title: [A pharmacogenetic analysis of dopaminergic and opioidergic genes in opioid addicts treated with the combination of naltrexone and guanfacine].
abstract: OBJECTIVE
  To evaluate an effect of opioid receptor and dopamine system gene polymorphisms on the efficacy of combined treatment with oral naltrexone and guanfacine in a randomized double blinded double dummy placebo controlled clinical trial.
  
  
  METHODS
  Three hundred and one patients with opioid dependence were randomized into 4 treatment groups: naltrexone 50 mg/day + guanfacine 1 mg/day (N+G); naltrexone + placebo guanfacine (N+GP); placebo naltrexone + guanfacine (NP+G); double placebo (NP+GP). The primary outcome was treatment retention. All enrolled participants were genotyped for polymorphisms in the following genes: mu- (OPRM1), kappa-opioid receptors (OPRK1), catechol-O-methyltransferase (COMT), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase, and dopamine transporter (SLC6A3, DAT1) and alpha-2-adrenoreceptor (ADRA2A) a pharmacological target of guanfacine.
  
  
  RESULTS
  The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone monotherapy. Regardless of treatment, several gene polymorphisms were associated with higher chance to complete the treatment program: allele Т DRD4 - 521 С/Т (rs1800955) (р=0.039; OR (95% CI)=3.7 (1.1-12.7); log-rank test: р=0.01); allele С DRD2 С957Т (rs6277) (р=0.03; HR=0.6 (0.34-0.95); genotype combination: DRD4 VNTR (LL) + OPRM1 A118G (rs1799971) (AA), р=0.051; DRD2 C957T (ТТ) + OPRM1 (rs1074287) (СС), р=0.025; DRD2 - 141С (II) + OPRM1 (rs510769) (АА), р=0.035; DBH Fau(СС) + OPRM1 (rs1074287) (СС), р=0.0497. Regardless of treatment several polymorphisms were associated with high risk of relapse: allele Т (rs510769) OPRM1 (р=0.053), allele А (rs1799971, A118G) OPRM1 (р=0.056), allele S exon III 48 bp DRD4 VNTR (р=0.001; HR=3.1 (ДИ 95% 1.57-6.18); genotype combinations: DRD4 - 521 С/Т (ТТ) + DRD2 Nco I (TT), р=0.026; DRD4 -521 С/Т (ТТ) + DRD2 -141 С (II), р=0.011; DRD4 - 521 С/Т (ТТ) + OPRM1 A118G (rs1799971) (AA), р=0.011; DRD2 Nco I(ТТ) + ADRA2A (СС), р=0.012; DRD2 Nco I(ТТ) + OPRM1 A118G (AA), р=0.02. The effects dependent on the treatment group were as follows: 1) in the N+G group, patients with the DRD4 -521 С/Т TT genotype had higher probability of completion of treatment program in comparison with other genotypes (CC and CT) (log-rank test: p=0.002); 2) in NP + GP group, patients with the OPRM1 rs510769 T allele had higher risk of relapse compared to the genotype GG (p=0.008) (FDR p<0.0125).
  
  
  CONCLUSIONS
  The additive effect of opioid receptor genes and dopaminergic system genes on outcomes of treatment opioid dependence with oral naltrexone and guanfacine was shown. Pharmacological effects of naltrexone and guanfacine were associated with genetic variants of the DRD4 - 521C/T polymorphism, since its effect was shown only in the N+G group. The effect of the OPRM1 rs510769 polymorphism was demonstrated in the double placebo group that was associated with personality traits (temperament, character) and determined compliance. Genetic analysis is useful for determining potential responders to treatment of opioid dependence; genotyping can increase the efficacy of pharmacotherapy.
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: А О
authors.initials: АО
authors.lastname: Kibitov
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: Е М
authors.initials: ЕМ
authors.lastname: Krupitsky
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: Е А
authors.initials: ЕА
authors.lastname: Blokhina
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: Е V
authors.initials: ЕV
authors.lastname: Verbitskaya
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: V М
authors.initials: VМ
authors.lastname: Brodyansky
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: N P
authors.initials: NP
authors.lastname: Alekseeva
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: N М
authors.initials: NМ
authors.lastname: Bushara
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: Т S
authors.initials: ТS
authors.lastname: Yaroslavtseva
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: V Yа
authors.initials: VY
authors.lastname: Palatkin
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: D V
authors.initials: DV
authors.lastname: Masalov
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: А М
authors.initials: АМ
authors.lastname: Burakov
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: Т N
authors.initials: ТN
authors.lastname: Romanova
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: G Yu
authors.initials: GY
authors.lastname: Sulimov
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: A Yа
authors.initials: AY
authors.lastname: Grinenko
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: Т
authors.initials: Т
authors.lastname: Kosten
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: D
authors.initials: D
authors.lastname: Nielsen
authors.affiliation: Pavlov First St.Petersburg State Medical University, St.Petersburg, Bekhterev St.Petersburg Research Psychoneurilogical Institute, St.Petersburg, Serbsky Federal Medical research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: E E
authors.initials: EE
authors.lastname: Zvartau
mesh_terms: D000483:Alleles; D000701:Analgesics, Opioid; D002394:Catechol O-Methyltransferase / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D005091:Exons; D014644:Genetic Variation; D005838:Genotype; D016316:Guanfacine / Q000627:therapeutic use*; D006801:Humans; D009271:Naltrexone / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D009293:Opioid-Related Disorders / Q000188:drug therapy / Q000235:genetics*; D000071185:Pharmacogenomic Testing; D011110:Polymorphism, Genetic; D017448:Receptors, Dopamine D2 / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics*
chemical_list: D000701:Analgesics, Opioid; C581293:DRD2 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D009292:Narcotic Antagonists; D017448:Receptors, Dopamine D2; D017450:Receptors, Opioid, mu; C493214:SLC6A3 protein, human; D016316:Guanfacine; D009271:Naltrexone; D004299:Dopamine beta-Hydroxylase; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase