Serum Methadone Concentrations Research Articles

A Patient With Sepsis-Induced Multiorgan Failure and Increasing Serum Methadone Concentration: A Case Study.

The authors describe a patient with substance use disorder admitted to the hospital with septic shock and multiorgan failure, in whom the serum concentration of methadone kept increasing despite discontinuation of the drug. Therapeutic drug monitoring was performed to monitor the methadone serum concentration during treatment of the underlying diseases.

Impact of liver fibrosis and clinical characteristics on dose-adjusted serum methadone concentrations

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.

Subjective symptoms and serum methadone concentrations: what should guide dose adjustments in methadone maintenance treatment? A naturalistic cohort study from Norway

BackgroundThere is little evidence-based guidance on how to optimize methadone dosages among patients with opioid addiction undergoing methadone maintenance treatment (MMT). This study aims to investigate whether self-perceived opioid withdrawal symptoms, adverse effects, and self-reported substance use in patients on MMT are related to serum methadone concentrations and the role that these variables could play in clinical decisions on dose adjustments.MethodsThis naturalistic prospective cohort study included clinical and laboratory measurements from 83 patients undergoing MMT in outpatient clinics in Bergen, Norway, from May 2017 to January 2020. Information on age, gender, methadone daily doses and serum concentrations, subjective opioid withdrawal symptoms using 16 items Subjective Opioid Withdrawal Scale (SOWS) questionnaire, self-reported adverse effects, and substance use was obtained. Linear mixed modelling was used for analyzing the data.ResultsThe mean age of the participants was 45 years, and 33% were women. Almost half reported mild to moderate subjective opioid withdrawal symptoms, and all had experienced at least one subjective adverse effect. The use of at least one substance was reported by 88% of the participants. Serum concentration-to-dose ratios were lower among those who had reported subjective opioid withdrawal symptoms (p) = 0.039). The total SOWS score (p < 0.001); the specific subjective withdrawal symptoms of anxiety (p = 0.004), bone and muscle aches (p = 0.003), restlessness (p = 0.017), and (slightly) shaking (p = 0.046), also use of heroin (p = 0.015) and alcohol (p = 0.011) were associated with lower methadone concentrations. Cannabis use was slightly related to higher methadone concentrations (p = 0.049).ConclusionsThe findings suggest that the patient’s self-perceived symptoms and current clinical condition are related to the serum concentrations of methadone. This interpretation supports dose adjustments based on patient-reported symptoms. In some aberrant cases, measurement of serum concentrations together with other individual assessments may be considered to support the clinical decision.

Abstract 13929: Methadone Lengthens Both Early and Late Ventricular Repolarization in Patients Undergoing Maintenance Therapy in an Urban Narcotic Treatment Center

Introduction: Methadone, a racemic mixture of S - and R -enantiomers, prolongs the QT interval and causes torsades de pointes. Methadone has been shown to lengthen late ventricular repolarization, represented by the T peak-Tend interval, which is modulated primarily by I Kr and I Ks . However, it is unknown whether methadone prolongs early ventricular repolarization, represented by the heart rate-corrected J-T peak (J-T peak c) interval, which is regulated primarily by L-type calcium and late sodium currents. In addition, the relationship between stereospecific serum methadone and metabolite concentrations and effects on J-T peak c and T peak -T end intervals are unknown. Hypothesis: 1) Methadone lengthens both J-T peak c and T peak -T end , and 2) Methadone effects on J-T peak c and T peak -T end correlate with serum S - and R -methadone and S - and R -metabolite [ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)] concentrations. Methods: Patients (n=81) on steady state maintenance methadone therapy at an urban narcotic treatment center who had undergone a pre-methadone 12-lead ECG within the previous 6 months were identified and asked to return for a followup ECG during steady-state methadone therapy. In a subset (n=41), blood was obtained to determine serum S - and R -methadone and S - and R -EDDP concentrations. Results: Compared to baseline, methadone lengthened mean ± SD J-T peak c (225 ± 26 vs 232 ± 28 ms, p=0.02) as well as T peak - T end (80 ±14 vs 90 ± 16 ms, p&lt;0.00001). Serum concentrations of S -methadone correlated with J-T peak c [R 2 = 0.41 (95% CI 0.11-0.65), p=0.007]. Serum R -methadone concentrations also correlated with J-T peak c [R 2 = 0.47 (0.17-0.68), p=0.002]. In addition, serum concentrations of S - and R -EDDP correlated with J-T peak c [R 2 = 0.39 (0.09-0.63), p=0.01] and [R 2 = 0.38 (0.07-0.62), p=0.02], respectively. There were no significant correlations between serum S - and R -methadone or S- and R-EDDP concentrations with T peak - T end intervals. Conclusions: Methadone lengthens both early and late ventricular repolarization, suggesting that methadone’s ion channel effects may extend beyond inhibition of I Kr . Serum S - and R -methadone and S -and R -EDDP concentrations are associated with effects on J-T peak c intervals.

