RESUMO
Novel synthetic opioids (NSOs) represent an emerging group of novel psychoactive substances, acting as agonists at the opioid receptors. NSOs include fentanyl-related compounds, e.g. methoxyacetylfentanyl (MeACF), and non-fentanyl analogs, e.g. "U compounds" including U-47700. Here we present three cases of death involving MeACF and U-47700, with particular reference to preliminary data on pharmacokinetics and tissue distribution.After a complete post-mortem examination, general unknown screenings and analysis of drugs of abuse were performed on postmortem samples by immunoassays, gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. To quantify the analytes of interest in post-mortem blood and tissues, the standard addition method was used. A toxicological significance score (TSS), weighing the role of the NSO in each death case, was assigned.Case 1 died at the hospital after consumption of U-47700, methadone (serum levels: 2,600 ng/ml and 37 ng/ml), tilidine and benzodiazepines. In case 2, U-47700 (204 ng/ml) together with methadone (290 ng/ml), flubromazepam (480 ng/ml) and diazepam (300 ng/ml) were detected in peripheral blood. In case 3, methoxyacetylfentanyl (266 ng/ml), furanylfentanyl (4.3 ng/ml) 4-ANPP (15 ng/ml) and alprazolam (69 ng/ml) were quantified in femoral blood. In all cases, the NSO likely contributed to the death (TSS = 3).NSOs appear to be often consumed in the setting of polydrug intoxications, especially in combination with other opioids and benzodiazepines, which often exert synergistic effects. The standard addition method remains the most reliable in post-mortem analysis and toxicological results should always be evaluated together with circumstantial and autopsy data.
Assuntos
Fentanila , Humanos , Fentanila/análogos & derivados , Fentanila/intoxicação , Fentanila/sangue , Fentanila/análise , Masculino , Adulto , Analgésicos Opioides/intoxicação , Analgésicos Opioides/sangue , Analgésicos Opioides/análise , Metadona/intoxicação , Metadona/sangue , Metadona/análise , Toxicologia Forense , Cromatografia Líquida , Benzodiazepinas/sangue , Benzodiazepinas/intoxicação , Feminino , Pessoa de Meia-Idade , Cromatografia Gasosa-Espectrometria de Massas , Drogas Ilícitas/sangue , Drogas Ilícitas/intoxicação , Detecção do Abuso de Substâncias , BenzamidasRESUMO
Methadone has two enantiomers, which exhibit differences in pharmacological effects, with R-methadone being the active and S-methadone the inactive enantiomer. A robust, simple and rapid method for chiral separation of the two enantiomers in serum samples using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MSMS) has been developed and validated. Enantiomeric separation was achieved using a Chiralpak IH-3 column with a mobile phase consisting of CO2 and 30mM ammonium acetate in methanol/water (98/2, v/v). Runtime was 4 minutes. Sample preparation was semi-automated using a Hamilton ML Star robot with protein precipitation, and phospholipid removal was carried out using a Waters OSTRO™ 96-well plate. The calibration range was 50.0-1,500 nM for each enantiomer. The between-assay relative standard deviations were in the range of 1.2-3.6%. Matrix effects ranged from 99% to 115% corrected with internal standard. The method has been implemented in our laboratory and has proven to be a robust and reliable method for determining the ratio of R/S-methadone in authentic patient samples.
