title: Methadone dose in heroin-dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity.
abstract: OBJECTIVE
  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.
authors.affiliation: Inserm, U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S1144, Paris, F-75006, France.|Université Paris Diderot, UMR-S1144, Paris, F-75010, France.|Unit of Therapeutic Research & Internal Medicine Department, Lariboisière-Saint Louis Hospital, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mouly
authors.affiliation: Inserm, U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S1144, Paris, F-75006, France.|Université Paris Diderot, UMR-S1144, Paris, F-75010, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bloch
authors.affiliation: Inserm, U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S1144, Paris, F-75006, France.|Université Paris Diderot, UMR-S1144, Paris, F-75010, France.|Laboratory of Biochemistry and Molecular Biology, Lariboisière-Saint Louis Hospital, Paris, France.
authors.forename: Katell
authors.initials: K
authors.lastname: Peoc'h
authors.affiliation: Laboratory of Pharmacology, Lariboisière-Saint Louis Hospital, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Houze
authors.affiliation: Inserm, U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S1144, Paris, F-75006, France.|Université Paris Diderot, UMR-S1144, Paris, F-75010, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Labat
authors.affiliation: Psychiatric Unit, Assistance Publique-Hôpitaux de Paris (APHP), Lariboisière-Saint Louis Hospital, Paris, France.
authors.forename: Kamilia
authors.initials: K
authors.lastname: Ksouda
authors.affiliation: Unit of Therapeutic Research & Internal Medicine Department, Lariboisière-Saint Louis Hospital, Paris, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Simoneau
authors.affiliation: Inserm, U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S1144, Paris, F-75006, France.|Université Paris Diderot, UMR-S1144, Paris, F-75010, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.affiliation: Inserm, U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S1144, Paris, F-75006, France.|Université Paris Diderot, UMR-S1144, Paris, F-75010, France.|Unit of Therapeutic Research & Internal Medicine Department, Lariboisière-Saint Louis Hospital, Paris, France.
authors.forename: Jean Francois
authors.initials: JF
authors.lastname: Bergmann
authors.affiliation: Inserm, U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S1144, Paris, F-75006, France.|Université Paris Diderot, UMR-S1144, Paris, F-75010, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.affiliation: Inserm, U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S1144, Paris, F-75006, France.|Université Paris Diderot, UMR-S1144, Paris, F-75010, France.|Laboratory of Biochemistry and Molecular Biology, Lariboisière-Saint Louis Hospital, Paris, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Laplanche
authors.affiliation: Inserm, U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S1144, Paris, F-75006, France.|Université Paris Diderot, UMR-S1144, Paris, F-75010, France.|Psychiatric Unit, Assistance Publique-Hôpitaux de Paris (APHP), Lariboisière-Saint Louis Hospital, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Lepine
authors.affiliation: Inserm, U1144, Paris, F-75006, France.|Université Paris Descartes, UMR-S1144, Paris, F-75006, France.|Université Paris Diderot, UMR-S1144, Paris, F-75010, France.|Psychiatric Unit, Assistance Publique-Hôpitaux de Paris (APHP), Lariboisière-Saint Louis Hospital, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Vorspan
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001711:Biotransformation / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000009:adverse effects; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D016903:Drug Monitoring; D055030:Drug Users; D005006:Ethnicity; D005260:Female; D005602:France / Q000453:epidemiology; D005787:Gene Frequency; D005838:Genotype; D006556:Heroin Dependence / Q000188:drug therapy* / Q000201:enzymology / Q000208:ethnology / Q000235:genetics; D006801:Humans; D007422:Intestines / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008691:Methadone / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D016017:Odds Ratio; D058850:Opiate Substitution Treatment; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019338:Polypharmacy; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D000701:Analgesics, Opioid; D065692:Cytochrome P-450 CYP3A Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008691:Methadone
keywords: concomitant medication; maintenance dose; methadone; pharmacogenetics; steady state