AT THE AAP ANNUAL MEETING
AVENTURA, FLA. (FRONTLINE MEDICAL NEWS) – Treatment with naltrexone was associated with reductions in drinking over 3 months in a study of alcohol-dependent adults, but whether these individuals had a polymorphism that has been associated with better responses to the drug in previous studies did not affect outcomes, Dr. David W. Oslin reported at the annual meeting of the American Academy of Addiction Psychiatry.
“We did not find that naltrexone … was moderated by genotype in this prospective trial,” said Dr. Oslin, professor of medicine at the University of Pennsylvania, Philadelphia.
Naltrexone, an opioid antagonist approved by the Food and Drug Administration for treating alcohol dependence, acts principally on the mu opioid receptor.
Various types of studies have shown that the Asp40 allele on the OPRM1, the gene that encodes for the mu-opioid receptor, is functionally active and might predict response to treatment with naloxone, Dr. Oslin said. Studies have found that individuals with the Asp40 allele had better responses to naloxon. A preliminary study led by Dr. Oslin found that those who had one or two copies of the Asp40 allele had significantly lower relapse rates and a longer time to return to heavy drinking than did those who had only the Asn40 allele ( Neuropsychopharmacology 2003;28:1546-52 ). A meta-analysis of observational clinical studies of patients treated with naltrexone found that those patients with the Asp40 allele were twice as likely not to relapse than were those who were homozygous for the Asn40 allele.
In another study, the COMBINE trial, which found a “robust” effect of treatment with naloxone over placebo among those with the Asp40 allele, “naltrexone seemed to be moderated by the presence of the Asp40 allele,” with “essentially no effect” of naltrexone in the homozygous (Asn40/Asn40) group, he noted Arch Gen Psychiatry 2008;65:135-44) . In all these studies, Dr. Oslin pointed out that genotyping was performed retrospectively.
But in the study he presented, genotyping was performed as part of the study, a prospective, double-blind, placebo-controlled study of 221 alcohol-dependent adults, mostly men (mean age 46-51 years). Most had undergone addiction treatment previously. Patients with one or two copies of the Asp40 allele and those who were homozygous for the Asn40 allele were randomized to naloxone 50 mg a day or placebo and the primary outcome measured was relapse to heavy drinking during treatment.
In the group overall, there was a “moderate to small” effect of naltrexone on the primary outcome over 12 weeks of treatment, but no statistically significant differences on responses by genotype, Dr. Oslin said. There was also no effect of genotype on craving, abstinence, or percent days of drinking, or any drinking.
Some differences in adverse events were found by genotype: Among those with the Asn40 allele, fatigue, nausea, sensory problems, and upper respiratory infections were more for those who received naloxone than for those who received placebo. Among those with the Asp40 allele, nausea and upper GI problems were more common for those on naltrexone than for those on placebo. Adverse events were slightly more common in the N/ASP40 group, he said.
Overall, the results of the study supported a moderate effect of naltrexone, similar to that seen in previous studies, but the lack of a genotype effect is not an indication it does not exist, Dr. Oslin said.
As to why the results were not what they expected, he speculated that age could be an explanation and that “the Asp40 dopamine release cascade may be more relevant “on cravings in younger people with alcohol dependence. The individuals in this study were in their 40s and 50s on average, most had been alcoholics for years, and they had more severe addictions to drinking than in some of the other studies, so “the dopamine response to craving may not be as relevant.”
While the study does not indicate that this single nucleotide polymorphism is not “robustly functional,” based on the current literature, it “doesn’t add to our clinical management” at this time, Dr. Oslin said. “We are in our infancy really in understanding how genetics influences treatment.”
The study received funding from the National Institutes of Health and the Department of Veterans Affairs. Dr. Oslin and five coinvestigators reported no conflicts; another investigator received funding from Alkermes at the time of the grant as a consultant on depot naltrexone.
