Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol dependence: results from the VA Cooperative Study.
BACKGROUND
Pharmacotherapy of alcohol dependence (AD) is at an early stage of development; currently available medications have limited efficacy. It would be clinically valuable to identify, before initiation of a course of treatment, those patients who, based on genetic markers, are most likely to respond to a specific pharmacotherapy. A previous report suggested that a functional variant at the genetic locus encoding the mu opioid receptor (Asn40Asp) is such a marker, in short-term (3-month) treatment with the opioid-blocking drug naltrexone (NTX).


METHODS
We studied polymorphic variants at each of the 3 opioid receptor genes--OPRM1, OPRD1, and OPRK1, which encode the mu, delta, and kappa opioid receptors, respectively--including the OPRM1 Asn40Asp variant--as predictors of response to NTX or placebo in 215 alcohol-dependent male subjects who participated in Veterans Affairs Cooperative Study 425, "Naltrexone in the Treatment of Alcohol Dependence."


RESULTS
At the 3-month time point, treatment condition, age, and the pretreatment number of drinks per drinking day were all significant (p<0.05) predictors of the rate of relapse and time to relapse. Although NTX had no significant effect on relapse to heavy drinking in the overall sample in CSP 425, it significantly reduced relapse in the subgroup that provided DNA for analysis (i.e., the present study sample). There were no significant interactions between any individual single nucleotide polymorphisms studied and NTX treatment response.


CONCLUSIONS
These results do not support association of the OPRM1 Asn40Asp polymorphism with NTX treatment response for AD.
Gelernter
Joel
J
VA Connecticut Healthcare System, West Haven Campus, West Haven, Connecticut 06516, USA. joel.gelernter@yale.edu
Gueorguieva
Ralitza
R
Kranzler
Henry R
HR
Zhang
Huiping
H
Cramer
Joyce
J
Rosenheck
Robert
R
Krystal
John H
JH
D000328:Adult; D000437:Alcoholism / Q000188:drug therapy* / Q000235:genetics*; D016001:Confidence Intervals; D004247:DNA / Q000235:genetics; D004311:Double-Blind Method; D005091:Exons / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D016017:Odds Ratio; D016016:Proportional Hazards Models; D011569:Psychiatric Status Rating Scales; D017465:Receptors, Opioid, delta / Q000235:genetics*; D017473:Receptors, Opioid, kappa / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000235:genetics*; D012907:Smoking / Q000453:epidemiology / Q000235:genetics; D016896:Treatment Outcome; D014481:United States; D014493:United States Department of Veterans Affairs
D009292:Narcotic Antagonists; C515653:OPRK1 protein, human; C485764:OPRM1 protein, human; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D004247:DNA