Pharmacokinetics Of Methadone Research Articles

Methadone pharmacokinetics in opioid agonist treatment: Influencing factors and clinical implications.

A considerable inter-individual variability has been reported in the relationship between methadone doses applied and serum concentrations achieved in methadone maintenance treatment. However, the underlying causes for this variability are not fully understood. We investigated the influence of genetic, pathophysiological and pharmacological factors on serum methadone concentration-to-dose ratio (CDR) and discussed the clinical implications of the findings. We used data from two retrospective laboratory databases and a prospective cohort study to investigate the impact on methadone CDR of hepatic cytochrome P450 enzyme system (CYP) genetic polymorphisms, age, sex, concomitant medication, liver fibrosis and body mass index through linear mixed model analyses. A positive association was found between CDR and the homozygous CYP2B6*6 genotype, concurrent treatment with CYP3A4 inhibitors and body mass index. CDR was lower among women and during concomitant use of CYP inducers. CDR was not associated with age or the degree of liver fibrosis in our investigations. This research work supports the need for individually tailored dosage considering the various factors that influence methadone CDR. The gained knowledge can contribute to reducing the risks associated with the treatment and optimizing the desired outcomes.

A genetic-based population PK/PD modeling of methadone in Chinese opiate dependence patients.

The full potential of methadone maintenance treatment (MMT) is often limited by the large inter-individual variability in both pharmacokinetics (PK) and pharmacodynamics (PD), and by the risk of torsade de pointes, a severe adverse effect caused by QTc prolongation. The current study aims to quantitate the contribution of genetic polymorphisms and other variables in PK/PD variability, and their contribution to the QTc interval prolongation in Chinese MMT patients. Population PK models were developed to fit (R)- and (S)-methadone PK data. Hierarchical models were tested to characterize the PK profile, the concentration-QTc relationship, and concentration-urinalysis illicit drug testing relationship, with demographics and genetic variants being included as covariates. Simulation based on the developed PK/PD models was performed to assess the effect of methadone dose and genetic variants on QTc interval prolongation. The PK data were best-fit by a one-compartment, first-order absorption model. Clearance of (R)- and (S)-methadone was both affected by the weighted activity score derived from genetic variants. A linear model was used to describe both the methadone concentration-urinalysis illicit drug testing relationship and the methadone concentration-QTc relationship. Concentration of (R)- and (S)-methadone exhibits a comparable effect on QTc prolongation. Simulation showed that the percentage of QTc higher than 450ms was almost doubled in the lowest clearance group as compared the highest when methadone dose was greater than 120mg. The large variability in PK/PD profiles can be partially explained by the genetic variants in an extent different from other population, which confirmed the necessity to conduct such a study in the specific Chinese patients.

Effect of HIV, antiretrovirals, and genetics on methadone pharmacokinetics: Results from the methadone antiretroviral pharmacokinetics study

BackgroundMethadone treatment of opioid use disorder in HIV-infected individuals is complicated by drug-drug interactions. Genetic and other cofactors further contribute to interindividual variability in methadone pharmacokinetics. We used population pharmacokinetics to estimate the effect of drug-drug interactions, genetics, and other cofactors on methadone pharmacokinetics in a methadone maintained population in Vietnam. MethodsPlasma R- and S-methadone levels were measured in 309 methadone maintained individuals just before and 2−5 h following methadone dosing. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction was used to evaluate methadone clearance (CL/F) and volume of distribution (V/F). The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included HIV status, antiretroviral use (efavirenz or nevirapine), weight, BMI, age, methadone dose, and 8 single nucleotide polymorphisms in across the CYP2B6, ABCB1, and NR1I3 genes. ResultsTaking either efavirenz or nevirapine increased R-methadone CL/F 220%. Nevirapine and efavirenz increased S-methadone CL/F by 404% and 273%, respectively. Variants in NR1I3 increased R- and S-methadone CL/F by approximately 20% only in patients taking efavirenz. Different alleles in ABCB1 rs2032582 either increased or decreased R-methadone CL/F by 10%. The CYP 2B6*4 variant decreased S-methadone CL/F by 18%. HIV-infection increased R- and S-methadone CL/F and V/F by 24%–39%. ConclusionsThe HIV antiretrovirals nevirapine and efavirenz significantly increase methadone clearance. Variants inNR1I3 increased the effect of efavirenz on methadone clearance. Other variants affecting methadone CL/F were also confirmed. To our knowledge, this is the first report of HIV itself affecting methadone pharmacokinetics.

