.53 (CV 47.6%) L. 70 kg-1 . CONCLUSION: Clearance, expressed as L. h-1. kg-1 , decreased with age from infancy. A dosing regimen of 0.5 mg. kg-1 every 6 hours maintains a trough concentration larger than 0.37 mg. L-1 in children 9 months to 16 years of age. This dosing regimen is consistent with current recommendations.

Evaluating Clinical Effectiveness and Pharmacokinetic Profile of Atomized Intranasal Midazolam in Children Undergoing Laceration Repair.

BACKGROUND: Atomized intranasal midazolam is a common adjunct in pediatrics for procedural anxiolysis. There are no previous studies of validated anxiety scores with pharmacokinetic data to support optimal procedure timing. OBJECTIVES: We describe the clinical and pharmacokinetic profile of atomized intranasal midazolam in children presenting for laceration repair. METHODS: Children 11 months to 7 years of age and weighing <26 kg received 0.4 mg/kg of atomized intranasal midazolam for simple laceration repair. Blood samples were obtained at 3 time points in each patient, and the data were fit with a 1-compartment model. Patient anxiety was rated with the Observational Scale of Behavioral Distress. Secondary outcomes included use of adjunctive medications, successful completion of procedure, and adverse events. RESULTS: Sixty-two subjects were enrolled, with a mean age of 3.3 years. The median time to peak midazolam concentration was 10.1 min (interquartile range 9.7-10.8 min), and the median time to the procedure was 26 min (interquartile range 21-34 min). There was a trend in higher Observational Scale of Behavioral Distress scores during the procedure. We observed a total of 2 adverse events, 1 episode of vomiting (1.6%) and 1 paradoxical reaction (1.6%). Procedural completion was successful in 97% of patients. CONCLUSIONS: Atomized intranasal midazolam is a safe and effective anxiolytic to facilitate laceration repair. The plasma concentration was >90% of the maximum from 5 to 17 min, suggesting this as an ideal procedural timeframe after intranasal midazolam administration.

Evaluation of drug use and medication compliance in adolescents admitted to a psychiatric facility from the pediatric emergency department.

OBJECTIVES: Knowledge of drug use and medication compliance during mental health evaluation can help guide evaluation and treatment. The objective was to evaluate drug use and medication compliance in a pediatric emergency department (PED) psychiatric population by comparing medical history, standard urine drug screen (EIA), and expanded urine drug screen (HPLC-MS/MS). METHODS: A prospective cohort study of admitted psychiatric patients ≥13years and ≤18years in a tertiary-care children's hospital psychiatric ED from January 31, 2013 through April 16, 2014. RESULTS: 100 patients in our PED were enrolled. Marijuana was the most commonly admitted and detected substance; 43% had co-ingestions. HPLC-MS/MS revealed 36 additional substance exposures than identified by history. All substances detected by EIA were also detected by HPLC-MS/MS. Combination of history and HPLC-MS/MS revealed the most substances used. HPLC-MS/MS identified antidepressants in 76% of patients prescribed a detectable antidepressant. CONCLUSION: Marijuana use was greater than nicotine use and was associated with concomitant polysubstance abuse. A combination of history and HPLC-MS/MS was the most thorough in obtaining history of drug use. Almost a quarter of patients did not have their prescribed antidepressant detected by HPLC-MS/MS. A rapid, affordable expanded drug screen should replace the more standard limited drug screen particularly for patients who are refractory to treatment.

An Atmospheric Pressure Chemical Ionization MS/MS Assay Using Online Extraction for the Analysis of 11 Cannabinoids and Metabolites in Human Plasma and Urine.

BACKGROUND: Although, especially in the United States, there has been a recent surge of legalized cannabis for either recreational or medicinal purposes, surprisingly little is known about clinical dose-response relationships, pharmacodynamic and toxicodynamic effects of cannabinoids such as Δ9-tetrahydrocannabinol (THC). Even less is known about other active cannabinoids. METHODS: To address this knowledge gap, an online extraction, high-performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous quantification of 11 cannabinoids and metabolites including THC, 11-hydroxy-Δ9-tetrahydrocannabinol, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-C-gluc), cannabinol, cannabidiol, cannabigerol, cannabidivarin, Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (THCV-COOH) was developed and validated in human urine and plasma. RESULTS: In contrast to atmospheric pressure chemical ionization, electrospray ionization was associated with extensive ion suppression in plasma and urine samples. Thus, the atmospheric pressure chemical ionization assay was validated showing a lower limit of quantification ranging from 0.39 to 3.91 ng/mL depending on study compound and matrix. The upper limit of quantification was 400 ng/mL except for THC-C-gluc with an upper limit of quantification of 2000 ng/mL. The linearity was r > 0.99 for all analyzed calibration curves. Acceptance criteria for intrabatch and interbatch accuracy (85%-115%) and imprecision (<15%) were met for all compounds. In plasma, the only exceptions were THCV (75.3%-121.2% interbatch accuracy) and cannabidivarin (interbatch imprecision, 15.7%-17.2%). In urine, THCV did not meet predefined acceptance criteria for intrabatch accuracy. CONCLUSIONS: This assay allows for monitoring not only THC and its major metabolites but also major cannabinoids that are of interest for marijuana research and clinical practice.