Methadone serum concentrations and influencing factors: A naturalistic observational study

Although methadone maintenance treatment (MMT) has long been used for opioid addiction, our knowledge on its pharmacokinetics is still limited. We aimed to investigate effects of age, gender, and various co-medications on methadone serum concentration-to-dose ratio (CDR) in a naturalistic setting. In total, 4425 routine serum methadone concentrations obtained from 1691 MMT patients in the period October 1999 to July 2017 were included. Information about doses, age, gender, and concurrent medications was available in the laboratory database at the Department of Clinical Pharmacology at St. Olav University Hospital in Trondheim, Norway. A log-linear mixed model was used when analyzing the data. Mean age was 38.4 (range, 21-78) years and 70% were men. Mean CDR was 332 (range, 7-1776) (ng/mL)/(100mg/d). Concomitant medication with at least one out of totally 170 drugs was recorded in 26% of the samples. CDRs were significantly lower in women (- 9%; confidence interval (CI), - 13%, - 4%; p= 0.001) and with concurrent use of CYP inducers (- 36%; CI, - 44%, - 28%; p< 0.001), but higher using CYP3A4 inhibitors as co-medications (+ 36%; CI, + 10%, + 68%; p = 0.005). Our results warrant taking into consideration gender differences in methadone metabolism as well as the impact of potential drug-drug interactions to obtain an optimal therapeutic effect and avoid adverse effects in MMT. Although the clinical implications of the altered drug levels require further study, our results call for close clinical monitoring of all patients undergoing MMT, preferably along with laboratory measurements of methadone serum concentrations.

Relationship between Serum Methadone Concentration and Cold Pressor Pain Sensitivity in Patients Undergoing Methadone Maintenance Therapy.

Hyperalgesia is a common clinical phenomenon among opioid dependent patients on methadone maintenance therapy (MMT) and it may be associated with undertreated pain and/or therapeutic failure. This study aimed to investigate association between serum methadone concentration (SMC) and cold pressor pain responses. Cold pressor pain responses in 147 opioid dependent patients on MMT were assessed using cold pressor test (CPT) at 0 h and at 2, 4, 8, 12, and 24 h after the dose intake. Blood samples were collected at 24 h after the dose. Serum methadone concentrations were measured using the Methadone ELISA kit and classified into two categories: < 400 ng/mL and ≥ 400 ng/mL. Eighty-eight patients (59.9%) had trough concentrations of < 400 ng/mL and 40.1% had trough concentrations of ≥ 400 ng/mL. There were significant effects of SMC on the cold pressor pain threshold (p = 0.019). Patients with concentrations < 400 ng/mL had significantly higher (almost 60% higher) cold pressor pain threshold (adjusted mean (95% CI) = 30.15 (24.29, 36.01) s) compared to those with concentrations of ≥ 400 ng/mL (18.93 (11.77, 26.08) seconds). There was also a 20% difference in pain tolerance, and 6% difference in cold pressor pain intensity score, neither of which were significant statistically (p > 0.05). Our results suggest an association of trough methadone concentration with the cold pressor pain threshold among opioid dependent patients on MMT. It would be useful to study the mechanisms underlying this association to help managing pain in such a population.