Pharmacokinetic modeling of R and S‐Methadone and their metabolites to study the effects of various covariates in post‐operative children

Methadone is a synthetic opioid used as an analgesic and for the treatment of opioid abuse disorder. The analgesic dose in the pediatric population is not well‐defined. The pharmacokinetics (PKs) of methadone is highly variable due to the variability in alpha‐1 acid glycoprotein (AAG) and genotypic differences in drug‐metabolizing enzymes. Additionally, the R and S enantiomers of methadone have unique PK and pharmacodynamic properties. This study aims to describe the PKs of R and S methadone and its metabolite 2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrrolidine (EDDP) in pediatric surgical patients and to identify sources of inter‐ and intra‐individual variability. Children aged 8–17.9 years undergoing orthopedic surgeries received intravenous methadone 0.1 mg/kg intra‐operatively followed by oral methadone 0.1 mg/kg postoperatively every 12 h. Pharmacokinetics of R and S methadone and EDDP were determined using liquid chromatography tandem mass spectrometry assays and the data were modeled using nonlinear mixed‐effects modeling in NONMEM. R and S methadone PKs were well‐described by two‐compartment disposition models with first‐order absorption and elimination. EDDP metabolites were described by one compartment disposition models with first order elimination. Clearance of both R and S methadone were allometrically scaled by bodyweight. CYP2B6 phenotype was a determinant of the clearance of both the enantiomers in an additive gene model. The intronic CYP3A4 single‐nucleotide polymorphism (SNP) rs2246709 was associated with decreased clearance of R and S methadone. Concentrations of AAG and the SNP of AAG rs17650 independently increased the volume of distribution of both the enantiomers. The knowledge of these important covariates will aid in the optimal dosing of methadone in children.

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.

Stereoselective methadone disposition after administration of racemic methadone to anesthetized Shetland ponies assessed by capillary electrophoresis.

The enantioselectivity of the pharmacokinetics of methadone was investigated in anesthetized Shetland ponies after a single intravenous (0.5 mg/kg methadone hydrochloride; n = 6) or constant rate infusion (0.25 mg/kg bolus followed by 0.25 mg/kg/h methadone hydrochloride; n = 3) administration of racemic methadone. Plasma concentrations of l‐methadone and d‐methadone and their major metabolites, l‐ and d‐2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrrolidine (EDDP), respectively, were analyzed by CE with highly sulfated γ‐cyclodextrin as chiral selector and electrokinetic analyte injection from liquid/liquid extracts prepared at alkaline pH. In both trials, the d‐methadone concentrations were lower than those of l‐methadone and the d‐EDDP levels were lower than those of L‐EDDP. For the case of a single intravenous bolus injection, the plasma concentration versus time profile of methadone enantiomers was analyzed with a two‐compartment pharmacokinetic model. l‐methadone showed a slower elimination rate constant, a lower body clearance, and a smaller steady‐state volume of distribution than d‐methadone. d‐methadone and d‐EDDP were eliminated faster than their respective l‐enantiomers. This is the first study that outlines that the disposition of racemic methadone administered to anesthetized equines is enantioselective.