Assuntos
Cromatografia com Fluido Supercrítico , Metadona , Espectrometria de Massas em Tandem , Humanos , Espectrometria de Massas em Tandem/métodos , Metadona/sangue , Cromatografia com Fluido Supercrítico/métodos , Estereoisomerismo , Limite de Detecção , Reprodutibilidade dos Testes , Cromatografia Líquida de Alta Pressão/métodos , Analgésicos Opioides/sangue , Detecção do Abuso de Substâncias/métodosRESUMO
Ultrasonic-assisted dispersive micro solid phase extraction (UA-DMSPE) is proposed as a fast and easy technique for the extraction and preconcentration of methadone and tramadol from serum samples. Different sorbents including carbon nanotubes, oxidized carbon nanotubes, and TiO2 nanoparticles were compared to extract methadone and tramadol. The best performance was obtained using oxidized carbon nanotubes due to the strong affinity between the drugs and carbon nanotube adsorbents. Final analysis of drugs performed by using gas chromatography-mass spectrometric detection. Different parameters affecting the extraction efficiency, such as the sample volume, amount of adsorbent, desorption solvent type and volume, centrifugation time, and speed were investigated and optimized. The striking features of this technique are correlated to its speed and the small volumes of sample (about 1 mL), desorption solvent (about 50 µL), and adsorbent (about 0.001 g) for analysis of drugs, and finally, milder centrifugation conditions relative to the previously reported adsorbent. The optimal parameters were achieved as follows: pH value was set at 9, the sample volume was adjusted to 1200 µL, the amount of adsorbent used was 1 mg, the extraction time was set at 5 min, and the volume of the desorption solvent was adjusted to 50 µL. The limits of detections (0.5 and 0.8 ng mL-1) and quantifications (1.5 and 2.5 ng mL-1) were obtained for methadone and tramadol, respectively. The developed method also showed good repeatability, relative standard deviation (RSD) of 9.49 % and 7.47 % (n = 5), for the spiked aqueous solution at the concentration level of 10, 50, and 100 ng mL-1 for analytes, and linearity, R ≥ 0.9809. The results showed that UA-DMSPE is a quick, relatively inexpensive, and environmentally friendly alternative technique for the extraction of opiate drugs from serum samples.
Assuntos
Cromatografia Gasosa-Espectrometria de Massas , Limite de Detecção , Metadona , Microextração em Fase Sólida , Tramadol , Tramadol/sangue , Metadona/sangue , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Microextração em Fase Sólida/métodos , Nanotubos de Carbono/química , Reprodutibilidade dos Testes , Adsorção , TitânioRESUMO
Available literature demonstrates that methadone is prone to moderate postmortem redistribution, but subject to high interindividual variability in the central to peripheral blood concentration ratios (C/P). In this case series, 10 cases of chronic methadone users displaying C/P < 1 (range 0.26-0.82) are described. Femoral, cardiac and ante-mortem blood concentrations of methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) are reported for all cases, as well as sex, age, case history, results of the pathological investigation, other toxicological findings and cause and manner of death. EDDP blood concentrations, similar in both central and peripheral blood, as well as antemortem blood concentration results in Case 4, demonstrate that this atypical C/P < 1 finding is attributable to postmortem changes and not analytical or pre-analytical artifacts. Case 4 is a particularly instructive example, with femoral blood concentration (966 ng/mL) approximately twice as high as cardiac blood (499 ng/mL) and ante-mortem blood (418 ng/mL, collected 38 min prior to death)-clearly demonstrating that cardiac blood methadone concentration is more representative of the antemortem blood concentration in this case. In Case 4 and four others, toxicological interpretation based on femoral blood concentration alone would have been misleading. Based on these results and evidence from the literature, it is hypothesized that methadone bioaccumulates in the tissues of chronic users and redistributes from thigh tissues into femoral blood, increasing the concentration postmortem. This case series highlights how femoral blood is not always preserved from postmortem changes and that the analysis of multiple blood sources is necessary to avoid a misleading toxicological interpretation-particularly for cases of chronic methadone users.
Assuntos
Metadona , Mudanças Depois da Morte , Humanos , Metadona/sangue , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Autopsia , Toxicologia Forense , Pirrolidinas/sangue , Detecção do Abuso de Substâncias/métodos , Transtornos Relacionados ao Uso de Opioides/sangue , Entorpecentes/sangueRESUMO
BACKGROUND: There is limited knowledge on the causes of large variations in serum methadone concentrations and dose requirements. OBJECTIVES: We investigated the impact of the degree of liver fibrosis on dose-adjusted steady-state serum methadone concentrations. METHODS: We assessed the clinical and laboratory data of 155 Norwegian patients with opioid use disorder undergoing methadone maintenance treatment in outpatient clinics in the period 2016-2020. A possible association between the degree of liver fibrosis and dose-adjusted serum methadone concentration was explored using a linear mixed-model analysis. RESULTS: When adjusted for age, gender, body mass index, and genotypes of CYP2B6 and CYP3A5, the concentration-to-dose ratio of methadone did not increase among the participants with liver fibrosis (Coefficient: 0.70; 95% CI: -2.16, 3.57; P: 0.631), even among those with advanced cirrhosis (-0.50; -4.59, 3.59; 0.810). CONCLUSIONS: Although no correlation was found between the degree of liver stiffness and dose-adjusted serum methadone concentration, close clinical monitoring should be considered, especially among patients with advanced cirrhosis. Still, serum methadone measurements can be considered a supplement to clinical assessments, taking into account intra-individual variations.
