Methadone Levels Research Articles

Increased risk of severe neonatal opioid withdrawal syndrome in pregnancies with low placental ABCB1 DNA methylation.

Neonatal opioid withdrawal syndrome (NOWS) is unpredictable. We assessed relationships between placental DNA methylation with in-utero opioid exposure and NOWS severity. Secondary analysis of a prospective multicenter cohort study of pregnancies on methadone or buprenorphine, ≥34 weeks, singleton, 18 or greater. Placental biopsies were collected. Placental DNA methylation levels of ABCG1, ABCG2, CYP19A1, and HSD11B2 were quantified via pyrosequencing following bisulfite conversion. CYP19A1 mRNA levels and umbilical cord drug levels were determined by RT-qPCR and LC-MS respectively. Severe NOWS was diagnosed through Finnegan scoring. P value < 0.05 was significant. Thirty-eight dyads were included. Promoter region methylation for placental ABCB1 was lower in severe NOWS compared to non-severe NOWS (p = 0.04). Placental CYP19A1 methylation was inversely related to CYP19A1 mRNA levels and associated with umbilical cord norbuprenorphine levels (p < 0.01), but not umbilical cord methadone levels. Lower placental ABCB1 methylation was associated with severe NOWS. Higher placental CYP19A1 methylation correlated with higher umbilical cord norbuprenorphine levels.

Methadone and neonatal abstinence syndrome (NAS): what we think we know, but do not.

Since the first use of methadone to treat OUD in pregnancy in the 1970s, there has been a long, controversial, and confusing history of studies, regulatory actions, and practice changes that have clouded an accurate perception of methadone's use in pregnancy. This review will trace this history with a focus on the effect of methadone exposure during pregnancy on neonatal abstinence syndrome (NAS). A new laboratory measure, the serum methadone/metabolite ratio (MMR), has provided a tool for documenting the profoundly dynamic nature of perinatal metabolism. Continuous induction of metabolic enzymes during pregnancy requires dose adjustments and dose frequency changes. The concept of "fetal methadone dosing" emphasizes that relative stability of methadone levels in the fetus is an important consideration for methadone dosing in pregnancy. Finally, the effects of the societal "war on drugs" on pediatric management of neonatal withdrawal risks will be discussed, as well as the importance of comprehensive services for mother and child including the "rooming-in" approach of neonatal care which has considerably replaced the older NICU care model of maternal/infant separation.

THU391 A Case Of Unrecognized Hypoglycemia Due To Methadone Use In A Non-Diabetes Patient

Abstract Disclosure: D. Owais: None. J.R. Fredrick: None. Y. Jamal: None. S. Sajnani: None. Introduction: Methadone is a rare cause of insulin-mediated hypoglycemia. Hypoglycemia can be manifested as autonomic instability (palpitations and diaphoresis) and neuroglycopenia (agitation and altered mentation). We present the case of hypoglycemia in a non-diabetic patient with no renal insufficiency and who was on a high dose of Methadone. Case: A 76-year-old male with a medical history of HTN, CAD, CVA, dementia, chronic opioid use (on methadone 80 mg) initially presented two times to an outside hospital for intractable seizures. The diagnosis of seizure disorder was made and was discharged on valproate. Per his wife, he had a few low blood sugars during those hospitalizations. Within a month of discharge, he was admitted to another hospital for severe bradycardia and had undergone pacemaker implantation. He was then discharged to nursing home (NH). In the NH, the routine laboratory work showed a serum blood glucose of 42; however, it was interpreted as a lab error. The next day, he developed severe metabolic encephalopathy, intractable seizures and transferred to our hospital. On arrival, serum blood sugar was 59, corrected by 50% of dextrose. His physical examination was significant for a thin-built elderly male, lethargic but in no acute distress. The dose of antiseizure medication was adjusted. The Methadone 80 mg daily was resumed. He continued to have intermittent hypoglycemia to as low as 33 despite being on intravenous (IV) dextrose solutions. His symptoms used to improve temporarily after the correction of hypoglycemia. (Positive Whipple’s triad). Blood cultures and urine cultures were negative. Serum cortisol level, IGF -1, TSH levels, blood pressure, and electrolytes were within normal limits. The hypoglycemia workup performed in a fasting state (off IV dextrose) showed endogenous hyperinsulinism with insulin level &amp;gt;3, C-peptide level &amp;gt;0.2, beta-hydroxybutyrate level of &amp;lt;2.7, and negative sulfonylurea screen. CT scan and ultrasound of the abdomen were performed to rule out insulinoma; however, it demonstrated complete atrophy of the pancreas. Therefore, a high dose of methadone was assumed to cause hypoglycemia, as the patient had no hypoglycemic episodes when he could not receive two doses of methadone due to encephalopathy. The trough levels of methadone in the blood were high at 650 ng/dl. Methadone dose was tapered to 60 mg daily. He was also started on octreotide to manage his hypoglycemia. However, the patient developed severe pneumonia, and family opted for hospice. Conclusion: Our case is unique as the patient was developing severe signs of hypoglycemia, including bradycardia and seizures, and treated with a pacemaker and antiseizure medications. His Methadone-induced hypoglycemia was identified late as the cause of his symptoms. Therefore, it is crucial to recognize this side effect of Methadone in differentials in a patient with hypoglycemia. Presentation: Thursday, June 15, 2023