Methadone Pharmacokinetics in Geriatric Critically Ill Patients Following Intramuscular and Intravenous Administration: A Pilot Stud

Background: Methadone is used for the pain management worldwide. Its special characteristics make it a potential alternative for pain management in critically ill and geriatric patients. Due to lack of studies in this population, we aimed to compare the pharmacokinetic behavior of Methadone following intramuscular and intravenous administration in geriatric ICU patients and with previously reports in healthy volunteers.
 Methods: According to the limitations in ICU setting, we could include 11 patients over 65 years old, who required opioid for pain relief in this study. Patients were randomized to receive 5 mg of Methadone IM or IV injection every 8 hours for 6 days. The Methadone plasma level detected with LC-mass tandem mass spectrometry, and pharmacokinetics parameters were evaluated for each subject in both 1st and 6th days of treatment.
 Results: Based on our results, bioavailability of intramuscular Methadone in geriatric ICU patients was low and less than 40% of the dose was absorbed within first 12 hours. The volume of distribution of Methadone in the first day was significantly lower than the previously reported values in healthy subjects and significantly increased during these 6 days. The Methadone half-life in this population also significantly increased through this period.
 Conclusion: Pharmacokinetic behavior of Methadone in geriatric ICU patients is unpredictable. Reduced volume of distribution and half-life may be observed initially, following with an increase to the normal range. It seems that IM administration of Methadone in geriatric critically ill patients may not provide target analgesic Methadone serum levels.

Population Pharmacokinetics of Methadone after Oral Administration in Japanese Patients with Cancer-Related Pain

Methadone tablets were approved for use in Japan in March 2013. The metabolism of methadone is complex and executed mainly by the cytochromes, CYP3A4 and CYP2B6. The aim of this study was to evaluate the pharmacokinetics of methadone upon oral administration in Japanese patients who experienced cancer-related pain. The concentration of the drug in blood samples was measured in 25 patients undergoing methadone therapy, and the factors leading to variations were investigated. A population pharmacokinetic analysis was evaluated using the Phoenix® NLMETM software. Based on this, the ALBI (albumin-bilirubin) score was identified as a significant factor that could be used to assess variations in the serum concentration of methadone, which was then incorporated into the following final model formula: clearance (L/h) = 5.38 × (ALBI score/-2.139)1.88. The results of these pharmacokinetic parameters suggested that, in clinical use, the dose of methadone should be reduced if liver function declined in patients with cancer-related pain.

Pharmacogenomics of methadone: a narrative review of the literature.

Background: Methadone, a synthetic opioid with longer duration of action and lower abuse potential compared with morphine, is used to prevent opioid withdrawal, as well as to manage chronic and acute surgical pain. The variability in response to methadone has been widely recognized. The purpose of this article is to review the literature on the pharmacogenetic factors underlying this variability. Materials & methods: This is a narrative overview of the literature on the genetic variants affecting pharmacodynamics and pharmacokinetics of methadone, retrieved from searches of databases such as PubMed and google scholar. Discussion: Clinical responses to methadone may be affected by genetic variants in the opioidergic, dopaminergic and neurotrophic pathways. Polymorphisms in genes related to disposition and elimination of methadone alter the pharmacokinetics, and possibly pharmacodynamics of methadone. Cytochrome P450 enzymes and P-glycoprotein variants contribute to the interindividual variability in methadone pharmacokinetics. Evidence for single gene variants affecting methadone response remains weak. Multiple genetic variants must be considered in conjunction to improve predictive ability. Conclusion: Evidence remains scarce at this time, to recommend pharmacogenetic testing before methadone administration. Well-powered clinical studies are needed with population pharmacokinetic-pharmacodynamic modeling and multigenetic signature-based predictions to enable tailored use of methadone in clinical practice.

Pharmacokinetics of Single Doses of Methadone and Buprenorphine in Blood and Oral Fluid in Healthy Volunteers and Correlation With Effects on Psychomotor and Cognitive Functions

