ABSTRACT
ß-Arrestin2 (ARRB2) is a component of the G-protein-coupled receptor complex and is involved in µ-opioid and dopamine D(2) receptor signaling, two central processes in methadone signal transduction. We analyzed 238 patients in methadone maintenance treatment (MMT) and identified a haplotype block (rs34230287, rs3786047, rs1045280 and rs2036657) spanning almost the entire ARRB2 locus. Although none of these single nucleotide polymorphisms (SNPs) leads to a change in amino-acid sequence, we found that for all the SNPs analyzed, with exception of rs34230287, homozygosity for the variant allele confers a nonresponding phenotype (n=73; rs1045280C and rs2036657G: OR=3.1, 95% CI=1.5-6.3, P=0.004; rs3786047A: OR=2.5, 95% CI=1.2-5.1, P=0.02) also illustrated by a 12-fold shorter period of negative urine screening (P=0.01). The ARRB2 genotype may thus contribute to the interindividual variability in the response to MMT and help to predict response to treatment.
Subject(s)
Analgesics, Opioid/therapeutic use , Arrestins/genetics , Methadone/therapeutic use , Opiate Substitution Treatment , Opioid-Related Disorders/genetics , Opioid-Related Disorders/rehabilitation , Polymorphism, Single Nucleotide , Adolescent , Adult , Aged , Chi-Square Distribution , Cross-Sectional Studies , Female , Gene Frequency , Genotype , Humans , Logistic Models , Male , Middle Aged , Odds Ratio , Pharmacogenetics , Phenotype , Precision Medicine , Retrospective Studies , Switzerland , Time Factors , Treatment Outcome , Young Adult , beta-Arrestin 2 , beta-ArrestinsSubject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Methadone/administration & dosage , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/pharmacokinetics , Dose-Response Relationship, Drug , Haplotypes , Humans , Methadone/pharmacokinetics , Polymorphism, Single NucleotideABSTRACT
Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing hERG showed that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone, electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone. The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 439+/-25 ms; n=11) than in extensive metabolizers (non *6/*6; 421+/-25 ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of (R)-methadone.
Subject(s)
Analgesics, Opioid/pharmacology , Aryl Hydrocarbon Hydroxylases/metabolism , Ether-A-Go-Go Potassium Channels/drug effects , Long QT Syndrome/chemically induced , Long QT Syndrome/genetics , Methadone/pharmacology , Oxidoreductases, N-Demethylating/metabolism , Potassium Channel Blockers , Adult , Alleles , Analgesics, Opioid/blood , Analgesics, Opioid/chemistry , Cytochrome P-450 CYP2B6 , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , ERG1 Potassium Channel , Electrocardiography/drug effects , Female , Genotype , Heart Rate/drug effects , Humans , Kinetics , Long QT Syndrome/physiopathology , Male , Methadone/blood , Methadone/chemistry , Middle Aged , Patch-Clamp Techniques , Reverse Transcriptase Polymerase Chain Reaction , StereoisomerismABSTRACT
OBJECTIVE: Intravenous methadone is associated with increased risk of morbidity and mortality. A previous report from a methadone center in Fribourg, Switzerland, found a high prevalence (43%) of patients who injected oral methadone. We therefore wished to assess the prevalence of methadone injection among patients in oral methadone programs in 3 other Swiss cities--Lausanne, Geneva, and La Chaux-de-Fonds. METHOD: Subjects were randomly selected and interviewed by assistant psychologists who were not on the staff of the study centers. Participation was voluntary and anonymous. RESULTS: 164 patients participated in the study (n = 58 in Lausanne, 52 in Geneva, and 54 in La Chaux-de-Fonds). The prevalence of methadone injection was low (5%) and did not differ significantly between the cities. DISCUSSION: Less liberal policies cannot explain the lower prevalence of methadone injection in these three centers than in Fribourg. The high prevalence of methadone injection there is probably related to its separate methadone injection program: patients in oral methadone programs may be more likely to injection methadone when other patients authorized to do so. IN CONCLUSION: Although the 5% prevalence of methadone injection found in the 3 cities surveyed is low, it is not negligible. These results suggest that information on the risks associated with injection of methadone syrup should be provided to all methadone maintenance. This information is especially necessary when maintenance therapy is provided in the same center, or city as injectable methadone maintenance.