Intrathecal Morphine Versus Extended-Release Epidural Morphine for Postoperative Pain Control in Pediatric Patients Undergoing Posterior Spinal Fusion.

BACKGROUND: Posterior spinal fusion for scoliosis is one of the most painful elective pediatric surgeries. Good postoperative pain control allows early ambulation and return of ability to tolerate oral intake. Options for analgesia in this patient population are suboptimal. We hypothesized that extended-release epidural morphine (EREM) would provide better pain control and less adverse effects compared to intrathecal (IT) morphine. METHODS: The primary outcome was total IV morphine consumption during 0-48 hours postoperatively. Secondary outcomes included time until first patient-controlled analgesia (PCA) demand, pain scores, and adverse opioid effects. After institutional review board approval, 71 subjects undergoing posterior spinal fusion for idiopathic scoliosis completed the study. The subjects were randomly allocated to 7.5 µg/kg IT morphine or 150 µg/kg EREM. The final IT morphine and EREM groups contained 37 and 34 subjects, respectively. Postoperative pain was treated with morphine PCA, ketorolac, oral oxycodone, and acetaminophen. Morphine consumption, pain scores, nausea and vomiting, pruritus, and respiratory depression were measured every 4 hours. Parents completed a caregiver questionnaire about their child's pain control regimen after the first postoperative day. RESULTS: There was no difference in total morphine consumption over the first 48 hours between subjects in the EREM and IT morphine groups: median (range) 42.2 (5.5-123.0) and 34.0 (4.5-128.8) mg, respectively (P = .27). EREM and IT morphine groups had no difference in time until first PCA demand. Pain scores were no different between the groups from 8 to 24 hours after surgery. Compared to IT morphine, EREM subjects had lower pain scores from 28 to 36 hours after surgery. The reported incidence of pruritus was lower in the EREM subjects. CONCLUSIONS: There was no difference in total morphine consumption or time until first PCA demand between the EREM and IT morphine groups. EREM provides a longer duration of analgesia after posterior spinal fusion for scoliosis and may be associated with less opioid-induced pruritus.

Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model.

BACKGROUND: Obesity causes multiorgan dysfunction, specifically metabolic abnormalities in the liver. Obese patients are opioid-sensitive and have high rates of respiratory complications after surgery. Obesity also has been shown to cause resistance to leptin, an adipose-derived hormone that is key in regulating hunger, metabolism, and respiratory stimulation. We hypothesized that obesity and leptin deficiency impair opioid pharmacokinetics (PK) independently of one another. METHODS: Morphine PK were characterized in C57BL/6J wild-type (WT), diet-induced obese (DIO), and leptin-deficient (ob/ob) mice, and in ob/ob mice given leptin-replacement (LR) therapy. WT mice received several dosing regimens of morphine. Obese mice (30 g) received one 80 mg/kg bolus of morphine. Blood was collected at fixed times after morphine injection for quantification of plasma morphine and morphine 3-glucuronide (M3G) levels. PK parameters used to evaluate morphine metabolism included area-under the curve (AUC150), maximal morphine concentration (CMAX), and M3G-to-morphine ratio, and drug elimination was determined by clearance (Cl/F), volume of distribution, and half-life (T1/2). PK parameters were compared between mouse groups by the use of 1-way analysis of variance, with P values less than .05 considered significant. RESULTS: DIO compared with WT mice had significantly decreased morphine metabolism with lower M3G-to-morphine ratio (mean difference [MD]: -4.9; 95% confidence interval [CI]: -8.8 to -0.9) as well as a decreased Cl/F (MD: -4.0; 95% CI: -8.9 to -0.03) Ob/ob compared with WT mice had a large increase in morphine exposure with a greater AUC150 (MD: 980.4; 95% CI: 630.1-1330.6), CMAX (MD: 6.8; 95% CI: 2.7-10.9), and longer T1/2 (MD: 23.1; 95% CI: 10.5-35.6), as well as a decreased Cl/F (MD: -7.0; 95% CI: -11.6 to -2.7). Several PK parameters were significantly greater in ob/ob compared with DIO mice, including AUC150 (MD: 636.4; 95% CI: 207.4-1065.4), CMAX (MD: 5.3; 95% CI: 3.2-10.3), and T1/2 (MD: 18.3; 95% CI: 2.8-33.7). When leptin was replaced in ob/ob mice, PK parameters began to approach DIO and WT levels. LR compared with ob/ob mice had significant decreases in AUC150 (MD: -779.9; 95% CI: -1229.8 to -330), CMAX (MD: -6.1; 95% CI: -11.4 to -0.9), and T1/2 (MD: -19; 95% CI: -35.1 to -2.8). Metabolism increased with LR, with LR mice having a greater M3G-to-morphine ratio compared with DIO (MD: 5.3; 95% CI: 0.3-10.4). CONCLUSIONS: Systemic effects associated with obesity decrease morphine metabolism and excretion. A previous study from our laboratory demonstrated that obesity and leptin deficiency decrease the sensitivity of central respiratory control centers to carbon dioxide. Obesity and leptin deficiency substantially decreased morphine metabolism and clearance, and replacing leptin attenuated the PK changes associated with leptin deficiency, suggesting leptin has a direct role in morphine metabolism.