We aimed to study the pharmacokinetics of methadone and buprenorphine in blood and oral fluid after single-dose administration and investigate correlations between concentrations in blood and neurocognitive functions. A 5-way, double-blind, randomized, placebo-controlled, double-dummy, crossover study was performed to study the pharmacokinetics and neurocognitive effects of methadone (5 and 10 mg per oral) and buprenorphine (0.2 and 0.4 mg sublingual) in 22 healthy volunteers. Blood and oral fluid were collected throughout the test days, and drug concentrations in both matrices were analyzed using ultrahigh-performance liquid chromatography-tandem mass spectrometry. On-road driving testing, neurocognitive computerized tests, and subjective questionnaires were performed. Large individual variations in concentrations of methadone and buprenorphine in blood and oral fluid, and accordingly oral fluid/blood drug concentration ratios, were observed. The mean ratio 6.5 hours after drug administration was 2.0 (range, 0.49-7.39) for methadone after both doses. Buprenorphine was not detected above the limit of quantification in blood after 6.5 hours. No significant correlation between methadone concentration in blood and effect was found. Significant correlations were found between buprenorphine concentration in blood and standard deviation of lateral position in the driving test and some measures of reaction time, divided attention, balance, alertness, contentedness. and sleepiness. Concentrations of methadone and buprenorphine in blood and oral fluid showed large interindividual variations. No concentration-effect correlations were found for methadone, whereas low to moderate correlations were observed between buprenorphine concentration and driving, psychomotor function, and subjective rating of sleep and alertness.

Effect of rilpivirine on the pharmacokinetics of methadone in HIV-Infected Chinese patients

ABSTRACTBackground: The combination of rilpivirine with methadone may result in complex interactions secondary to the induction of oxidative metabolism by rilpivirine.Research design and methods: TMC278IFD4007 was a single-center, prospective, open-label, multiple-dose study with 12 HIV-infected Chinese participants. The objective was to evaluate the potential effect of rilpivirine on the pharmacokinetics of methadone. The participants received a daily dose of 25 mg rilpivirine for 11 days with individualized methadone ranging from 25 to 100 mg. Pharmacokinetic studies of methadone were conducted on day 1 and 11. Opiate withdrawal symptoms were evaluated.Results: A large inter-subject variability was noted in methadone pharmacokinetics. Rilpivirine increased methadone minimum and maximum plasma concentrations (Cmin; Cmax) and area under the plasma concentration-time curve versus methadone alone (least-square mean ratio; 90% confidence interval) by 5% (1.05; 0.46, 2.39), 5% (1.05; 0.73, 1.52), and 6% (0.75; 0.74, 1.50) as measured in S-methadone, and 5% (1.05; 0.50, 2.22), 5% (1.05; 0.74, 1.50), and 5% (1.05; 0.76, 1.46) as measured in R-methadone, respectively. No opioid withdrawal symptoms or methadone dose adjustments were reported. Co-administration was well tolerated without serious adverse effects or discontinuations.Conclusion: Concomitant administration of rilpivirine was unlikely to have significant effects on the pharmacokinetics of methadone.Trial registration: Chinese Clinical Trial Registry identifier: ChiCTR-TRC-14004908.

Methadone dosing strategies in preterm neonates can be simplified.

A dramatic increase in newborn infants with neonatal abstinence syndrome has been observed and these neonates are frequently treated with complex methadone dosing schemes to control their withdrawal symptoms. Despite its abundant use, hardly any data on the pharmacokinetics (PK) of methadone is available in preterm neonates. Therefore we investigated developmental PK of methadone and evaluated current dosing strategies and possible simplification in this vulnerable population. A single-centre open-label prospective study was performed to collect PK data after a single oral dose of methadone in preterm neonates. A population PK model was built to characterize developmental PK of (R)- and (S)-methadone. Model-based simulations were performed to identify a simplified dosing strategy to reach and maintain target methadone exposure. A total of 121 methadone concentrations were collected from 31 preterm neonates. A one-compartment model with first order absorption and elimination kinetics best described PK data for (R)- and (S)-methadone. Clearance increases with advancing gestational age and differs between R- and S-enantiomer, being slightly higher for the former (0.244 vs 0.167L/h). Preterm neonates reached target exposure after 48hours with currently used dosing schedules. Output from simulations revealed that target exposures can be achieved with a simplified dosing strategy during the first 4days of treatment. Methadone clearance in preterm neonates increases with advancing gestational age and its disposition is influenced by its chirality. Simulations that account for developmental PK changes indicate a shorter methadone dosing strategy can maintain target exposure to control withdrawal symptoms.