Assuntos
Metadona , Transtornos Relacionados ao Uso de Opioides , Humanos , Analgésicos Opioides/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Metadona/sangue , Metadona/uso terapêutico , Tratamento de Substituição de Opiáceos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/genéticaRESUMO
Methadone (MTD) is a synthetic analgesic drug used for treating opioid dependence and effectively used clinically for patients with severe pain. The abuse of MTD may lead to poisoning, disorder in the central nervous system and even death. The regular monitoring of MTD in biological matrices including serum, plasma and urine samples is an effective way to control abuse of MTD. In this manner, the selection of analytical monitoring of MTD in biological matrices is of paramount importance. This study was conducted to review high-performance liquid chromatography (HPLC) techniques carried out on MTD and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in the biological samples during 2015-June 2021.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Metadona/sangue , Metadona/urina , Entorpecentes/sangue , Entorpecentes/urina , Monitoramento de Medicamentos/métodos , Cabelo/química , Humanos , Metadona/análise , Metadona/metabolismo , Unhas/química , Entorpecentes/análise , Entorpecentes/metabolismo , Detecção do Abuso de Substâncias/métodosRESUMO
This study describes two bioanalytical methods for the quantitation of the two methadone enantiomers in dried matrix spots using high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) and high performance supercritical chromatography tandem mass spectrometry (HPSFC-MS/MS). Dried matrix spots were obtained by spotting 10 µL of each sample fluid on a Whatman paper. Methadone and its main metabolite, EDDP, were extracted with 100 µL methanol and subsequently injected into the LC-MS/MS and SFC-MS/MS systems. Enantiomeric separation was achieved with AGP-column for the LC conditions and with Chiralpak IH-3 in SFC. The two methods were fully validated and 93 post-mortem samples were analysed with both analytical methods. Results from validation parameters and results obtained for all post-mortem samples were compared with a significant spearman correlation of rs = 0.9978 for R-methadone and rs = 0.9981 for S-methadone. The LC method provided better results in terms of uncertainty, retention factor and resolution, whereas SFC provides better sensitivity, with lower LOD. Median R-/S-methadone ratio in peripheral blood was found equal to 1.60 (N = 32), varying from 0.79 to 4.23. The reported values were in good agreement with previously published results. Based on the results obtained here, SFC-MS/MS can be considered a reliable alternative to the widely used LC-MS/MS for the quantitation of methadone enantiomers in bioanalysis and should be evaluated for other bioanalytical methods. Both methods can be easily and quickly used in toxicological routine analysis for the methadone quantitation in human fluids matrices, even if considering that the polysaccharide coated column IH-3 used in SFC does not allow the enantiomeric EDDP separation.
Assuntos
Cromatografia Líquida/métodos , Cromatografia com Fluido Supercrítico/métodos , Teste em Amostras de Sangue Seco/métodos , Metadona , Espectrometria de Massas em Tandem/métodos , Toxicologia Forense/métodos , Humanos , Limite de Detecção , Modelos Lineares , Metadona/sangue , Metadona/química , Reprodutibilidade dos Testes , EstereoisomerismoRESUMO
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.
Assuntos
Analgésicos Opioides/intoxicação , Metadona/intoxicação , Adulto , Analgésicos Opioides/sangue , Concentração Alcoólica no Sangue , Pré-Escolar , Feminino , Patologia Legal , Cardiopatias/patologia , Dependência de Heroína/mortalidade , Dependência de Heroína/reabilitação , Humanos , Itália/epidemiologia , Masculino , Metadona/sangue , Pessoa de Meia-Idade , Tratamento de Substituição de Opiáceos , Estudos Prospectivos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto JovemRESUMO
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.
Assuntos
Analgésicos Opioides/administração & dosagem , Monitoramento de Medicamentos , Tórax em Funil/cirurgia , Metadona/administração & dosagem , Medição da Dor , Dor Pós-Operatória/prevenção & controle , Escoliose/cirurgia , Fusão Vertebral/efeitos adversos , Adolescente , Fatores Etários , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/sangue , Analgésicos Opioides/farmacocinética , Criança , Esquema de Medicação , Feminino , Humanos , Indiana , Masculino , Metadona/efeitos adversos , Metadona/sangue , Metadona/farmacocinética , Medição da Dor/efeitos adversos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Assistência Perioperatória , Náusea e Vômito Pós-Operatórios/induzido quimicamente , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
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.