Relationship between ABCB1 polymorphisms and serum methadone concentration in patients undergoing methadone maintenance therapy (MMT)

ABSTRACTBackground: Methadone is a substrate of the permeability glycoprotein (P-gp) efflux transporter, which is encoded by the ABCB1 (MDR1) gene. Large interindividual variability in serum methadone levels for therapeutic response has been reported. Genetic variations in ABCB1 gene may be responsible for the variability in observed methadone concentrations. Objective: This study investigated the associations of ABCB1 polymorphisms and serum methadone concentration over the 24-hour dosing interval in opioid-dependent patients on methadone maintenance therapy (MMT). Methods: One hundred and forty-eight male opioid-dependent patients receiving MMT were recruited. Genomic deoxyribonucleic acid (DNA) was extracted from whole blood and genotyped for ABCB1 polymorphisms [i.e. 1236C>T (dbSNP rs1128503), 2677G>T/A (dbSNP rs2032582), and 3435C>T (dbSNP rs1045642)] using the allelic discrimination real-time polymerase chain reaction (PCR). Blood samples were collected at 0, 0.5, 1, 2, 4, 8, 12, and 24 hours after the dose. Serum methadone concentrations were measured using the Methadone ELISA Kit. Results: Our results revealed an association of CGC/TTT diplotype (1236C>T, 2677G>T/A, and 3435C>T) with dose-adjusted serum methadone concentration over the 24-hour dosing interval. Patients with CGC/TTT diplotype had 32.9% higher dose-adjusted serum methadone concentration over the 24-hour dosing interval when compared with those without the diplotype [mean (SD) = 8.12 (0.84) and 6.11 (0.41) ng ml−1 mg−1, respectively; p = 0.033]. Conclusion: There was an association between the CGC/TTT diplotype of ABCB1 polymorphisms and serum methadone concentration over the 24-hour dosing interval among patients on MMT. Genotyping of ABCB1 among opioid-dependent patients on MMT may help individualize and optimize methadone substitution treatment.

The Grocery Store Blues: Recognizing a Toxic Syndrome When History Fails

Altered mental status and decreased respiratory effort are potentially life-threatening symptoms that encompass a wide variety of etiologies including toxic ingestions. We report a case of methadone toxicity in a 34-month-old girl with Noonan syndrome who presented to the emergency department with episodes of altered mental status, bradypnea/apnea, and miosis. Initial history and comprehensive evaluation including urine drug screen did not reveal a diagnosis; however, response to naloxone indicated that her presentation was likely caused by opioid toxicity. This diagnosis was later confirmed with toxicologic testing, which demonstrated an elevated serum methadone concentration. This case illustrates the need for a high index of suspicion for ingestions in children presenting with altered mental status and respiratory depression without an obvious pulmonary or central nervous system cause as well as the importance of recognizing a toxidrome, despite a lack of history of a toxic exposure.

Dosing and Monitoring of Methadone in Pregnancy: Literature Review

The pharmacokinetics of methadone is altered during pregnancy, but the most appropriate dosing and monitoring regimen has yet to be identified. To review dosing and monitoring of methadone therapy in pregnancy. A literature search was performed in several databases (PubMed, MEDLINE, Embase, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews) from inception to May 2012. The search terms were "methadone", "pregnancy", "pharmacokinetic", "clearance", "metabolism", "therapeutic drug monitoring", and "methadone dosing". Additional papers were identified by searching the bibliographies of primary and review articles. All English-language primary articles related to methadone pharmacokinetics in pregnancy were included. Articles not related to maternal outcomes were excluded. The literature search yielded 1 case report and 10 studies discussing use of methadone by pregnant women. Methadone pharmacokinetics in pregnancy has been studied in 3 pharmacokinetic trials, and split dosing of methadone in pregnant women has been described in 1 case report and 3 dosing trials. Only 4 trials evaluated monitoring of methadone concentration in pregnancy. The studies included in this review confirm that methadone pharmacokinetics is altered in pregnancy and is potentially correlated with increases in maternal withdrawal symptoms. Insufficient evidence is available to warrant routine monitoring of serum methadone concentrations in pregnant women with opioid dependence. Few studies of methadone pharmacokinetics and therapeutic drug monitoring are available for pregnant women with opioid dependence. Although it is known that methadone pharmacokinetics is altered in pregnancy, there is insufficient evidence to guide dosage adjustments and serum concentration monitoring. Until further studies are available, regular follow-up of maternal withdrawal symptoms and empiric dosage adjustments throughout pregnancy are still recommended.