Personalizing pediatric pain medicine: using population-specific pharmacogenetics, genomics, and other -omics approaches to predict response.

Personalized medicine is the science of individualized prevention and therapy. The notion that "one size fits all" has been replaced by the idea of patient-tailored health care. Within this paradigm, the research community has turned to examine genetic predictors of disease and treatment responses. Pain researchers have produced genetic studies over the last decade that evaluate the association of genetic variability with pain sensitivity and analgesic response. While most of these studies have been conducted among cohorts of subjects of European descent, some have included other racial and ethnic groups, providing evidence of variable responses to analgesics. Simultaneously, there is an increased recognition regarding the complexity of pain research, acknowledging the additional role of epigenetic, transcriptomic, proteomic, and metabolomic factors in the development, experience, and treatment of pain. This article provides an introduction to population-specific pharmacogenetics, proteomics and other "-omics" technologies to predict drug response to pain medications in children. It aims to provide anesthesiologists with the basic knowledge to understand the potential implications of genetic and epigenetic factors managing the pain of pediatric patients.

Long-term cross-validation of everolimus therapeutic drug monitoring assays: the Zortracker study.

BACKGROUND: This ongoing academic collaboration was initiated for providing support to set up, validate, and maintain everolimus therapeutic drug monitoring assays and to study long-term interlaboratory performance. METHODS: This study was based on EDTA whole blood samples collected from transplant patients treated with everolimus in a prospective clinical trial. Samples were handled under controlled conditions during collection, storage and were shipped on dry ice to minimize freeze-thaw cycles. For more than 1.5 years, participating laboratories received a set of 3 blinded samples on a monthly basis. Among others, these samples included individual patient samples, patient sample pools to assess long-term performance, and patient samples pools enriched with isolated everolimus metabolites. RESULTS: The results between liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and the everolimus Quantitative Microsphere System (QMS, Thermo Fisher) assay were comparable. The monthly interlaboratory variability (coefficient of variation %) for cross-validation samples ranged from 6.5% to 23.2% (average of 14.8%) for LC-MS/MS and 4.2% to 26.4% (average of 11.1%) for laboratories using the QMS assay. A blinded long-term pool sample was sent to the laboratories for 13 months. The result was 5.31 ± 0.86 ng/mL (range, 2.9-7.8 ng/mL) for the LC-MS/MS and 5.20 ± 0.54 ng/mL (range, 4.0-6.8 ng/mL) for QMS laboratories. Enrichment of patient sample pools with 5-25 ng/mL of purified everolimus metabolites (46-hydroxy everolimus and 39-O-desmethyl everolimus) did not affect the results of either LC-MS/MS or QMS assays. CONCLUSIONS: Both LC-MS/MS and QMS assays gave similar results and showed similar performance, albeit with a trend toward higher interlaboratory variability among laboratories using LC-MS/MS than the QMS assay.

Off-label use of drugs in children.

The passage of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act has collectively resulted in an improvement in rational prescribing for children, including more than 500 labeling changes. However, off-label drug use remains an important public health issue for infants, children, and adolescents, because an overwhelming number of drugs still have no information in the labeling for use in pediatrics. The purpose of off-label use is to benefit the individual patient. Practitioners use their professional judgment to determine these uses. As such, the term "off-label" does not imply an improper, illegal, contraindicated, or investigational use. Therapeutic decision-making must always rely on the best available evidence and the importance of the benefit for the individual patient.