Assuntos
Analgésicos Opioides/sangue , Teste em Amostras de Sangue Seco , Metadona/sangue , Síndrome de Abstinência Neonatal/sangue , Pirrolidinas/sangue , Analgésicos Opioides/uso terapêutico , Anticonvulsivantes/uso terapêutico , Feminino , Humanos , Recém-Nascido , Trabalho de Parto/sangue , Metadona/uso terapêutico , Morfina/uso terapêutico , Síndrome de Abstinência Neonatal/tratamento farmacológico , Fenobarbital/uso terapêutico , GravidezRESUMO
Opioids represent a broad family of compounds that can be used in several indications: analgesics, antitussives, opioid substitution therapy (e.g. methadone, buprenorphine ). When these products are misused, they are often addictive. Thus, we aimed to develop an analytical method able to rapidly quantify several opiates and opioids (6-monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, ethylmorphine, heroin, methadone, morphine, nalbuphine, naloxone, norbuprenorphine, norcodeine, norpropoxyphene, oxycodone and propoxyphene) in whole blood by ultra-high performance liquid chromatography combined with high resolution mass spectrometry (UHPLC-HRMS). The validated assay requires only 100 µL of the blood sample. The sample is prepared by a rapid liquid-liquid extraction using 5% zinc sulfate (W/V), methanol and acetonitrile. Calibration curves range from 0.98 to 1000 µg/L, except for buprenorphine (0.39-100 µg/L) and norbuprenorphine (0.20-100 µg/L). Inter- and intra-analytical accuracy was less than 15%. Therefore, we describe the development and full validation of an accurate, sensitive and precise assay using UHPLC-HRMS for the analysis of opioids in whole blood. After validation, this new assay is successfully applied on a routine laboratory application basis.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Toxicologia Forense/métodos , Espectrometria de Massas/métodos , Metadona/sangue , Alcaloides Opiáceos/sangue , Humanos , Limite de Detecção , Modelos Lineares , Extração Líquido-Líquido , Reprodutibilidade dos TestesRESUMO
Methadone is a synthetic opioid used as maintenance treatment for patients addicted to heroin. Skin irritation is one of the adverse events caused by opioid use. 344 methadone maintenance treatment (MMT) patients were recruited with records and measurements on methadone dose, plasma methadone concentrations, and treatment emergent symptom scales (TESS). 15 patients reported with skin irritation. Five SNPs located within the NECTIN4 genetic region were genotyped. The NECTIN4 gene within the adherens junction interaction pathway was associated with methadone dose in pathway-based genome wide association analyses (P = 0.0008). Three highly-linked SNPs, rs11265549, rs3820097, and rs4656978, were significantly associated with methadone dose (P = 0.0003), plasma concentrations of R,S-methadone (P = 0.0004) and TNF-α (P = 0.010) in all 344 MMT patients, and with self-report skin irritation symptom scores (P = 0.010) in the 15 MMT patients who reported with skin irritation. To identify the possible roles of plasma level of Nectin-4 in the responses to MMT and opioid use, additional age- and gender-matched 51 controls and 83 methadone-free abstinent former heroin users were recruited. Plasma level of Nectin-4 was the highest in MMT patients among the three groups. The results suggest involvement of genetic variants on NECTIN4 in methadone dose. Plasma Nectin-4 level is likely an indicator for continued use of opioids.