GC-MS Analysis of Methadone and EDDP in Addicted Patients under Methadone Substitution Treatment: Comparison of Urine and Plasma as Biological Samples

(1) Background: Methadone, along with buprenorphine, is the most commonly used drug for the treatment of opioid dependence. This study aimed to analyze methadone and its major metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenyl pyrrolidine (EDDP), in the urine and plasma of opiate addicts. The study group consisted of drug users voluntarily admitted to the detoxification center C.E.T.T.T. "St. Stelian" of Bucharest. Secondly, the study aimed to identify whether urine or plasma provides better results for the proposed method. (2) Methods: A GC-MS method, using an internal standard (diphenylamine) in the FULL-SCAN and SIM modes of operation and using the m/z = 72 ion for methadone and the m/z = 277 ion for EDDP, combined with a liquid-liquid extraction procedure was performed. (3) Results: The applied procedure allows the detection and quantification of methadone in both urine and plasma samples. EDDP was identified in patients with higher levels of methadone. Higher levels of methadone were detected in urine than in plasma samples. (4) Conclusions: This procedure can be used in clinical laboratories for the rapid determination of methadone levels in urine rather than in plasma. The procedure can be applied for the monitoring of methadone substitution treatment.

Abstract 15476: Methadone-Related Sudden Death in the Community

Introduction: Non-toxic levels of methadone have been associated with ventricular dysrhythmias and sudden death, but current community-based data are lacking. We studied demographics and resuscitation circumstances at the time of cardiac arrest in these individuals. Methods: We prospectively ascertained all residents of Multnomah Co., OR (2002-18) and Ventura Co., CA (2015-21) who suffered out-of-hospital cardiac arrest and had toxicology reports available. We excluded individuals under age 18 or with evidence of recreational drug use or drug overdose. Methadone levels were captured on toxicology reports from the medical examiner and resuscitation variables were obtained from emergency medical services. We used logistic regression to compare demographics and resuscitation features in those with and without methadone. Results: Of the 789 subjects who met criteria, the mean (SD) age was 49 (13) years, 34% were females, and 85 (11%) had therapeutic levels of methadone (Table). After adjusting for age, females were 2.26 times more likely to have methadone on their toxicology report (1.42-3.57; p-value=0.0005). Subjects with methadone-related deaths were younger and 3.5 times more likely to suffer cardiac arrest in a home setting compared to those without methadone. Although the prevalence of night-time arrest was similar in those with and without methadone, those with methadone were more likely to have an unwitnessed event or no resuscitation attempted. When resuscitation was attempted, 97% of those with therapeutic methadone levels had a non-shockable presenting rhythm. Conclusion: Although males account for 66% of overall sudden death events, females were twice as likely to have a methadone-related sudden death compared to males. Methadone-related cardiac arrests are difficult to resuscitate. These findings highlight the need to enhance primary prevention of methadone-related sudden deaths, and a renewed investigative focus on higher risk in women.

