At least part of the reason why patients with alcohol dependence
respond differently to naltrexone treatment appears to lie in a particular
variation in the opioid receptor gene known as OPRM1, according to a study in
the February 4 Archives of General
Researchers at the Medical University of South Carolina found a significant
link between a genetic polymorphism and the likelihood of good clinical
response to naltrexone treatment based on genetic and outcome data collected
in the multicenter, Combined Pharmacotherapies and Behavioral interventions
for alcohol Dependence (COMBINE) study.
The COMBINE study was funded by the National Institute on Alcohol Abuse and
Alcoholism and conducted from 2001 through 2004. Patients with diagnosed
alcoholism were treated with 100 mg of naltrexone or placebo for 16 weeks. The
authors analyzed the genetic data prospectively collected from 1,013
According to previous research, most people carry the Asn40 polymorphism
type of the OPRM1 gene on both of their chromosomes, which means that the
amino acid asparagine resides at position 40 in the receptor protein. Because
of a single nucleotide mutation, however, this amino acid may be substituted
with aspartate (Asp40). Previous research estimated that 15 percent to 25
percent of the human population carry at least one copy of the Asp40 allele,
and this slight change in the μ-opioid receptor protein may affect the
carrier's response to alcohol and pharmacologic treatment for alcoholism.
Naltrexone is an antagonist for several opioid receptors and binds
preferentially to the μ-opioid receptors. It is approved for the treatment
of alcoholism and has been shown to reduce alcohol-induced highs and alcohol
cravings. The drug's effect size over placebo is "in the small to
moderate range," the authors noted.
In the COMBINE study, naltrexone increased the percentage of days abstinent
and decreased the percentage of heavy-drinking days, compared with placebo,
among patients who carried at least one copy of the Asp40 allele. In those who
carried two copies of it, however, naltrexone was not significantly different
from placebo in these drinking-related outcomes. These differences were
statistically significant in participants who underwent brief
medical-management sessions, but not in those who received the more intense
and specific combined behavioral intervention (CBI). The behavioral
interventions may have obscured the interaction between genetics and
naltexone, the authors suggested.
Among the participants who carried at least one Asp40 allele, 87 percent of
those who took naltrexone had a good clinical outcome, defined as abstinence
or moderate drinking without problems, during the last eight weeks of the
treatment. In contrast, about 55 percent of those with two Asn40 alleles had
similar response to naltrexone. The difference was statistically significant.
The two genotypes responded to treatment without naltrexone in similar rates
around 50 percent.
The effect of genetic variations on the efficacy of naltrexone revealed in
this study "could have immense clinical importance," lead author
Raymond Anton, M.D., and colleagues said. For example, the development of anyμ
-opioid antagonist should also consider potential interaction with the
OPRM1 genetic variance. "We can't say for sure that all μ-opioid
antagonists will have this type of interaction, and perhaps they have slightly
different binding sites, kinetics, etc., but there is a high probability that
they will," Anton, a professor of psychiatry and director of the Center
for Drug and Alcohol Programs at the Medical University of South Carolina,
commented to Psychiatric News.
He cautioned that prospectively randomized studies based on genetic
variations are needed to confirm the interaction between this genetic
variation and naltrexone. In addition, "this finding is largely limited
to Caucasians; we could not explore African Americans, Hispanics, or Asians
independently [in the COMBINE study]," he said. At this point, he
recommended that clinicians and patients "weigh the evidence and decide
for themselves whether a genetic test should be performed prior to the
decision to use or not use naltrexone for alcohol treatment."
Genetic research has been quietly making its way into pharmacotherapy of
various diseases. Scientists have found specific gene variations that predict
who is more likely to experience certain effects from drugs, such as emerging
suicidal thoughts from selective serotonin reuptake inhibitors, excessive
bleeding with normal warfarin dosage, and severe skin reactions to
carbamazepine (Psychiatric News, January 18). The link between the
OPRM1 gene and naltrexone efficacy is another example of how genetic
variations explain why a drug helps some patients but not others.
An abstract of "An Evaluation of μ-Opioid Receptor
(OPRM1) as a Predictor of Naltrexone Response in the Treatment of Alcohol
Dependence" is posted at<http://archpsyc.ama-assn.org/cgi/content/abstract/65/2/135>.▪