ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics.

Filed under: Methadone Detox

Pharmgenomics Pers Med. 2012; 5: 53-62
Barratt DT, Coller JK, Hallinan R, Byrne A, White JM, Foster DJ, Somogyi AA

BACKGROUND: Genetic variability in ABCB1, encoding the P-glycoprotein efflux transporter, has been linked to altered methadone maintenance treatment dose requirements. However, subsequent studies have indicated that additional environmental or genetic factors may confound ABCB1 pharmacogenetics in different methadone maintenance treatment settings. There is evidence that genetic variability in OPRM1, encoding the mu opioid receptor, and ABCB1 may interact to affect morphine response in opposite ways. This study aimed to examine whether a similar gene-gene interaction occurs for methadone in methadone maintenance treatment. METHODS: Opioid-dependent subjects (n = 119) maintained on methadone (15-300 mg/day) were genotyped for five single nucleotide polymorphisms of ABCB1 (61A > G; 1199G > A; 1236C > T; 2677G > T; 3435C > T), as well as for the OPRM1 118A > G single nucleotide polymorphism. Subjects’ methadone doses and trough plasma (R)-methadone concentrations (C(trough)) were compared between ABCB1 haplotypes (with and without controlling for OPRM1 genotype), and between OPRM1 genotypes (with and without controlling for ABCB1 haplotype). RESULTS: Among wild-type OPRM1 subjects, an ABCB1 variant haplotype group (subjects with a wild-type and 61A:1199G:1236C:2677T:3435T haplotype combination, or homozygous for the 61A:1199G:1236C:2677T:3435T haplotype) had significantly lower doses (median ± standard deviation 35 ± 5 versus 180 ± 65 mg/day, P < 0.01) and C(trough) (78 ± 22 versus 177 ± 97 ng/mL, P < 0.05) than ABCB1 wild-type subjects. Among subjects with the most common ABCB1 haplotype combination (wild-type with 61A:1199G:1236T:2677T:3435T), the OPRM1 118 A/G genotype was associated with a significantly higher C(trough) than 118 A/A (250 ± 126 versus 108 ± 36 ng/mL, P = 0.016). No ABCB1 haplotype group or OPRM1 genotype was associated with dose or C(trough) without taking into account confounding genetic variability at the other locus. Therefore, two interacting pharmacogenetic determinants of methadone maintenance treatment response were identified, ie, ABCB1, where variants are associated with lower methadone requirements, and OPRM1, where the variant is associated with higher methadone requirements. CONCLUSION: These opposing pharmacogenetic effects therefore need to be considered in combination when assessing methadone maintenance treatment pharmacogenetics. HubMed – Methadone

[Costs-analysis of methadone program in the autonomous community la rioja, Spain].

Filed under: Methadone Detox

Rev Esp Salud Publica. 2012 Oct; 86(5): 543-9
Del Pozo Iribarría J, Soldevilla Iñiguez D, Murga García JA, Antoñanzas Villar F

Background: Methadone programs have been organized in each Spanish region in a specific way. In spite of the regional interests to manage those programs in a more efficient way, so far the costs of the programs are unknown. As a previous step, it would be desirable to understand the activities related to these programs as well as their respective costs. This article aims to calculate the cost of the Methadone program in the autonomous community of La Rioja, and to understand those parameters which generate a greater cost to this programme. Methods: The study followed a similar structure as the research recently applied to the region of Murcia. The reference year for the study of the annual costs of the Methadone program was 2010. Data were obtained from different registries of several institutions involved in the regional program. Costs were classified according to different stages and dispensation centres which participated in this programme. Results: Data analysis, for a concentration of 2 mg/ml of methadone, showed an approximate annual cost of 165.759 euros. Taking the total number of patients into consideration the individual cost was 412,34 euros. Conclusions: Dispensation is the stage which caused the largest cost to the programme, the highest per patient cost corresponded to the centre with less patients due to the fact that fixed costs are shared by a smaller group of persons; the biggest global cost of the programme came from Logroño’s center but its average cost is lower.
HubMed – Methadone

OPRM1 genetic polymorphisms are associated with the plasma nicotine metabolite cotinine concentration in methadone maintenance patients: a cross sectional study.