Abstract 11953: Sudden Death Associated With Therapeutic Levels of Methadone: Significance of Drug Interactions

Introduction: Methadone for treatment of addiction or chronic pain can be complicated by QT interval prolongation and increased risk of sudden cardiac death (SCD). The concurrent use of additional QT-prolonging medications, such as selective serotonin reuptake inhibitors (SSRIs), may contribute to additional increased risk. We conducted a community-based study to assess the potential role of drug combinations in SCD. Methods: We ascertained residents of Multnomah Co., OR (2002-18) and Ventura Co., CA (2015-21) who suffered SCD and had toxicology reports available. We excluded those under age 18 and those with evidence of recreational drug use or drug overdose. Methadone levels and medications were captured on toxicology reports from the medical examiner. We used logistic regression to compare characteristics and the presence of select medications in those with and without therapeutic levels of methadone at the time of SCD. Results: Of the 789 subjects who met our criteria, the mean (25th-75th percentile) age was 49 (39-59) years, 34% were females, and 85 (11%) had therapeutic levels of methadone. Subjects on methadone were younger, more likely to be female, and had a higher prevalence of SSRIs and benzodiazepines compared to those without methadone (Table). Subjects with methadone had a 3.37 higher odds of SSRI use compared to those without methadone (95% CI: 1.87-6.09). When stratified by mechanistic category, those with methadone had higher odds of QT-prolonging SSRIs [OR (95% CI) = 2.87 (1.35-6.13)] and higher odds of other SSRIs [OR (95% CI) = 3.20 (1.40-7.32)] compared to those without methadone. Combinations of methadone with other selected drug classes did not reach statistical significance. Conclusion: These postmortem findings suggest that the combination of methadone with SSRIs may be associated with additional risk of SCD and warrant further investigation. Drug interactions are a potentially avoidable risk factor for SCD in patients receiving methadone.

Methadone and buprenorphine-related deaths among people prescribed and not prescribed Opioid Agonist Therapy during the COVID-19 pandemic in England.

BackgroundThe coronavirus pandemic resulted in many changes which had the potential to impact mortality related to opioid agonist therapy (OAT; methadone, buprenorphine), including changes in the prescribing and dispensing of OAT and patterns of drug availability and use. We aimed to assess the impact of the first lockdown (initiated March 23rd 2020) on methadone- and buprenorphine-related deaths in England in people both prescribed and not prescribed OAT using data from the National Programme on Substance Abuse Deaths.MethodsThis was a retrospective post-mortem toxicology study of OAT-related deaths which occurred in the 3-month period March 23rd to June 22nd in the years 2016-2020. Provisional data regarding numbers accessing treatment for opioid use disorder was provided by the National Drug Treatment Monitoring System.ResultsWe found a 64% increase in methadone-related deaths in March to June 2020 compared to March to June 2019 (2019 n = 96; 2020 projected n = 157). There were increases in the mortality rate of both in-treatment decedents (22% increase; 2019 n = 45; an exponential smoothing model of the 2016-19 trend [α=0.5] predicted 44 deaths in 2020, 55 were reported) and decedents not prescribed methadone (74% increase; 2019 n = 46; 2016-19 trend predicted 43 deaths in 2020, 80 were reported). There was no increase in buprenorphine-related deaths (2019 n = 9/529; 2020 n = 11/566). There were no changes in the numbers of deaths where other opioids or multiple substances were detected, or in methadone levels detected. Numbers of people accessing treatment for opioid use disorder in 2020 did not decrease relative to previous years (p >0.05).ConclusionsMethadone-related deaths in non-prescribed individuals, but not prescribed individuals, increased considerably above the annual trend forecast for 2020 during the first COVID-19 lockdown in England. Further studies are thus needed to understand this difference.

