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.

A Novel Perioperative Multidose Methadone-Based Multimodal Analgesic Strategy in Children Achieved Safe and Low Analgesic Blood Methadone Levels Enabling Opioid-Sparing Sustained Analgesia With Minimal Adverse Effects.

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.

Genetic polymorphisms in the opioid receptor delta 1 (OPRD1) gene are associated with methadone dose in methadone maintenance treatment for heroin dependence.

Delta opioid receptor (DOR) is well known to be involved in heroin dependence. This study tested the hypothesis that single nucleotide polymorphisms (SNPs) in the opioid receptor delta 1 (OPRD1) gene coding region are associated with treatment responses in a methadone maintenance therapy (MMT) cohort in Taiwan. Three hundred forty-four MMT patients were recruited. Diastolic/systolic blood pressure, heart rate, methadone dosage, and plasma concentrations of methadone were recorded. Twenty-five SNPs located within the OPRD1 genetic region were selected and genotyped from the genomic DNA of all 344 participants. After pairwise tagger analyses, tagger SNP rs204047 showed a significant association with methadone dosage (P = 0.0019), and tagger SNPs rs204047 and rs797397 were significantly associated with plasma R, S-methadone concentrations (P < 0.0006) in patients tested negative in the urine morphine test, which indicated patients with a better response to MMT. The major genotype carriers showed a higher methadone dosage and higher plasma concentrations of R, S-methadone than the minor genotype carriers. The results indicated that OPRD1 genetic variants were associated with methadone dosage and methadone plasma concentration in MMT patients with a negative morphine test result.

Determination of methadone and EDDP in oral fluid using the dried saliva spots sampling approach and gas chromatography-tandem mass spectrometry.

The present work describes the development and validation of a novel approach to determine methadone (MTD) and its main metabolite (EDDP) in oral fluid samples, using the dried saliva spots (DSS) sampling approach and gas chromatography-tandem mass spectrometry (GC-MS/MS). Oral fluid samples (50 µL) were applied into Whatman™ 903 protein saver filter paper cards and were allowed to dry overnight. The extraction was carried out by immersion of the spot in 1 mL of isopropyl alcohol with agitation for 1 min. Afterwards, the extract was centrifuged for 15 min at 3500 rpm and the supernatant evaporated to dryness and reconstituted with 50 µL of methanol. The procedure was considered linear in the range of 10 to 250 ng/mL for both compounds, with determination coefficients greater than 0.99. Intra- and inter-day precision and accuracy revealed coefficients of variation (CVs) lower than 15% at the studied concentrations, with mean relative errors within ± 15% of the nominal concentrations. Recoveries ranged from 45 to 74%. The limits of detection and quantification were 5 and 10 ng/mL respectively for both analytes. All studied parameters complied with the defined criteria and the method enabled the successful determination of MTD and EDDP in oral fluid samples from patients undergoing opiate substitution/maintenance therapy.

[Opioid switch and change of route of administration in cancer patients treated by morphine]. / La morphine dans le cadre du changement d'opioïdes ou de voie d'administration, chez l'adulte avec une douleur due au cancer.

This paper reviewed the 2002 guidelines established by the National Federation of Cancer Centres. A group of experts nominated by the 3 French Societies involved in the treatment of cancer pain (AFSOS, SFAP, SFETD), established new guidelines ratios for morphine switching and/or changing of route of administration, in patients for whom either pain was not adequatly managed or adverse effects were unbearable. After a rapid reminder of the pharmacokinetics and metabolism properties of morphine, experts explained why the theory of opioid rotation (oxycodone, hydromorphone, fentanyl, methadone, tapentadol) using fixed equianalgesic ratios is not any more appropriate for a secure clinical practice. In the light of recent publications enhancing our knowledge on the efficacy of new drug switching ratios and for changing the route of administration of morphine, the group of experts recommended to use reconsidered switching ratios favoring security upon efficacy, to minimize overdosing and adverse effects. Consequently, after the new conversion ratio (using slow release opioids) was applied, a second titration should be done by means of normal release rescue formulations for breakthrough pain episodes. A smartphone App. OpioConvert® will be available for rapid and secure dose conversions.

Methadone: Maximizing Safety and Efficacy for Pain Control in Patients with Cancer.