Assuntos
Moléculas de Adesão Celular/genética , Dependência de Heroína/genética , Metadona/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/genética , Adulto , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Moléculas de Adesão Celular/sangue , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Dependência de Heroína/sangue , Dependência de Heroína/tratamento farmacológico , Dependência de Heroína/patologia , Humanos , Masculino , Metadona/efeitos adversos , Metadona/sangue , Tratamento de Substituição de Opiáceos/métodos , Transtornos Relacionados ao Uso de Opioides/sangue , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/patologiaRESUMO
Postmortem redistribution (PMR) describes the artificial postmortem concentration changes of xenobiotics that may pose major challenges in forensic toxicology. Only a few studies have systematically investigated time-dependent postmortem drug concentration changes so far and the a posteriori estimation of the occurrence of PMR is not yet possible. In this context, the general concept that postmortem biochemical changes in blood might parallel drug redistribution mechanisms seems promising. Thus, the current study investigated the possible correlations between time-dependent postmortem concentration changes of xenobiotic and endogenous compounds; exemplified for authentic morphine (n = 19) and methadone (n = 11) cases. Peripheral blood samples at two time-points postmortem were analyzed for morphine and methadone concentrations and an (un)targeted postmortem metabolomics approach was utilized to combine targeted quantitative analysis of 56 endogenous analytes and untargeted screening for endogenous compounds (characterizing 1174 features); liquid and gas chromatography-mass spectrometry was used respectively. Individual statistically significant correlations between morphine/methadone and endogenous compounds/features could be determined. Hence, the general applicability of the proposed concept could successfully be confirmed. To verify the reproducibility and robustness of the correlating behavior, a larger dataset must be analyzed next. Once a marker/set of markers is found (e.g. robust correlation with specific xenobiotic or xenobiotic class), these could be used as surrogates to further study the time-dependent PMR in a broader variety of cases (e.g. independent of a xenobiotic drug present). A crucial next step will also be the attempt to create a statistical model that allows a posteriori estimation of PMR occurrence of xenobiotics to assist forensic toxicologists in postmortem case interpretation.
Assuntos
Metabolômica/métodos , Metadona/sangue , Morfina/sangue , Mudanças Depois da Morte , Adulto , Idoso , Autopsia , Cromatografia Líquida , Feminino , Toxicologia Forense/métodos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fatores de Tempo , Xenobióticos/sangue , Adulto JovemRESUMO
The use of cannabidiol products in pediatric patients is becoming more frequent because of the increased ease of accessibility. This case report illustrates the potential for cannabidiol to interact with stable medication regimens. A 13-year-old girl with metastatic cancer and chronic pain presented with increased sleepiness and fatigue. She had been started on 7.5 mg of methadone by mouth twice daily 4 months earlier. Unbeknownst to her physicians, her parents had commenced her on cannabidiol and subsequently increased the dose leading up to her presentation, thinking it would result in tumor shrinkage. The initial serum methadone level was 271 ng/mL, which decreased to 125 ng/mL 14 days after discontinuing cannabidiol. The reduced serum methadone level coincided with improved sleepiness and fatigue. Cannabidiol inhibits CYP3A4 and CYP2C19, both of which are involved in the metabolism of methadone. Pediatricians should be aware of this potential interaction and inquire if their patients are receiving cannabidiol.
Assuntos
Analgésicos Opioides/sangue , Dor do Câncer/sangue , Dor do Câncer/tratamento farmacológico , Canabidiol/sangue , Metadona/sangue , Adolescente , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Canabidiol/administração & dosagem , Canabidiol/efeitos adversos , Interações Medicamentosas/fisiologia , Quimioterapia Combinada/métodos , Fadiga/sangue , Fadiga/induzido quimicamente , Feminino , Humanos , Metadona/administração & dosagem , Metadona/efeitos adversosRESUMO
INTRODUCTION: Immunoassay (IA) tests are not widely applied in post-mortem samples, since they are based on technologies requiring relatively non-viscous specimens, and compounds originating from the degradation of proteins and lipids during the post-mortem interval can alter the efficiency of the test. However, since the extraction techniques for IA tests are normally rapid and low-cost, IA could be used as near-body drug-screening for the classes of drugs most commonly found in Italy and Europe. In this study, semi-quantitative results on post-mortem whole blood samples obtained through CEDIA analysis (cannabinoids, cocaine, amphetamine compounds, opiates and methadone), were compared with results of confirmatory analysis obtained using GC-MS. Screening cut-offs for all drugs were retrospectively optimized. METHODS: Post-mortem whole blood samples from autopsy cases of suspected fatal intoxication were collected over 3 years. Samples were initially analyzed through CEDIA (CEDIA, ILab 650, Werfen). Confirmatory analyses were then performed by GC-MS (QP 2010 Plus, Shimadzu). Screening cut-offs were retrospectively optimized using Receiver Operating Characteristic (ROC) analysis. RESULTS: CEDIA results were available for 125 samples. Two-hundred-eighty-nine (289) positive screening results were found. Among these, 162 positive confirmation results were obtained. Optimized screening cut-offs were as follows: 6.5ng/ml for THC; 4.2ng/ml for THC-COOH; 12.0ng/ml for cocaine; 6.6ng/ml for benzoylecgonine; 6.4ng/ml for opiates; 2.0ng/ml for methadone. Analysis of ROC-curves showed a satisfying degree of separation in all tests except for amphetamine compounds, with areas under the curve (AUC) between 0.915 (THC) and 0.999 (for benzoylecgonine and methadone). DISCUSSION: The results of the study showed that CEDIA screening at the optimized cut-offs exhibits a very high sensitivity and good specificity and positive predictive value (PPV) for cannabinoids, cocaine and metabolites, opiates and methadone. A high number of false positives (n=19) for amphetamine compounds was observed at the optimized cut-off, resulting in a very low PPV, which is also influenced by the very low number of TP (n=4). CONCLUSION: The results of the study show that the CEDIA is a valuable screening test on post-mortem whole blood for cannabinoids, cocaine and metabolites, opiates and methadone, but it is not recommended for amphetamine compounds, due to the high number of false positives. The strengths of the study are the large sample size, the inclusion of post-mortem cases only and the high level of sensitivity and specificity obtained at the optimized cut-offs.