Metabolomics profiling for identification of potential biomarkers in chickens infected with avian leukosis virus subgroup J (ALV-J)

There are currently no vaccines or effective drugs to prevent the disorders caused by avian leukosis virus subgroup J (ALV-J). Hence, it is critical to identify potential biomarkers in ALV-J-infected chickens to prevent ALV-J-induced disorders. We hypothesized that ALV-J infection alters metabolic profile in chickens. In the present study, a nontargeted metabolomics approach based on liquid chromatography coupled with mass spectrometry (LC-MS) was used to find differential metabolites in plasma samples from ALV-J-infected chickens and healthy controls. The parametric statistical test (Student's t-test) and fold change analysis were used for univariate analysis. Multivariate statistical analyses included principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA). The levels of methyl bromide, pyraclonil, hexaflumuron, lythidathion, 3-phosphoglycerol-glutathione, bis-4-nitrophenyl phosphate, 4-ketocyclophosphamide, oxidized photinus luciferin, phenyl sulfate, and aryl sulfate significantly decreased, whereas the levels of 2-methylthiobenzothiazole, irinotecan, methadone, 3-o-ethyl-l-ascorbic acid, and o-acetylneuraminic acid markedly increased in ALV-J-infected chickens as compared to those in healthy controls. These data provide metabolic evidence and potential biomarkers for ALV-J-induced alterations in plasma metabolism.

Novel associations between CYP2B6 polymorphisms, perioperative methadone metabolism and clinical outcomes in children.

Aim:Methadone exhibits significant variability in clinical response. This study explores the genetic influence of variable methadone pharmacokinetics.Methods:This is a prospective study of methadone in children undergoing major surgery. CYP2B6 genotyping, plasma methadone and metabolite levels were obtained. Clinical outcomes include pain scores and postoperative nausea and vomiting (PONV).Results:CYP2B6 poor metabolizers (*6/*6) had >twofold lower methadone metabolism compared with normal/rapid metabolizers. The incidence of PONV was 4.7× greater with CYP2B6 rs1038376 variant. AG/GG variants of rs2279343 SNP had 2.86-fold higher incidence of PONV compared with the wild variant (AA). Nominal associations between rs10500282, rs11882424, rs4803419 and pain scores were observed.Conclusion:We have described novel associations between CYP2B6 genetic variants and perioperative methadone metabolism, and associations with pain scores and PONV.

Precision dosing of methadone during pregnancy: A pharmacokinetics virtual clinical trials study

BackgroundMethadone use for the management of opioid dependency during pregnancy is commonplace. Methadone levels are altered during pregnancy due to changes in maternal physiology. Despite this, a paucity of data exist regarding the most appropriate optimal dosing regimens during pregnancy. MethodsThis study applied a pharmacokinetic modeling approach to examine gestational changes in R- and S-methadone concentrations in maternal plasma and fetal (cord) blood. This study did so to derive a theoretical optimal dosing regimen during pregnancy, and to identify the impact of Cytochromes P450 (CYP) 2B6 and 2C19 polymorphisms on methadone maternal and fetal pharmacokinetics. ResultsThe study noted significant decreases in maternal R- and S-methadone plasma concentrations during gestation, with concomitant increases in fetal levels. At a dose of 90 mg once daily, 75% (R-) and 94% (S-) of maternal methadone trough levels were below the lower therapeutic window at term (week 40). The developed optimal dosing regimen escalated doses to 110 mg by week 5, followed by 10 mg increments every 5 weeks up to a maximum of 180 mg once daily near term. This increase resulted in 27% (R-) and 11% (S-) of subjects with trough levels below the lower therapeutic window at term. CYP2B6 poor metabolizers (PM) and either CYP2C19 extensive metabolizers (EM), PM, or ultra-rapid (UM) metabolizer phenotypes demonstrated statistically significant increases in concentrations when compared to their matched CYP2B6 EM counterparts. ConclusionsSpecific and gestation-dependent dose titrations are required during pregnancy to reduce the risks associated with illicit drug use and to maintain fetal safety.

The Role of Risk or Contributory Death Factors in Methadone-Related Fatalities: A Review and Pooled Analysis.