Methadone is a valuable opioid in the management of patients who have cancer with pain. Methadone is a mu-, kappa-, and delta-opioid agonist, and an N-methyl-D-aspartate receptor antagonist. These mechanisms of action make methadone an attractive option for complex pain syndromes. It is critically important that providers consider a patient's risk status before beginning methadone. Careful consideration must be given to dosing methadone in both opioid-naïve and opioid-tolerant patients, with vigilant monitoring for therapeutic effectiveness and potential toxicity until the patient achieves steady state.

Time-Dependent Postmortem Redistribution of Opioids in Blood and Alternative Matrices.

Forensic postmortem case interpretation can be challenging, in particular due to postmortem redistribution (PMR) phenomena. Recent studies have shown that computed tomography (CT)-guided collection of biopsy samples using a robotic arm (virtobot) provides a valuable tool for systematic studies on time-dependent PMR. Utilizing this strategy, several cases involving opioid use such as methadone, fentanyl, tramadol, codeine, oxycodone and hydrocodone were evaluated for time-dependent concentration changes and potential redistribution mechanisms. Upon admission to the institute (t1), blood (femoral and right ventricle heart blood) and tissue biopsy samples (lung, kidney, liver, spleen, thigh muscle and adipose tissue) were collected utilizing CT-guided biopsy. Approximately 24 h later (t2; mean 28 ± 15 h), during the autopsy, samples from the same body regions were collected manually and in addition brain tissue, gastric content, urine and left ventricle heart blood. Analysis was conducted with liquid chromatography tandem mass spectrometry. Significant time-dependent methadone concentration increases in femoral blood (pB) indicate the occurrence of PMR, however, ultimately not relevant for forensic interpretation. The main metabolite of methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), showed a less significant trend for PMR. Redistribution by passive diffusion along the muscle-to-pB concentration gradient seems likely for methadone, but not for EDDP. Results for fentanyl suggest extensive PMR. Other opioids such as tramadol, codeine, hydrocodone and oxycodone showed no consistent trend for significant PMR. Overall, CT-guided biopsy sampling proved to be a valuable tool for the investigation of PMR mechanisms.

Can Saliva and Plasma Methadone Concentrations Be Used for Enantioselective Pharmacokinetic and Pharmacodynamic Studies in Patients With Advanced Cancer?

PURPOSE: Methadone is a potent analgesic used to treat refractory cancer pain. It is administered as a racemic mixture, with the l-enantiomer being primarily a µ-receptor agonist, whereas the d-enantiomer is an N-methyl-d-aspartate antagonist and inhibits serotonin and norepinephrine reuptake. Dose requirements vary greatly among patients to achieve optimal pain control and to avoid the risk of adverse effects. The relationship between plasma and saliva methadone enantiomer concentrations was investigated to determine if saliva could be a substitute for plasma in pharmacodynamic and pharmacokinetic studies for clinical monitoring and dose optimization of methadone in patients with advanced cancer. METHODS: Patients with advanced cancer who were prescribed varying doses of oral methadone for pain management were recruited to obtain paired plasma and saliva samples. Pain scores were recorded at the time of sampling. The total and unbound plasma and saliva concentrations of the l- and d-enantiomers of methadone were quantified by using an HPLC-MS/MS method. The relationship between plasma (total and unbound) and saliva concentrations were compared. The saliva-to-plasma concentration ratio was compared versus the dose administered and the time after dosing for both enantiomers. The association of methadone concentrations with reported pain scores was compared by using a Mann-Whitney U test for significance. FINDINGS: Fifty patients receiving a mean dose of 11mg/d of methadone provided 151 paired plasma and saliva samples. The median age of the population was 61 years with an interquartile range of 53-71 years with total body weight ranging from 59-88 kg. Median (interquartile) total plasma concentrations for l- and d-methadone were 50.78 ng/mL (30.6-113.0 ng/mL) and 62.0 ng/mL (28.7-116.0 ng/mL), respectively. Median (interquartile range) saliva concentrations for l- and d-methadone were 81.5 ng/mL (28.0-203.2 ng/mL) and 44.2 (16.2-149.7 ng/mL). No relationship could be established between plasma and saliva concentrations for l- and d-methadone (r2 = 0.35 and 0.25). The saliva-to-plasma concentration analyzed with the methadone dose showed higher saliva concentrations at lower doses. Dose-normalized saliva concentrations followed a similar pattern over time compared with plasma concentrations. No correlation was found between l-methadone plasma, d-methadone plasma, l-methadone saliva, d-methadone saliva concentrations, and pain score. IMPLICATIONS: Saliva concentration was not a better predictor of pain control than plasma concentration for dose optimization and monitoring studies of methadone in patients with cancer. Although the saliva-to-plasma ratio of the concentration of methadone enantiomers was stable across the dosing range, due to the variability in individual saliva-to-plasma ratios, saliva sampling may not be a valid substitute in pharmacokinetic studies of methadone in cancer.

Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction.

Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the estrogen-response element single nucleotide polymorphism (ERE-SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R- or S-) of 2-ethylidene-1,5-dimethyl-3,3-dipheny-pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug-seeking behaviour, implicating oestradiol-CYP-EDDP/methadone axis decreasing MMT efficacy. In mouse model, oestrogen mitigates methadone antinociceptive response, facilitates methadone catabolism and up-regulates methadone-associated metabolizing enzymes. Oestrogen also ablates chronic methadone administration-induced rewarding response. Mechanism dissection revealed the CC genotype of CYP2B6-ERE-SNP exerts higher ERE sequence alignment score, higher estrogenic response as compared to TT genotype. At last, preclinical study via targeting estrogen signal that tamoxifen (TMX; selective estrogen receptor modulator, SERM) could facilitate the tolerance phase rewarding response of methadone. Strikingly, TMX also reduces tapering/abstinence phases methadone liability in mice. In conclusion, this study demonstrates altering methadone metabolism through targeting estrogen signals might be able to free morphine addictive patients from the addiction of opioid replacement therapy. Therefore, the add-on therapy clinical trial introducing SERM in MMT regimen is suggested.

Pharmacogenomics study on cadherin 2 network with regard to HIV infection and methadone treatment outcome.

Heroin dependent patients have a high incidence of HIV infection. In contrast to the gene expression method, we developed a systemic correlation analysis method built upon the results of pharmacogenomics study in a methadone maintenance treatment (MMT) cohort consisting of 344 Taiwanese heroin dependent patients. We identified genetic variants and their encoding proteins that may be involved with HIV infection and MMT treatment outcome. Cadherin 2 (CDH2) genetic determinants were identified through the genome-wide pharmacogenomic study. We found significant correlations among HIV infection status, plasma levels of CDH2, cytokine IL-7, ADAM10, and the treatment responses to methadone. Two single nucleotide polymorphisms located within CDH2 gene showed associations with blood pressure and plasma CDH2 concentration. Plasma concentration of CDH2 showed correlations with the level of cytokine IL-7, status of HIV infection, and urine morphine test result. Plasma level of IL-7 was correlated with corrected QT interval (QTc) and gooseflesh skin withdrawal symptom score, while level of ADAM10 was correlated with plasma concentrations of vitamin D metabolite, nicotine metabolite, and R-methadone. The results suggest a novel network involving HIV infection and methadone treatment outcome.

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

BACKGROUND: 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. PROCEDURE: 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 (0.1-0.125 mg/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. RESULTS: 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 ± 9 hr, respectively. In adults, R- and S-methadone half-lives were 52 ± 17 and 38 ± 12 hr, 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. CONCLUSIONS: 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.

Bioavailability of Methadone After Sleeve Gastrectomy: A Planned Case Observation.

OBJECTIVE: Morbidly obese patients on opioid-replacement therapy may be at risk for treatment refusal with regard to bariatric surgery. However, patients on opioid replacement may have the personal skills to facilitate the lifestyle changes required for successful outcomes after bariatric surgery. This planned case observation assessed the effects of sleeve gastrectomy on the pharmacokinetic properties of methadone. METHODS: A white woman in her 40s on methadone maintenance therapy and with morbid obesity was referred for bariatric surgery. Serial blood samples for methadone concentration measurements were obtained before and at 5 days and 1, 7, and 11 months after surgery. FINDINGS: Serum methadone concentrations increased from before to 5 days after surgery and continued to increase for 7 months thereafter. The predose measurement at 11 months postoperatively suggests a further increase compared with the previous predose measurements. IMPLICATIONS: Clinicians should beware the potential for altered effects of methadone after bariatric surgery. We recommend that serum concentrations be routinely measured pre- and postoperatively, and that the dose be adjusted according to these measurements and regular clinical assessments.

Effect of intramuscular methadone on pharmacokinetic data and thermal and mechanical nociceptive thresholds in the cat.