The effect of fluconazole on oral methadone in dogs

ObjectiveTo determine the effects of fluconazole on oral methadone pharmacokinetics and central effects mediated by opioid receptors in dogs. Study designProspective, incomplete block. AnimalsA total of 12 healthy Beagle dogs. MethodsDogs were randomly allocated into two groups of six dogs. In total, four treatments (two treatments/group) were administered including: oral methadone (1 mg kg–1); oral fluconazole (5 mg kg–1) every 12 hours starting 24 hours prior to oral methadone (1 mg kg–1); oral fluconazole (2.5 mg kg–1) every 12 hours starting 24 hours prior to oral methadone (1 mg kg–1); and oral fluconazole (5 mg kg–1) every 24 hours starting 12 hours prior to oral methadone (1 mg kg–1). At least 28 days were implemented as a washout period between fluconazole treatments. Rectal temperature (RT), heart rate (HR), respiratory rate (fR), sedation scores and blood samples were obtained for 24 hours after methadone administration. Plasma drug concentrations were measured with liquid chromatography/mass spectrometry. ResultsSignificantly higher maximum plasma methadone concentration (mean, 25–46 ng mL–1) occurred in all fluconazole-administered treatments than in methadone alone (1.5 ng mL–1). The mean 12 hour methadone plasma concentration in fluconazole treatments was 11–20 ng mL–1. Significantly decreased RT and variable sedation occurred in all fluconazole treatments, but no changes occurred with methadone alone. There were no differences in HR or fR among treatments. Conclusions and clinical relevanceFluconazole significantly increases the extent and duration of oral methadone exposure in dogs resulting in significant central opioid effects.

Inhibitory effect of isavuconazole, ketoconazole, and voriconazole on the pharmacokinetics of methadone in vivo and in vitro.

The aim of this study was to investigate the possible effect of orally administered isavuconazole, ketoconazole, or voriconazole on the pharmacokinetics of methadone in rats. Twenty Sprague-Dawley (SD) rats were divided randomly into four groups: Group A (control), group B (5mg/kg isavuconazole), group C (5mg/kg ketoconazole), and group D (5mg/kg voriconazole). A single dose of methadone was administrated half an hour later. Methadone in plasma concentrations and its metabolite EDDP in microsomes were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS), and pharmacokinetic parameters were calculated by DAS version 3.0. The Cmax of methadone in groups C and D increased to 2.7-fold and 5-fold, respectively. While AUC increased in three groups and group D increased the most. Also, isavuconazole, ketoconazole, and voriconazole showed inhibitory effect on human and rat microsomes. The inhibition ratios of isavuconazole, ketoconazole, and voriconazole in rat liver microsome were 97.87%, 96.74% and 78.9%, respectively (p<0.01), while in human liver microsome, inhibition ratios were 86.97%, 96.46%, and 53.11%, respectively. And the IC50 for inhibition activity of isavuconazole, ketoconazole, and voriconazole in rat microsomes were 7.76μM, 8.33μM, and 4.45μM, respectively. Our study indicated that taking methadone combine with ketoconazole, isavuconazole, or voriconazole could reduce the metabolism rate of methadone and prolong the pharmacological effects in vivo and in vitro.

Combined Effect of CYP2B6 Genotype and Other Candidate Genes on a Steady-State Serum Concentration of Methadone in Opioid Maintenance Treatment.