Methadone-related deaths are characterized by a wide range of post-mortem blood concentrations, due to the high pharmacokinetic/dynamic inter-individual variability, the potential subjective tolerance state and to other risk factors or comorbidities, which might enhance methadone acute toxicity. In the present study, the association among pre-existing and external conditions and diseases and the resultant methadone death capacity have been investigated. Beside a systematic literature review, a retrospective case-control study was done, dividing cases in which methadone was the only cause of death (controls), and those with associated clinical-circumstantial (naive/non-tolerant state), pathological (pulmonary or cardiovascular diseases) or toxicological (other drugs detected) conditions. Methadone concentrations were compared between the two groups and the association with conditions/diseases was assessed by multiple linear and binomial logistic regressions. Literature cases were 139, in house 35, consisting of 22 controls and 152 cases with associated conditions/diseases. Mean methadone concentrations were 2122 ng/mL and 715 ng/mL in controls and cases respectively, with a statistically significant difference (p < 0.05). Lower methadone concentrations (by 24, 19 and 33% respectively) were detected in association with naive/non-tolerant state, pulmonary diseases and presence of other drugs, and low levels of methadone (<600 ng/mL) might lead to death in the presence of the above conditions/diseases.

Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry.

Despite the rising prevalence of methadone treatment in pregnant women with opioid use disorder, the effects of methadone on neurobehavioral development remain unclear. We developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. We investigated the effects of PME on physical development, sensorimotor behavior, and motor neuron properties using a multidisciplinary approach of physical, biochemical, and behavioral assessments along with brain slice electrophysiology and in vivo magnetic resonance imaging. Methadone accumulated in the placenta and fetal brain, but methadone levels in offspring dropped rapidly at birth which was associated with symptoms and behaviors consistent with neonatal opioid withdrawal. PME produced substantial impairments in offspring physical growth, activity in an open field, and sensorimotor milestone acquisition. Furthermore, these behavioral alterations were associated with reduced neuronal density in the motor cortex and a disruption in motor neuron intrinsic properties and local circuit connectivity. The present study adds to the limited body of work examining PME by providing a comprehensive, translationally relevant characterization of how PME disrupts offspring physical and neurobehavioral development.

Pharmacogenomics biomarkers for personalized methadone maintenance treatment: The mechanism and its potential use.

Methadone has a wide pharmacokinetic interindividual variability, resulting in unpredicted treatment response. Pharmacogenomic biomarkers seem promising for personalized methadone maintenance treatment. The evidence supports the use of ABCB1 single-nucleotide polymorphism (SNP) 1236C>T with genotypes C/T or C/C (Jewish) and haplotypes AGCTT carrier, AGCGC heterozygote, or non-carrier (Caucasian), which have a predicted lower methadone dose requirement. In contrast, ABCB1 SNP 1236C>T with genotype T/T (Jewish); haplotypes AGCGC homozygote, AGCTT non-carrier (Caucasian), and ABCB1 3435C>T variant carrier; and haplotypes CGT, TTC, and TGT (Han Chinese) have a predicted higher methadone dose. For methadone plasma levels, ABCB1 diplotype non-CGC/TTT (Malay) predicted lower, and diplotype CGC/TTT (Malay), 3435C>T allelic carrier, haplotypes (CGT, TTC, TGT) (Han Chinese) predicted higher methadone levels. In terms of metabolism biomarkers, a lower methadone requirement was related to carriers of CYP2B6 genotypes *4(G/G) and *9(T/T) among Jewish patients, CYP2B6*9 genotype (T/T) and haplotypes (TA/TG); and CYP2C19 (*2/*2,*2/*3, and *3/*3; Han Chinese). Higher methadone dose was observed in CYP2C19*1 allelic carriers (Han Chinese) and CYP2D6 ultrarapid metabolizer (Caucasian). Lower methadone levels were reported in CYP2B6 SNPs, haplotypes TTT, and AGATAA (Han Chinese), CYP2C19 genotype *1/*1 (Han Chinese), allelic carrier *1xN (Caucasian), and CYP3A4 genotype *1/*1 (Caucasian). Carriers of CYP2B6 genotype *6/*6 (Caucasian), CYP2B6 haplotypes ATGCAG and ATGCTG (Han Chinese), and CYP3A4 genotype *1/*1B (Caucasian) had predicted higher methadone plasma levels. Specific pharmacokinetics biomarkers have potential uses for personalized methadone treatment in specific populations.

Toward precision prescribing for methadone: Determinants of methadone deposition.