Objectives The aim of the study was to assess simultaneous pharmacokinetics and thermal and mechanical antinociception after intramuscular methadone (0.6 mg/kg) in 10 cats. Methods Thermal and mechanical threshold (TT and MT, respectively) testing and blood collection were conducted at baseline and up to 24 h after administration. Methadone plasma concentrations were determined by liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were estimated by a non-compartmental method. TT and MT were analysed using ANOVA ( P <0.05). Time of maximum plasma concentration (Tmax), time of onset of antinociception and time of reaching cut-out threshold (TT 55°C; MT 30 Newtons [N]) were determined. Results TT and MT increased above baseline from 20-240 mins and 5-40 mins, respectively, after intramuscular (IM) administration ( P <0.005). Mean maximum delta T (measured as TT minus baseline threshold) was 7.9°C (95% confidence interval [CI] 4.3-11.6) at 60 mins and mean maximum delta F (measured as MT minus baseline threshold) was 4.2 (95% CI 1.6-6.7) N at 45 mins. IM methadone concentration-time data decreased curvilinearly, and gave a clearance estimate of mean 9.1 ml/kg/min (range 5.2-15.7) with median Tmax at 20 mins (range 5-360 mins). Conclusions and relevance IM data followed classical disposition and elimination in all cats. Plasma concentrations after IM administration were associated with an antinociceptive effect, including negative hysteresis. These data can be used for devising dosing schedules for methadone in clinical feline practice.

Methadone dose in heroin-dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity.

AIMS: Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients. METHODS: Eighty-one stable patients (60 men and 21 women, 43.7 ± 8.1 years old, 63.1 ± 50.9 mg day(-1) methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes. RESULTS: Methadone maintenance dose was correlated to the highest dose ever used (r(2) = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27-18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01-2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day(-1) in never-addict patients, P = 0.005) and ethnicity (Asian > Caucasian > African, P = 0.04) were independently associated with high-dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (Spearman rank correlation coefficient [rs ] = 0.21, P = 0.06) but not with highest dose ever used (rs = 0.15, P = 0.18) or dose-normalized R,S-methadone trough concentrations (rs = -0.05, P = 0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose. CONCLUSIONS: Methadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients.

The pharmacokinetics of methadone and its metabolites in neonates, infants, and children.

BACKGROUND: The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg·l(-1) , while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg·l(-1) . The racemate of methadone which is commonly used in pediatric and anesthetic care is metabolized to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP). METHODS: Data from four studies (age 33-week PMA-15 years) were pooled (n = 56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70-kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n = 7) allowed further study of R- and S-enantiomer pharmacokinetics. RESULTS: A three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between-subject variability) were central volume (V1) 21.5 (29%) l.70 kg(-1) , peripheral volumes of distribution V2 75.1 (23%) l.70 kg(-1) and V3 484 (8%) l.70 kg(-1) , clearance (CL) 9.45 (11%) l·h(-1) .70 kg(-1) , and intercompartment clearances Q2 325 (21%) l·h(-1) .70 kg(-1) and Q3 136 (14%) l·h(-1) .70 kg(-1) . EDDP formation clearance was 9.1 (11%) l·h(-1) .70 kg(-1) , formation clearance of EMDP from EDDP 7.4 (63%) l·h(-1) .70 kg(-1) , elimination clearance of EDDP was 40.9 (26%) l·h(-1) .70 kg(-1) and the rate constant for intermediate compartments 2.17 (43%) h(-1) . CONCLUSIONS: Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg·kg(-1) per 8 h in neonates achieves a target concentration of 0.06 mg·l(-1) within 36 h. Infusion, rather than intermittent dosing, should be considered if this target is to be achieved in older children after cardiac surgery.

The association of genetic polymorphisms in the κ-opioid receptor 1 gene with body weight, alcohol use, and withdrawal symptoms in patients with methadone maintenance.