A considerable interindividual variability in methadone pharmacokinetics is seen in patients on methadone maintenance treatment. The aim of this study was to clarify the impact of the reduced function CYP2B6*6 variant allele together with variants in other candidate genes on a steady-state methadone concentration in a naturalistic setting. Information of methadone serum concentration, dose, age, sex, and CYP2C9, CYP2C19, and CYP2D6 genotypes were collected from a routine therapeutic drug monitoring database, whereas variant alleles in CYP2B6 and CYP3A5 were retrospectively genotyped. Linear mixed model analyses were used to study the impact of gene variants on methadone serum concentration/dose (C/D) ratios, including age, sex, and time since the last dose intake as covariates. Overall, 155 serum samples from 62 patients were included in this study. The estimated mean methadone C/D ratios was 17.8 nmol·L·mg for homozygous carriers of CYP2B6*6, which was significantly (P < 0.001) higher than noncarriers (9.2 nmol·L·mg). There was no difference in C/D ratios between heterozygous carriers of CYP2B6*6 (9.1 nmol·L·mg) and noncarriers. An increase in mean methadone C/D ratios was also seen for homozygous carriers of CYP3A5*3 and heterozygous carriers of CYP2C9*2 or *3 and CYP2C19*2 or *3. Patients homozygous for CYP2B6*6 had a >90% higher methadone C/D ratio. Genotyping of CYP2B6 may therefore be of value when assessing dose requirements in methadone maintenance treatment.

Silibinin affects the pharmacokinetics of methadone in rats.

The aim of the present study was to investigate the pharmacokinetic effect of silibinin on methadone in rats. Twenty-four male Sprague-Dawley rats were randomly divided into 4 groups: control group, single dose of 100mg/kg group, multiple doses of 100mg/kg group, and multiple doses of 30mg/kg group. A single dose of 6mg/kg methadone was administrated to rats orally without or with silibinin. Plasma samples were collected via tail vein at different time points and concentrations of methadone and its metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), were determined by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Compared with the control group (without silibinin), both 30 and 100mg/kg silibinin significantly increased the Cmax of methadone, but only 100mg/kg silibinin significantly increased the AUC(0-t) of methadone and decreased its clearance. Pharmacokinetics parameters of EDDP were not altered by 30mg/kg silibinin; its Tmax was decreased by 100mg/kg silibinin and the Cmax was increased by single dose of 100mg/kg silibinin. It is concluded that silibinin significantly altered the pharmacokinetics of methadone in rats by increasing the exposure of methadone. Further investigations in human should be conducted. Therapeutic drug monitoring of methadone in individuals undergoing methadone maintenance therapy is recommended when silibinin is concomitant.

Current Concepts in Methadone Metabolism and Transport.

Methadone is a cornerstone therapy for opioid addiction and a public health strategy for HIV/AIDS and hepatitis C reduction. Methadone is also used for acute and chronic pain. As use for chronic pain has grown, so too have adverse events. Constitutive and acquired (drug interactions) inter- and intraindividual variability in methadone pharmacokinetics and pharmacodynamics confounds reliable clinical use. Identification of enzymes and transporters responsible for methadone disposition has been a long-sought ideal. Initial in vitro studies identified CYP3A4 as metabolizing methadone. Subsequently, by extrapolation, CYP3A4 was long assumed to be responsible for clinical methadone disposition. However, CYP2B6 is also a major catalyst of methadone metabolism in vitro. It has now been unequivocally established that CYP2B6, not CYP3A4, is the principal determinant of methadone metabolism, clearance, elimination, and plasma concentrations in humans. Methadone disposition is susceptible to inductive and inhibitory drug interactions. CYP2B6 genetics also influences methadone metabolism and clearance, which were diminished in CYP2B6*6 carriers and increased in CYP2B6*4 carriers. CYP2B6 genetics can explain, in part, interindividual variability in methadone metabolism and clearance. Thus, both constitutive variability due to CYP2B6 genetics, and CYP2B6-mediated drug interactions, can alter methadone disposition, clinical effect, and drug safety. Methadone is not a substrate for major influx or efflux transporters.

Tell-Tale SNPs: The Role of CYP2B6 in Methadone Fatalities.

