Does OPRM1 asp40 Allele Status Influence Naltrexone Response? Results From a Prospective Randomized Clinical Trial

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Anton RF, Book S, Latham P, Randall P, Voronin K

Alcohol Research Center, Addiction Sciences Division, Dept. of Psychiatry, Medical University of South Carolina, Charleston, SC 29401 USA

Purpose: There is growing interest in “personalized” treatment of AUD with naltrexone. Whether OPRM1 asp40 allele status influences naltrexone response is controversial, with retrospective studies being positive (Oslin 2003, Anton 2008) and one prospective study reportedly negative (Oslin 2015). Other studies, such as the COMBINE Study (Fucito 2012), suggest that smoking status influences naltrexone response. Data from a prospective clinical trial examining these issues will be presented.

Methods: 146 alcohol dependent individuals (DSM IV) with a mean 80% heavy drinking days (HDD) were randomized to naltrexone (50mg) or placebo, based on their OPRM1 allele status (asp40 vs. asn40 homozygotes – taqman PCR) on a one to one basis in a blinded fashion to produce a 2 medication X 2 OPRM1 gene design. Smoking (40%), antidepressant use (33%), and sex (30% Female) were equally distributed across groups. Nine sessions of Medical Management (wks. 1,2,3,4,6,8,10,12,16) were provided and drinking assessed by TLFB during the 16-week treatment and up to 4 months later.

Results: Study completers (73%) and complete drinking data (86%) did not differ across groups. While there was a main effect of naltrexone over placebo in lower %HDD over the trial (p=0.003), only during the last treatment-month did OPRM1 asp40, but not asn40, subjects have less %HDD if treated with naltrexone (p=0.04). Once treatment ended, asp40 individuals had accelerated %HDD – not seen in other groups (p= 0.015). Naltrexone was most effective in smokers (med. x smoking status x time p=0.043).

Conclusion: While naltrexone reduced %HDD overall, OPRM1 asp40 effects emerged only at the end of the trial. Also, those asp40 individuals treated with naltrexone had accelerating %HDD once medication was stopped – an effect not observed in other groups. These data suggest that the OPRM1 asp40 influence on naltrexone response might take time to emerge, something observed in the COMBINE Study (Anton 2008), and importantly asp40 individuals might need prolonged treatment. The superior effect of naltrexone in smokers is also consistent with previous results from the COMBINE Study (Fucito 2012). Limitations include low power for determining the interaction of OPRM1 genotype and smoking on naltrexone response.

Supported by NIAAA R01AA017633 and K05AA017435

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