Methadone is a synthetic opioid that binds to the κ-opioid receptor with a low affinity. This study tested the hypotheses that the genetic polymorphisms in the κ-opioid receptor 1 (OPRK1) gene region are associated with methadone treatment responses in a Taiwan methadone maintenance treatment (MMT) cohort. Seventeen single nucleotide polymorphisms (SNPs) in OPRK1 were selected and genotyped on DNA of 366 MMT patients. Six SNPs from rs7843965 to rs1051660 (intron 2 to exon 2) were significantly associated with body weight (P < 0.007). A haplotype of 4 SNPs rs7832417-rs16918853-rs702764-rs7817710 (exon 4 to intron 3) was associated with bone or joint aches (P ≤ 0.004) and with the amount of alcohol use (standard drinks per day; global P < 0.0001). The haplotype rs10958350-rs7016778-rs12675595 was associated with gooseflesh skin (global P < 0.0001), yawning (global P = 0.0001), and restlessness (global P < 0.0001) withdrawal symptoms. The findings suggest that genetic polymorphisms in OPRK1 were associated with the body weight, alcohol use, and opioid withdrawal symptoms in MMT patients.

Functional genetic polymorphisms in CYP2C19 gene in relation to cardiac side effects and treatment dose in a methadone maintenance cohort.

Abstract Methadone maintenance therapy is an established treatment for heroin dependence. This study tested the influence of functional genetic polymorphisms in CYP2C19 gene encoding a CYP450 enzyme that contributes to methadone metabolism on treatment dose, plasma concentration, and side effects of methadone. Two single nucleotide polymorphisms (SNPs), rs4986893 (exon 4) and rs4244285 (exon 5), were selected and genotyped in 366 patients receiving methadone maintenance therapy in Taiwan. The steady-state plasma concentrations of both methadone and its EDDP metabolite enantiomers were measured. SNP rs4244285 allele was significantly associated with the corrected QT interval (QTc) change in the electrocardiogram (p=0.021), and the Treatment Emergent Symptom Scale (TESS) total score (p=0.021) in patients who continued using heroin, as demonstrated with a positive urine opiate test. Using the gene dose (GD) models where the CYP2C19 SNPs were clustered into poor (0 GD) versus intermediate (1 GD) and extensive (2 GD) metabolizers, we found that the extensive metabolizers required a higher dose of methadone (p=0.035), and showed a lower plasma R-methadone/methadone dose ratio (p=0.007) in urine opiate test negative patients, as well as a greater QTc change (p=0.008) and higher total scores of TESS (p=0.018) in urine opiate test positive patients, than poor metabolizers. These results in a large study sample from Taiwan suggest that the gene dose of CYP2C19 may potentially serve as an indicator for the plasma R-methadone/methadone dose ratio and cardiac side effect in patients receiving methadone maintenance therapy. Further studies of pharmacogenetic variation in methadone pharmacokinetics and pharmacodynamics are warranted in different world populations.

The pharmacokinetics of methadone in adolescents undergoing posterior spinal fusion.

BACKGROUND: The optimal methadone dosing regimen for children undergoing spinal surgery is uncertain because of sparse pediatric pharmacokinetic data and a paucity of analgesic effect data. The minimum effective analgesic concentration of methadone in opioid naïve adults is 58 mcg · L(-1). METHODS: Adolescents aged 12-19 years undergoing idiopathic scoliosis correction were administered 0.25 mg · kg(-1) racemic methadone IV prior to surgical incision. Arterial blood samples for methadone assay were obtained at 0 min, 5 min, 10 min, 15 min, 20 min, 40 min, 1 h, 2 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 48 h. Compartment analysis was undertaken using nonlinear mixed effects models. Parameter estimates were standardized to a 70-kg person using allometric models. RESULTS: A three-compartment linear disposition model best described observed time-concentration profiles. Population parameter estimates (between-subjects variability) were central volume (V1) 19.1 (126%) L 70 kg(-1), peripheral volumes of distribution V2 65.5 (60%) L 70 kg(-1), V3 485 (23%) L 70 kg(-1), clearance (CL) 9.3 (11%) L · h(-1) · 70 kg(-1), and inter-compartment clearances Q2 282 (95%) L · h(-1) 70 kg(-1), Q3 139 (42%) L · h(-1) 70 kg(-1). The terminal elimination half-life was 44.4 h. The mean observed methadone concentration was <58 mcg · L(-1) by the first hour after administration. CONCLUSIONS: Current pharmacokinetic parameter estimates in adolescents are similar to those reported in adults. Methadone undergoes rapid redistribution after bolus administration. This may result in plasma concentrations that provide inadequate analgesia postoperatively. We would suggest following the bolus (0.25 mg.kg(-1)) with an infusion (0.1-0.15 mg · kg(-1) · h(-1) for 4 h) during spinal surgery to ensure adequate plasma concentrations for 24 h.