Assuntos
Toxicologia Forense/métodos , Drogas Ilícitas/sangue , Técnicas Imunoenzimáticas , Detecção do Abuso de Substâncias/métodos , Anfetaminas/sangue , Canabinoides/sangue , Cocaína/sangue , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Metadona/sangue , Alcaloides Opiáceos/sangue , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: The purpose of this study was to describe an identified association between necrotizing enterocolitis (NEC) and prenatal opioid exposure with neonatal abstinence syndrome (NAS) in late preterm and full-term neonates. STUDY DESIGN: In this single-center retrospective cohort study, we analyzed inborn neonates with the diagnosis of NEC discharged from 2012 through 2017. We compared infants with NECâ>â35 weeks' gestation to those with NEC<35 weeks' gestation. We compared gestational age, birth weight, age of onset of symptoms, and incidence of prenatal drug exposure between groups. Significance was determined using Mann-Whitney and Fisher's exact tests. RESULTS: Over the study period, 23 infants were identified with NEC, 9 (39%) were babiesâ>â35 weeks at birth and 14 (61%)â<â35 weeks. Thoseâ>â35 weeks had a higher birth weight, earlier onset of symptoms, and a higher percentage of prenatal exposure to opioids compared to thoseâ<â35 weeks' gestation. We further described seven infants with late gestational age onset NEC associated with prenatal opioid exposure. CONCLUSIONS: In this cohort of infants with NEC discharged over a 6 year period we found a higher than expected percentage of infants born at a later gestational age. We speculate that prenatal opioid exposure might be a risk factor for NEC in neonates born atâ>â35 weeks.
Assuntos
Analgésicos Opioides/efeitos adversos , Enterocolite Necrosante/epidemiologia , Idade Gestacional , Síndrome de Abstinência Neonatal/epidemiologia , Analgésicos Opioides/sangue , Buprenorfina/efeitos adversos , Buprenorfina/sangue , Estudos de Coortes , Feminino , Sangue Fetal , Heroína/efeitos adversos , Heroína/sangue , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Metadona/efeitos adversos , Metadona/sangue , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Estudos RetrospectivosRESUMO
A magnetic nanocomposite adsorbent based on Zn-Al layered double hydroxide (LDH) intercalated with tyrosine has been synthesized for ultrasound-assisted extraction of two drugs of abuse: tramadol (TRA) and methadone (MET). Analysis was carried out using gas chromatography-mass spectrometry. The synthesized LDH was characterized by Fourier transform-infrared spectroscopy, X-ray diffraction, field emission scanning electron microscopy, and energy-dispersive X-ray spectroscopy. The most important extraction parameters such as type of the elution solvent, pH value of the sample solution, and the amount of the adsorbent were optimized. With assistance of ultrasound radiation, the maximum extraction of target drugs using the fabricated LDH was achieved within 5 min. Under the optimized conditions, the limits of determination were 0.45, 0.45, 2.5, and 0.8 µg L-1 for TRA and 0.15, 0.15, 1.2, and 0.5 µg L-1 for MET in water, urine, plasma, and saliva samples, respectively. The preconcentration factors obtained were in the range of 50-145. The matrix effect for MET and TRA is considerable in plasma (66%, 18%) and saliva (72%, 34%), respectively. The precision was found to be better 11% RSD. The maximum adsorption capacity is 4.84 (mg g-1) (L mg-1)1/n based on the Freundlich isotherm. The proposed method presents good results for trace determination of tramadol and methadone in biological samples with satisfactory repeatability. Graphical abstract.