Cytochrome P450 (CYP) enzyme 2B6 plays a significant role in the stereo-selective metabolism of (S)-methadone to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, an inactive methadone metabolite. Elevated (S)-methadone can cause cardiotoxicity by prolonging the QT interval of the heart's electrical cycle. Large inter-individual variability of methadone pharmacokinetics causes discordance in the relationship between dose, plasma concentrations and side effects. The purpose of this study was to determine if one or more single nucleotide polymorphisms (SNPs) located within the CYP2B6 gene contributes to a poor metabolizer phenotype for methadone in these fatal cases. The genetic analysis was conducted on 125 Caucasian methadone-only fatalities obtained from the West Virginia and Kentucky Offices of the Chief Medical Examiner. The frequency of eight exonic and intronic SNPs (rs2279344, rs3211371, rs3745274, rs4803419, rs8192709, rs8192719, rs12721655 and rs35979566) was determined. The frequencies of SNPs rs3745274 (*9, c516G > T, Q172H), and rs8192719 (21563 C > T) were enhanced in the methadone-only group. Higher blood methadone concentrations were observed in individuals who were genotyped homozygous for SNP rs3211371 (*5, c1459C > T, R487C). These results indicate that these three CYP2B6 SNPs are associated with methadone fatalities.

Pharmacokinetics and analgesic effects of methadone in children and adults with sickle cell disease.

Vaso-occlusive episodes (VOEs) are a significant source of morbidity among children and adults with sickle cell disease (SCD). There is little information on methadone use for SCD pain. This investigation evaluated methadone pharmacokinetics in children and adults with SCD, with a secondary aim to assess pain relief and opioid consumption. Participants included children (<18 years) and adults with a VOE requiring hospitalization. Patients were randomly assigned to receive standard care (opioid patient-controlled analgesia; control group) or one dose of intravenous methadone (0.1-0.125mg/kg) in addition to standard care (methadone group). Venous methadone and metabolite concentrations were measured. Pain scores, pain relief scores, and opioid consumption were recorded. Twenty-four children (12 methadone, 12 controls) and 23 adults (11 methadone, 12 controls) were studied. In children, the half-life of R- and S-methadone enantiomers was 34 ± 16 and 24 ± 9hr, respectively. In adults, R- and S-methadone half-lives were 52 ± 17 and 38 ± 12hr, respectively. Pain scores were lower (P = 0.002) and pain relief scores were higher (P = 0.0396) in children receiving methadone versus controls. There was no difference in pain scores and pain relief in adults receiving methadone versus controls. There was no difference in opioid consumption between methadone and control groups, in both adults and children. Intravenous methadone disposition in children and adults with SCD was comparable to that in subjects without SCD from prior studies. Methadone produced more pain relief than standard care in children with SCD. Higher methadone doses may be more effective and should be evaluated in both children and adults with SCD.

Relationship between CYP2B6*6 and cold pressor pain sensitivity in opioid dependent patients on methadone maintenance therapy (MMT)

BackgroundCYP2B6 polymorphisms contribute to inter-individual variations in pharmacokinetics of methadone. Increased pain sensitivity is frequently reported by opioid dependent patients on methadone maintenance therapy (MMT). It is possible, therefore, that genetic polymorphisms in CYP2B6, which affects the metabolism of methadone, influence pain sensitivity among patients on MMT. This study investigated CYP2B6 polymorphisms and pain sensitivity in this group. MethodsThe cold pressor pain responses of 148 opioid dependent patients receiving MMT were evaluated using the cold pressor test (CPT). DNA was extracted from whole blood and subjected to polymerase chain reaction (PCR)-genotyping. ResultsOf the 148 subjects, 77 (52.0%) were carriers of CYP2B6*6 allele. CYP2B6*6 allele carriers had shorter cold pain threshold and pain tolerance times than non-carriers of CYP2B6*6 allele (21.05s vs 33.69s, p=0.036 and 27.15s vs 44.51s, p=0.020, respectively). Pain intensity scores of the CYP2B6*6 allele carriers was 67.55, whereas that of the CYP2B6*6 allele non-carriers was 64.86 (p=0.352). ConclusionOur study indicates that the CYP2B6*6 allele is associated with a lower pain threshold and lower pain tolerance among males with opioid dependence on MMT. The CYP2B6*6 allele may provide a mechanistic explanation for clinical observations of heightened pain sensitivity among opioid dependent patients receiving MMT.