Bioavailability and pharmacokinetics of oral and injectable formulations of methadone after intravenous, oral, and intragastric administration in horses

To characterize the bioavailability and pharmacokinetics of oral and injectable formulations of methadone after IV, oral, and intragastric administration in horses. 6 healthy adult horses. Horses received single doses (each 0.15 mg/kg) of an oral formulation of methadone hydrochloride orally or intragastrically or an injectable formulation of the drug orally, intragastrically, or IV (5 experimental treatments/horse; 2-week washout period between each experimental treatment). A blood sample was collected from each horse before and at predetermined time points over a 360-minute period after each administration of the drug to determine serum drug concentration by use of gas chromatography-mass spectrometry analysis and to estimate pharmacokinetic parameters by use of a noncompartmental model. Horses were monitored for adverse effects. In treated horses, serum methadone concentrations were equivalent to or higher than the effective concentration range reported for humans, without induction of adverse effects. Oral pharmacokinetics in horses included a short half-life (approx 1 hour), high total body clearance corrected for bioavailability (5 to 8 mL/min/kg), and small apparent volume of distribution corrected for bioavailability (0.6 to 0.9 L/kg). The bioavailability of methadone administered orally was approximately 3 times that associated with intragastric administration. Absorption of methadone in the small intestine in horses appeared to be limited owing to the low bioavailability after intragastric administration. Better understanding of drug disposition, including absorption, could lead to a more appropriate choice of administration route that would enhance analgesia and minimize adverse effects in horses.

Pharmacokinetics of the injectable formulation of methadone hydrochloride administered orally in horses

Methadone hydrochloride is a synthetic mu-opioid receptor agonist with potent analgesic properties. Oral methadone has been successfully used in human medicine and may overcome some limitations of other analgesics in equine species for producing analgesia with minimal adverse effects. However, there are no studies describing the pharmacokinetics (PK) of oral opioids in horses. The aim of this study was to describe the PK of orally administered methadone (0.1, 0.2 and 0.4 mg/kg) and physical effects in 12 healthy adult horses. Serum methadone concentrations were measured by gas chromatography/mass spectrometry at predetermined time points for 24 h, and PK parameters were estimated using a noncompartmental model. Physical effects were observed and recorded by experienced clinicians. No drug toxicity, behavioural or adverse effects were observed in the horses. The disposition of methadone followed first order elimination and a biphasic serum profile with rapid absorption and elimination phases. The PK profile of methadone was characterized by high clearance (Cl/F), small volume of distribution (V(d)/F) and short elimination half-life (t(1/2)). The mean of the estimated t(1/2) (SD) for each dose (0.1, 0.2 and 0.4 mg/kg) was 2.2 (35.6), 1.3 (46.1) and 1.5 (40.8), and the mean for the estimated C(max) (SD) was 33.9 (6.7), 127.9 (36.0) and 193.5 (65.8) respectively.

Concerns About Consensus Guidelines for QTc Interval Screening in Methadone Treatment

Concerns About Consensus Guidelines for QTc Interval Screening in Methadone Treatment

Divided Doses for Methadone Maintenance

Divided Doses for Methadone Maintenance

False Reduction in Serum Methadone Concentrations by BD Vacutainer® Serum Separator Tubes (SST™)

Methadone maintenance is the primary treatment modality in the US for opioid dependence, with doses typically titrated to therapeutic response such as improvement of withdrawal symptoms or abstinence from drug use. Serum methadone concentrations are used to guide dosing in patients who do not respond to high methadone doses, may be poorly compliant, have excessive sedation or withdrawal symptoms, are pregnant, or have potential drug interactions. In settings with limited onsite laboratory facilities, such as methadone maintenance clinics, it is common practice to collect blood samples in serum separator tubes (SST). The gel in the SST™ forms a barrier between cells and serum after centrifuging, allowing for easier storage and transport. However, the gel in the SST may bind to and decrease the concentration of certain hydrophobic drugs, leading to erroneously low results (1)(2)(3)(4). Factors such as specimen volume, storage time, storage temperature, and the type of gel used …

Impact of methadone treatment on cardiac repolarization and conduction in opioid users

We prospectively assessed the effect of oral methadone on the corrected QT interval (QTc) among 160 patients free of structural heart disease and measured serum methadone concentrations and simultaneous QTc intervals in a subset of 44 participants. Mean +/- SD QTc increased by 12.4 +/- 23 ms (p <0.001) at 6 months, by 10.7 +/- 30 ms (p <0.001) at 12 months, and the QTc change from baseline to 12 months correlated with the trough (r = 0.37, p = 0.008) and peak (r = 0.32, p = 0.03) serum methadone concentrations.

