An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study.
BACKGROUND
Naltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the mu-opioid receptor gene (OPRM1), might predict naltrexone response.


OBJECTIVE
To evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone.


METHODS
Pharmacogenetic analysis conducted between January 1, 2001, and January 31, 2004.


METHODS
Eleven academic sites in the COMBINE Study.


METHODS
Recently abstinent volunteers who met all 3 of the following conditions: (1) DSM-IV criteria for primary alcohol dependence; (2) participation in the COMBINE Study; and (3) availability of DNA.


METHODS
Alcoholic subjects were treated for 16 weeks with 100 mg of naltrexone hydrochloride (234 Asn40 homozygotes and 67 with at least 1 copy of the Asp40 allele) or placebo (235 Asn40 homozygotes and 68 with at least 1 copy of the Asp40 allele). All participants received medical management (MM) alone or with combined behavioral intervention (CBI).


METHODS
Time trends in percentage of days abstinent, percentage of heavy drinking days, and rates of good clinical outcome.


RESULTS
Alcoholic subjects with an Asp40 allele receiving MM alone (no CBI) had an increased percentage of days abstinent (P = .07) and a decreased percentage of heavy drinking days (P = .04) if treated with naltrexone vs placebo, while those with the Asn40/Asn40 genotype showed no medication differences. If treated with MM alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of individuals with the Asn40/Asn40 genotype (odds ratio, 5.75; confidence interval, 1.88-17.54), while, if treated with placebo, 48.6% of Asp40 carriers and 54.0% of individuals with the Asn40/Asn40 genotype had a good clinical outcome (interaction between medication and genotype, P = .005). No gene x medication interactions were observed in those treated with both MM and CBI.


CONCLUSIONS
These results confirm and extend the observation that the functionally significant OPRM1 Asp40 allele predicts naltrexone treatment response in alcoholic individuals. This relationship might be obscured, however, by other efficacious treatments. OPRM1 genotyping in alcoholic individuals might be useful to assist in selecting treatment options.


BACKGROUND
clinicaltrials.gov Identifier: NCT00006206.
Anton
Raymond F
RF
Center for Drug and Alcohol Programs, Medical University of South Carolina, 67 President St, PO Box 250861, Charleston, SC 29425, USA. antonr@musc.edu
Oroszi
Gabor
G
O'Malley
Stephanie
S
Couper
David
D
Swift
Robert
R
Pettinati
Helen
H
Goldman
David
D
D000077443:Acamprosate; D000328:Adult; D000437:Alcoholism / Q000235:genetics* / Q000534:rehabilitation*; D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D001216:Asparagine / Q000235:genetics; D001224:Aspartic Acid / Q000235:genetics; D015928:Cognitive Behavioral Therapy; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D005260:Female; D006580:Genetic Carrier Screening; D005819:Genetic Markers / Q000235:genetics*; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000009:adverse effects / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000235:genetics*; D013654:Taurine / Q000031:analogs & derivatives / Q000627:therapeutic use; D013695:Temperance; D016896:Treatment Outcome
D005819:Genetic Markers; D009292:Narcotic Antagonists; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D013654:Taurine; D001224:Aspartic Acid; D009271:Naltrexone; D001216:Asparagine; D000077443:Acamprosate