Filed under: Methadone Detox

J Hum Genet. 2012 Dec 6;
Chen YT, Tsou HH, Kuo HW, Fang CP, Wang SC, Ho IK, Chang YS, Chen CH, Hsiao CF, Wu HY, Lin KM, Chen AC, Tsai-Wu JJ, Liu YL

Majority of the heroin-dependent patients smoke cigarettes. Although it has been reported that the OPRM1 genetic polymorphism is associated with the brain mu-opioid receptor binding potential in cigarette smokers, there is no direct evidence showing the impact of plasma cotinine, a nicotine metabolite, on treatment responses to methadone maintenance treatment (MMT). In this study, we aimed to test the hypothesis that the genetic polymorphisms in the OPRM1 are associated with the methadone treatment responses and the severity of cigarette smoking directly measured by the plasma concentration of cotinine in a Taiwanese MMT cohort. Fifteen OPRM1 single-nucleotide polymorphisms (SNPs) were selected and genotyped on DNA samples of 366 MMT patients. Plasma concentrations of cotinine were measured by cotinine enzyme-linked immunosorbent assay. The plasma cotinine concentration had positive correlation with concentrations of methadone (P=0.042) and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine (P=0.037). Methadone treatment non-responders, defined by a positive urine morphine test, had a higher plasma concentration of cotinine (P=0.005), but a lower plasma concentration-to-dose ratio of both R- and S-methadone (P=0.001 and 0.012, respectively) than the responders. OPRM1 genetic variants, rs1074287, rs6912029, rs1799971, rs12209447, rs510769, rs3798676, rs553202, rs7748401, rs495491, rs10457090, rs589046, rs3778152 and rs563649, were significantly associated with the plasma concentration of cotinine when using recessive model for genotypes (general linear model (GLM), P<0.038; false discovery rate (FDR)<0.035) and additive model for allele types (GLM, P<0.03; FDR<0.049) in association analyses. The G allele carriers of SNP rs1799971 (A118G) on exon 1 of OPRM1 gene had a lower plasma cotinine concentration than the A allele carriers (GLM, P=0.029). OPRM1 genetic polymorphisms are associated with the plasma concentration of cotinine in a Taiwanese MMT cohort. Carriers with the major allele of SNP rs1799971 had a higher plasma cotinine concentration.Journal of Human Genetics advance online publication, 6 December 2012; doi:10.1038/jhg.2012.139. HubMed – Methadone

Efficacy and safety of intraoperative intravenous methadone during general anaesthesia for caesarean delivery: a retrospective case-control study.

Filed under: Methadone Detox

Int J Obstet Anesth. 2012 Dec 6;
Russell T, Mitchell C, Paech MJ, Pavy T

BACKGROUND: Most patients undergoing caesarean delivery with general anaesthesia require systemic opioid administration. Due to its rapid onset and long duration of action, intravenous methadone may make it suitable for analgesia after caesarean delivery. Intraoperative methadone combined with postoperative intravenous patient-controlled analgesia with fentanyl or morphine has recently been introduced in our unit. METHODS: A retrospective case-control study of 25 patients who had received methadone was performed. Fifty control patients undergoing elective or emergency caesarean delivery were matched for the use of postoperative intravenous patient-controlled analgesia, transversus abdominis plane (TAP) block and regular non-steroidal anti-inflammatory drugs. Exclusion criteria included preoperative neuraxial analgesia or pre-delivery opioid consumption greater than 10mg of intravenous morphine equivalents. RESULTS: Patients in the methadone group had lower pain scores and were less likely to require intravenous opioid supplementation in the post-anaesthetic care unit (P<0.001). Opioid consumption over 48h was significantly lower in the methadone group. Delayed discharge from the post-anaesthesia care unit was due to sedation in one patient in the methadone group compared to three control patients in whom it was due to sedation and inadequate analgesia. CONCLUSION: A single intraoperative bolus of intravenous methadone appeared to provide effective analgesia with an acceptable side-effect profile. HubMed – Methadone

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