Cocaine-Related Torsade de Pointes in a Methadone Maintenance Patient

A patient maintained on methadone for opioiddependency developed recurrent syncope. Episodes occurred within hours after using cocaine, and were initially presumed secondary to seizure disorder. However, the patient subsequently suffered a cardiac arrest, and polymorphic ventricular tachycardia (torsade de pointes) was documented. Other than cocaine and methadone the patient was receiving no additional agents known to prolong the QT interval. Low serum methadone concentrations and marked reversible left ventricular systolic dysfunction were noted during the hospitalization. These findings, in conjunction with a history of torsade de pointes temporally related to cocaine abuse, suggest that cocaine was a major precipitant of arrhythmia. Recent experimental studies have shown that cocaine and methadone prolong the QT interval through the same mechanism. We examine the effects of cocaine and methadone on cardiac conduction in the context of the opioid-dependent population.

Can methadone concentrations predict the severity of withdrawal in infants at risk of neonatal abstinence syndrome?

Aim: To assess the usefulness of cord and serum methadone concentrations at 2 days of age in predicting the severity of neonatal abstinence syndrome (NAS) in infants whose mothers received...

Cocaine abuse in methadone maintenance patients is associated with low serum methadone concentrations.

Cocaine abuse in methadone maintenance patients has emerged as a significant clinical problem. To determine if raising the daily methadone dosage is an effective way to eliminate cocaine abuse, 74 methadone maintenance patients maintained at daily dosages between 30 and 80 mg and who chronically abused cocaine were studied by a standard protocol. A total of 21 (28.4%) subjects ceased cocaine abuse when their methadone dosage was progressively raised to a maximal daily dose of 160 mg. Cocaine abuse appeared to accelerate elimination of methadone, since inadequate methadone serum concentrations (below 100 ng/ml) were found in 48 of 67 (71.6%) subjects tested 24 hours after a 100 mg oral methadone dose. Although cocaine abuse in methadone maintenance patients may respond to raising the daily methadone dosage, alternative treatments for cocaine abuse in methadone maintenance patients must be identified since cocaine abuse may lower serum methadone concentrations.

Methadone levels and neonatal withdrawal

The purpose of this study was to observe the effects of methadone exposure in utero, with special reference to maternal and neonatal methadone concentrations and neonatal withdrawal. Two groups of mother-infant pairs were studied. In the first group, serum methadone concentrations were determined in infants at 1, 6 and 24 h after delivery. In the second group, blood was obtained at 24, 48, 72 and 96 h after birth. There was no correlation between neonatal serum levels and the intensity of withdrawal symptoms. There was no relationship between maternal methadone dose at delivery or maternal serum levels and neonatal methadone levels. The results of this study may be complicated by the prenatal exposure of the neonates to other drugs of abuse apart from methadone.

Pharmacokinetics of Continuous Intravenous Infusion of Methadone in the Early Post‐Burn Period

The pharmacokinetics of methadone were studied in 14 patients with acute, severe burns and receiving an intravenous infusion of methadone to control their pain. Serum methadone concentrations were measured by gas chromatography on 5 mL arterial blood samples obtained at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0 and 24 hours after the start of infusion. Albumin and Alpha-1-Acid glycoprotein (AAG) were measured by radial immunodiffusion. Serum methadone concentration-time data were fit with the appropriate sum of exponentials equation using iterative nonlinear regression analysis. All serum methadone concentration-time data were best described by a monoexponential equation. Estimates of Vd (180 +/- 62 L) were not significantly different from those predicted for Vc from body weight using literature values (156 +/- 41). Estimates of Vd were, however, significantly lower than those predicted for Vz using literature values (282 +/- 74) (P less than 0.001). In addition, CL values (53.0 +/- 19.3 L/h) were significantly higher than those predicted from body weight using literature values (9.2 +/- 2.3 L/h) (P less than 0.001). These changes resulted in estimates of the elimination half-life for methadone of 2.6 +/- 1.1 h. Methadone protein binding was independent of both albumin and AAG concentration. Multiple regression demonstrated that the significant predictors of CL in the early post burn injury period were serum albumin, days post injury and age. The coefficient of determination (r2) for this model was 0.8190. In summary, methadone CL is markedly elevated while the Vc is essentially unchanged during the early post burn injury period.(ABSTRACT TRUNCATED AT 250 WORDS)