BackgroundDespite the World Health Organization listing methadone as an essential medication, effective dose selection is challenging, especially in racial and ethnic minority populations. Subtherapeutic doses can result in withdrawal symptoms while supratherapeutic doses can result in overdose and death. Although CYP3A4 was conventionally considered the principal methadone metabolizing enzyme, more recent data have identified CYP2B6 as the principal enzyme. CYP2B6 has ethnically-associated polymorphisms that affect the metabolic rate. Our objective was to investigate the effects of genetic and nongenetic factors on methadone metabolism.MethodsWe measured trough plasma methadone levels in 100 participants with opioid use disorder. We assessed methadone metabolism by calculating the metabolite ratio (major metabolite: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine [EDDP] divided by methadone concentration). We assessed hepatic fibrosis and steatosis by transient elastography and CYP2B6 alleles, principally responsible for methadone metabolism. Mixed effects models modeled the data in 97 participants.ResultsParticipants were largely male (58%), minority (61% African American) and non-Hispanic (68%). Forty percent were HCV mono-infected, 40% were uninfected, and 20% were HCV/HIV co-infected. Female sex had significant effects on (R)- and (S)-methadone metabolism (p = 0.016 and p = 0.044, respectively). CYP2B6 loss of function (LOF) alleles significantly affected (S)-methadone metabolism (p = 0.012). Body mass index (BMI) significantly affected (R)-methadone metabolism (p = 0.034). Methadone metabolism appeared to be lower in males, in individuals with LOF alleles, and elevated BMI.ConclusionsGenetic analysis, especially in minority populations, is essential to delivering individualized treatments. Although the principal methadone metabolizing enzyme remains controversial, our results suggest that sex, CYP2B6 genotype, and BMI should be incorporated into multivariate models to create methadone dosing algorithms. Methadone dosing algorithms should facilitate medication delivery, improve patient satisfaction, and diminish overdose potential.

Relevance of CYP2B6 and CYP2D6 genotypes to methadone pharmacokinetics and response in the OPAL study.

Our study aimed to evaluate the impacts of the cytochrome P450 (CYP) 2B6-G516T and CYP2D6 genetic polymorphisms on pharmacokinetic and clinical parameters in patients receiving methadone maintenance treatment. Opioid PhArmacoLogy (OPAL) was a clinical survey of the sociodemographic characteristics, history and consequences of pathology associated with methadone maintenance treatment response and current addictive comorbidities. A subgroup of 72 methadone patients was genotyped. When comparing the three CYP2B6 genotype groups, the methadone (R)- and (S)-methadone enantiomer concentrations/doses (concentrations relative to doses) were different (P = .029, P = .0019). The CYP2D6 phenotypes did not seem to be relevant with regard to methadone levels. On multivariate analysis, neither the CYP2B6 genotype nor the CYP2D6 phenotype explained the (R)-methadone concentration/dose values (P= .92; P = .86); the (S)-methadone concentration/dose values (P = .052; P = .95 [although there was a difference between the TT group and GT and GG groups {P = .019}]); or opiate cessation (P = .12; P = .90). The genotyping of CYP2B6 G516T could be an interesting tool to explore methadone intervariability.

Methadone-Related Delirium: Prevalence, Causes, and Outcomes.

Goals consist of determining 5-year prevalence and recurrence of methadone-related delirium (MRD), along with causes, treatments, and outcomes. Sample comprised 81 patients in methadone maintenance treatment. Criteria for MRD encompassed delirium with high methadone serum levels plus alleviation of delirium upon lowering methadone serum levels. MRD occurred in 14 cases who had 25 episodes. MRD precipitants included physician prescribing (i.e., excessive methadone or medications slowing methadone metabolism), drug misuse, and renal-fluid alterations. Social affiliation (housing with family, intimate partner) reduced MRD; employment increased MRD. Recovery occurred in 23/25 episodes of MRD; two episodes progressed to dementia. Obtaining serum methadone levels fostered prompt recognition.

Enantioselective capillary electrophoresis for pharmacokinetic analysis of methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in equines anesthetized with ketamine and isoflurane.

