These data, from the large and well-controlled multisite COMBINE Study, support and extend evidence that the reportedly functional OPRM1
Asn40Asp substitution, altering β-endorphin binding to the receptor, influences treatment response to naltrexone among alcoholic patients. In the main COMBINE Study trial,7
naltrexone showed efficacy compared with placebo only in patients not receiving CBI therapy. Therefore, we had hypothesized that the MM-alone (no CBI) group would most likely show a gene × medication interaction. In the COMBINE Study, CBI, a more intensive and specific alcohol intervention, may have compensated for the placebo effect, thereby suppressing the chances of observing a main effect of naltrexone or a genetic interaction. The data presented herein are consistent with this thinking. A gene×medication interaction may be observable only in patients who can show obvious benefit from the medication over placebo. External influences, such as alcoholism severity, psychosocial instability, other illnesses, and the use of an effective adjunctive treatment (in this case, CBI), might all obscure meaningful biological effects of genes on which a specific medication can act. In our case, the MM-alone (no CBI) condition enabled enough interindividual variability in clinical response for both the naltrexone7
and the naltrexone×gene interaction to emerge.
Oslin and colleagues29
previously reported in a retrospective analysis of several disparate studies that naltrexone reduced relapse drinking after controlling for therapy, age (>55 years), sex, and marital status, and including only patients who received at least 5 weeks of treatment. The analysis presented in that report suggested a naltrexone×gene interaction on 1 outcome variable (relapse to a day of heavy drinking) in 141 subjects (42 with an Asp40 allele). Nevertheless, using somewhat different and more complex drinking and outcome variables, we have replicated and extended their initial observations. More recently, Gelernter and colleagues,31
in a reanalysis of the Veterans Affairs Naltrexone Cooperative Study,30
did not find a significant gene×naltrexone interaction on relapse drinking. Interestingly, they did report a main effect of naltrexone, which was not observed in the initial intent-to-treat analysis. The reasons for these discrepancies are not obvious, but the authors speculate that individuals who provided genetic samples may have been more motivated, more adherent to the medication regimen, and, perhaps, more socially stable than those who did not, leading to a more favorable naltrexone response in those subjects. The lack of an observable naltrexone×gene interaction in their hands is difficult to reconcile with the favorable data of Oslin et al29
and the data reported herein. However, the COMBINE Study used a naltrexone hydrochloride dosage of 100 mg/d, as did 2 of the 3 studies in the report by Oslin et al,29
while the Veterans Affairs Naltrexone Cooperative Study30
used a standard 50-mg/d dosage. It is unknown whether this could alter the treatment interaction with the Asp40 allele. It is also important that we observed that the gene×naltrexone interaction emerges over time, consistent with the antireinforcement effects of naltrexone. This is particularly evident in a reduction in heavy drinking days over time, consistent with previous observations on naltrexone's action.59
Therefore, various outcome variables and time effects may need to be considered to completely appreciate gene×medication interactions in the treatment of alcohol dependence.
Despite several reports suggesting that Asp40 carriers may respond differently to alcohol, prestudy drinking and alcoholism severity in our study did not differ between alcoholic subjects with and without Asp40. This is in contrast to a Korean study in which homozygous Asp40 carriers had higher levels of pretreatment drinking.60
Finally, although we did not perform a case-control study, the Asp40 and Asn40 allele frequencies observed in our alcoholic subjects are similar to allele frequencies in population studies, suggesting no major effect of the Asp40 allele on the development of alcoholism or its severity.
Our data speak most clearly to the interaction of the OPRM1 genotype and naltrexone. While the strength of this interaction leading to differential treatment efficacy might be surprising in view of the clinical diversity, different neurobiologic origins of vulnerability, and genetic heterogeneity of alcoholism, naltrexone is a unique medication engineered for specificity of action at the μ-opioid receptor, although it also binds to δ- and κ-opioid receptors. Therefore, either a direct effect on μ-opioid receptor function or a shift in balance between μ-opioid and δ- and κ-opioid receptor function caused by the OPRM1 genetic variant might form the basis of naltrexone's therapeutic action. This may not be as clear for medications that lack such specificity of action.
The increased naltrexone response in Asp40 carriers could have immense clinical importance, especially because, in our population, noncarriers (Asn40 homozygotes) responded no better than if given placebo. In our hands, and in the context of MM, the odds of a good clinical outcome with naltrexone were 5 times better in Asp40 carriers than noncarriers. Because almost 25% of the treatment-seeking population carries the Asp40 allele, genetic testing of individuals before naltrexone treatment might be worth the cost and effort, especially if structured behavioral treatment were not being considered. Given that alternative treatments such as CBI,7
can be offered, one could make the case that naltrexone should be used first, or primarily, in OPRM1
Asp40 allele carriers. Naltrexone is relatively easy to administer and free of serious adverse effects and, as we observed in the Asp40 carriers we studied, it appears to be highly effective.
Future reports from this study will evaluate whether other more extensive genotyping (other single-nucleotide polymorphisms and haplotypes) of the OPRM1 gene might lead to improved prediction of naltrexone response, adverse events, or other salient clinical information.
There are a number of limitations of this study. Although genetic samples were obtained to examine this and other treatment-related issues, subjects were not randomized by OPRM1 genotype. It is possible that consent for the substudy differed by genotype because some subjects (about 27%) either completed or dropped out of the study before genetic consent and an additional 10% of the remaining had nonusable DNA. Although key variables seem to be equally distributed between patients with and without the Asp40 allele, it is possible that some other genetic/nongenetic influence biased responding. Also, the numbers of Asp40 carriers were somewhat limited, especially in the MM-only cells. However, confluence of effect across drinking variables, along with the consistency of the observation of naltrexone response in the subgroup that also showed a naltrexone effect in the main trial, argues against a spurious result. Nevertheless, the foregoing caveats suggest that these results be replicated in a prospective trial where individuals are initially randomized by OPRM1 Asp40 status.
In addition, because the numbers of different racial/ethnic minorities were relatively low, we could not directly assess the effect of the allele differences in these subgroups. However, adding individuals of African American and Hispanic origin into the analysis did not change the directionality of the main finding that naltrexone improved clinical global outcome primarily in Asp40 carriers. Future studies might want to consider this issue more thoroughly. In addition, we did not separately explore the effects of acamprosate. However, acamprosate did not demonstrate efficacy or added benefits to naltrexone in the main COMBINE Study trial.7
Also, acamprosate is thought to be a glutamate modulator and would not be expected to show differential efficacy based on changes in the μ-opioid receptor.
In summary, in alcoholic individuals who received naltrexone in the context of MM (the most purely pharmacologic condition studied), there was a greater response and improvement if a person had at least 1 copy of the OPRM1 Asp40 allele. This finding could have considerable theoretical importance for drug development (such as studying only Asp40 carriers during opioid antagonist development) and also for selectively targeting μopioid antagonist medications and other treatments for alcohol-dependent individuals.