The Glycosylation of AGP and Its Associations with the Binding to Methadone.

Biomed Res Int. 2013; 2013: 108902
Behan JL, Cruickshank YE, Matthews-Smith G, Bruce M, Smith KD

Methadone remains the most common form of pharmacological therapy for opioid dependence; however, there is a lack of explanation for the reports of its relatively low success rate in achieving complete abstinence. One hypothesis is that in vivo binding of methadone to the plasma glycoprotein alpha-1-acid glycoprotein (AGP), to a degree dependent on the molecular structure, may render the drug inactive. This study sought to determine whether alterations present in the glycosylation pattern of AGP in patients undergoing various stages of methadone therapy (titration < two weeks, harm reduction < one year, long-term > one and a half years) could affect the affinity of the glycoprotein to bind methadone. The composition of AGP glycosylation was determined using high pH anion exchange chromatography (HPAEC) and intrinsic fluorescence analysed to determine the extent of binding to methadone. The monosaccharides galactose and N-acetyl-glucosamine were elevated in all methadone treatment groups indicating alterations in AGP glycosylation. AGP from all patients receiving methadone therapy exhibited a greater degree of binding than the normal population. This suggests that analysing the glycosylation of AGP in patients receiving methadone may aid in determining whether the therapy is likely to be effective.
HubMed – Methadone

Hepatitis C virus infection influences the s-methadone metabolite plasma concentration.

PLoS One. 2013; 8(7): e69310
Wu SL, Wang SC, Tsou HH, Kuo HW, Ho IK, Liu SW, Hsu YT, Chang YS, Liu YL

Heroin-dependent patients typically contract hepatitis C virus (HCV) at a disproportionately high level due to needle exchange. The liver is the primary target organ of HCV infection and also the main organ responsible for drug metabolism. Methadone maintenance treatment (MMT) is a major treatment regimen for opioid dependence. HCV infection may affect methadone metabolism but this has rarely been studied. In our current study, we aimed to test the hypothesis that HCV may influence the methadone dosage and its plasma metabolite concentrations in a MMT cohort from Taiwan.A total of 366 MMT patients were recruited. The levels of plasma hepatitis B virus (HBV), HCV, human immunodeficiency virus (HIV) antibodies (Ab), liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were measured along with the urine morphine concentration and amphetamine screening.Of the 352 subjects in our cohort with HCV test records, 95% were found to be positive for plasma anti-HCV antibody. The liver functional parameters of AST (Wilcoxon Rank-Sum test, P?=?0.02) and ALT (Wilcoxon Rank-Sum test, P?=?0.04), the plasma methadone concentrations (Wilcoxon Rank-Sum test, P?=?0.043) and the R-enantiomer of methadone concentrations (Wilcoxon Rank-Sum test, P?=?0.032) were significantly higher in the HCV antibody-positive subjects than in the HCV antibody-negative patients, but not the S-EDDP/methadone dose ratio. The HCV levels correlated with the methadone dose ([Formula: see text]?=?14.65 and 14.13; P?=?0.029 and 0.03) and the S-EDDP/methadone dose ratio ([Formula: see text]?=?-0.41 and -0.40; P?=?0.00084 and 0.002) in both univariate and multivariate regression analyses.We conclude that HCV may influence the methadone dose and plasma S-EDDP/methadone dose ratio in MMT patients in this preliminary study.
HubMed – Methadone

Differential effects of methadone and buprenorphine on the response of D2/D3 dopamine receptors in adolescent mice.

Drug Alcohol Depend. 2013 Aug 8;
Barwatt JW, Hofford RS, Emery MA, Bates ML, Wellman PJ, Eitan S

There is a lack of studies that examine the effects of opioid maintenance drugs on the developing adolescent brain, limiting the ability of physicians to conduct a science-based risk assessment on the appropriateness of these treatments for that age group. Our recent observations indicate higher potential risks in repeated exposure to morphine during adolescence, specifically to the D2/D3 dopamine receptors’ signaling. Disturbances in dopaminergic signaling could have broader implications for long-term mental health. Thus, this study examined whether buprenorphine and methadone differentially alter the responses of the D2/D3 dopamine receptors in adolescents.Adolescent mice were orally administered buprenorphine (0.1-0.4mg/kg), methadone (25-100mg/kg), or saline once daily for 6 days. Two hours or three days later, the mice were tested for their locomotor response to 10mg/kg quinpirole, a D2/D3 dopamine receptor agonist.Buprenorphine-treated adolescent mice did not significantly differ from control drug-naïve animals in their response to quinpirole. However, an enhanced response was observed in methadone-treated adolescent animals. This enhanced locomotion was significantly higher two hours following the final dose of methadone, as compared to three days afterwards.This study suggests that exposure to various opioids carries differential probabilities of altering the highly sensitive neurochemistry of adolescent brains. Methadone exposure disturbs the D2-like receptor’s response, indicating a potential risk in administering methadone to adolescents (either for the treatment of opioid dependency/abuse or for pain management). In contrast, buprenorphine appears to have a significantly lower effect on the behavioral sensitivity of D2/D3 dopamine receptors in adolescents.
HubMed – Methadone

The long-term outcomes of heroin dependent-treatment-resistant patients with bipolar 1 comorbidity after admission to enhanced methadone maintenance.

J Affect Disord. 2013 Aug 6;
Maremmani AG, Rovai L, Bacciardi S, Rugani F, Pacini M, Paolo Pani P, Osso LD, Akiskal H, Maremmani I

The aim of this study was to compare the long-term outcomes of treatment-resistant bipolar 1 heroin addicts with peers who were without DSM-IV axis I psychiatric comorbidity (dual diagnosis).104 Heroin-dependent patients (TRHD), who also met criteria for treatment resistance – 41 of them with DSM-IV-R criteria for Bipolar 1 Disorder (BIP1-TRHD) and 63 without DSM-IV-R axis I psychiatric comorbidity (NDD-TRHD) – were monitored prospectively (3 years on average, min. 0.5, max. 8) along a Methadone Maintenance Treatment Programme (MMTP).The rates for survival-in-treatment were 44% for NDD-TRHD patients and 58% for BIP1-TRHD patients (p=0.062). After 3 years of treatment such rates tended to become progressively more stable. BIP1-TRHD patients showed better outcome results than NDD-TRHD patients regarding CGI severity (p<0.001) and DSM-IV GAF (p<0.001). No differences were found regarding urinalyses for morphine between groups during the observational period. Bipolar 1 patients needed a higher methadone dosage in the stabilization phase, but this difference was not statistically significant.The observational nature of the protocol, the impossibility of evaluating a follow-up in the case of the patients who dropped out, and the multiple interference caused by interindividual variability, the clinical setting and the temporary use of adjunctive medications.Contrary to expectations, treatment-resistant patients with bipolar 1 disorder psychiatric comorbidity showed a better long-term outcome than treatment-resistant patients without psychiatric comorbidity. HubMed – Methadone

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