An enantioselective assay for the determination of methadone and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in equine plasma based on capillary electrophoresis with highly sulfated γ-cyclodextrin as chiral selector and electrokinetic analyte injection is described. The assay is based on liquid/liquid extraction of the analytes at alkaline pH from 0.1 mL plasma followed by electrokinetic sample injection of the analytes from the extract across a buffer plug without chiral selector. Separation occurs cationically at normal polarity in a pH 3 phosphate buffer containing 0.16% (w/v) of highly sulfated γ-cyclodextrin. The developed assay is precise (intra- and interday RSD < 4% and < 7%, respectively), is capable to determine enantiomer levels of methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in plasma down to 2.5ng/mL, and was successfully applied to monitor enantiomer drug and metabolite levels in plasma of a pony that was anesthetized with racemic ketamine and isoflurane and received a bolus of racemic methadone and a bolus followed by constant rate infusion of racemic methadone. The data suggest that the assay is well suited for pharmacokinetic purposes.

Comprehensive Review on Methadone-Induced QT Prolongation and Torsades

An alternative analgesic to morphine is methadone, which is used to control chronic pain and is used in opioid rehabilitation treatment programs due to methadone having a long half-life and being relatively inexpensive as compared to extended-release forms of morphine. Despite its benefits, methadone accumulates in adipose tissue due to being lipophilic, binds strongly to plasma proteins, and is metabolized in the liver by the cytochrome P450 system causing methadone levels to be variable and subject to influence according to the individual body compositions and concurrent use of cytochrome P450 inhibitors. In addition to methadone being able to cause both respiratory and central nervous system depression, methadone can also prolong the QT interval and cause potentially life-threatening arrhythmias including torsades de pointes. The susceptibility of unintentional overdosing of methadone due to its varied pharmacologic properties and potentially fatal induction of arrhythmias may cause the risks of methadone use to outweigh its benefits and therefore must be closely monitored.

Torsades de Pointes on Chronic Methadone Use

Methadone is a drug associated with the development of prolonged Correcred QT (QTc) interval, as QT interval prolongation can occur in up to 15% of methadone-maintenance patients. In recent years, methadone found to be associated with an increased risk of sudden death in a community-based study (1, 2). ‘‘Torsades de Pointes’’ is a quick and dangerous rhythm that quickly becomes ventricular fibrillation. If this rhythm is rapid or prolonged, it can lead to ventricular fibrillation or sudden cardiac death. The usual clinical manifestations of TdP are palpitations, dizziness, and syncope. It is certain that no cardiac drugs are recognized to increase the propensity for TdP. The most common risk factors of methadone-associated QT prolongation and TdP include a high dose of methadone or chronic use, old age, accompaniment with enhancing drugs methadone levels, infections such as AIDS, old age, low potassium, kidney failure, heart disease, female gender, and cirrhosis of the liver (3). Despite the availability of methadone for over 60 years, only in the past 10 years has this medication received attention for its potential to cause QTc prolongation leading to Torsades de Pointes (4-6). We report 4 cases of methadone-induced Torsades de pointes. Through rapid taper of methadone, the patient’s ECG normalized.

Methadone Dose Adjustments, Plasma R-Methadone Levels and Therapeutic Outcome of Heroin Users: A Randomized Clinical Trial

Aims: We aimed to improve the retention in treatment and therapeutic outcome of methadone maintenance treatment (MMT) patients by adjusting the oral methadone dose in order to reach a “target” plasma R-methadone level (80–250 ng/mL). Methods: A multicenter randomized controlled trial was organized. Results: The intention-to-treat statistical analysis showed that repeated dose adjustments performed in order to obtain therapeutic plasma R-methadone levels did not improve retention in treatment of heroin-dependent patients. However, patients having plasma methadone levels in the “target range” at the beginning of the study had a better retention in treatment than controls. Furthermore, patients succeeding in keeping plasma R-methadone target levels (per protocol analysis) remained in treatment and improved their social scores better than controls. ­Conclusion: Although the primary endpoint of this study was not demonstrated, a post hoc and a per protocol analysis suggested that patients in MMT with plasma R-methadone concentrations in the target range have a better therapeutic outcome than controls.