Assuntos
Hidróxidos/química , Metadona/isolamento & purificação , Microextração em Fase Sólida/métodos , Tramadol/isolamento & purificação , Tirosina/química , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Limite de Detecção , Nanopartículas de Magnetita/química , Metadona/sangue , Nanocompostos/química , Dióxido de Silício/química , Tramadol/sangue , Ondas UltrassônicasRESUMO
Background: Methadone, buprenorphine, and implant naltrexone have comparable efficacy in preventing death from drug intoxication during treatment, but there may be differences between treatments in the specific drugs contributing to death and in the risk of death during different phases of treatment.Objective: The objective of this study was to compare concentrations of individual drugs in decedents for evidence that the three medications use to treat opioid use disorders differed in the protection they offered against fatal overdose.Methods: Fatalities with a primary or co-diagnosis of alcohol or other drug poisoning in patients treated with methadone (n = 66, 74.2% male), buprenorphine (n = 54, 74.1% male), or naltrexone (n = 28, 85.7% male) were identified by combining treatment (Monitoring of Drugs of Dependence System and clinical records) and mortality records (Western Australian Death Registry). Quantitative postmortem blood drug analysis data were obtained for drug-related deaths. The presence/absence of drugs were compared between the three medication groups and between phases of treatment (on-treatment/off-treatment).Results: Opioids (89.8%) and benzodiazepines (76.2%) were most commonly identified in postmortem blood. The three medication groups did not differ materially in the drugs present postmortem, except that alcohol was less prevalent in naltrexone-treated cases. Morphine or heroin intoxication was implicated in more patients dying off-treatment than on-treatment but levels of morphine and other drugs were comparable across the two phases.Conclusion: Comparisons of postmortem concentrations of specific drugs indicated that patients treated with methadone, buprenorphine, and implant naltrexone had comparable susceptibilities to lethal co-intoxication and that similar drug mixtures contributed to death.
Assuntos
Overdose de Drogas/sangue , Transtornos Relacionados ao Uso de Opioides/sangue , Preparações Farmacêuticas/sangue , Buprenorfina/uso terapêutico , Implantes de Medicamento , Overdose de Drogas/mortalidade , Etanol/intoxicação , Feminino , Humanos , Masculino , Metadona/sangue , Metadona/uso terapêutico , Naltrexona/uso terapêutico , Tratamento de Substituição de Opiáceos/mortalidade , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/mortalidadeRESUMO
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 = 310.2â265.1 was 0.1-100 mcg/L and for the ion transition m/z = 310.2â223.1 5-1000 mcg/L. For EDDP, on the range of reliable response for the ion transition, m/z = 278.2â234.3 was 0.1-100 mcg/L and for the ion transition m/z = 278.2â186.1 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.
Assuntos
Cromatografia Líquida/métodos , Teste em Amostras de Sangue Seco/métodos , Metadona/sangue , Metadona/química , Espectrometria de Massas em Tandem/métodos , Analgésicos Opioides/sangue , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Monitoramento de Medicamentos , Humanos , Metadona/metabolismo , Sensibilidade e EspecificidadeRESUMO
Chronic intrauterine exposure to psychoactive drugs often results in neonatal abstinence syndrome (NAS). NAS is the symptomatic drug withdrawal in newborns that generally occurs after in utero chronic opioid exposure. Methadone is an opioid analgesic commonly prescribed for pharmacologic management of NAS. It exhibits high pharmacokinetic (PK) variability. The current study used physiologically based PK modeling to predict the PK profile of methadone in 20 newborns treated for NAS. The physiologically based PK simulations adequately predicted the PK profile of the clinical data for 45% of the patients. Sensitivity analyses were conducted to explore contributing factors to methadone PK variability. The data suggest that P450 enzymatic activity impacts the clearance of methadone in virtual adults and neonates, while the contribution of cardiac output may be negligible. Understanding maturational and/or pharmacogenetic changes in cytochrome P450 enzymatic activity may further explain the large PK variability of methadone in newborns with NAS and will help individualized treatment.