The efficacy of naltrexone in treating alcohol use disorder is increased in nicotine users, according to a randomized clinical trial follow-up report that confirmed researchers’ previous hypotheses regarding predictors of naltrexone effectiveness, as reported in Alcoholism: Clinical and Experimental Research. Smoking was found to be a better predictor of efficacy than the single nucleotide polymorphism (SNP) OPRM1 A118G, which was initially identified for this purpose.

There has been much variability in the capacity for pharmacological treatments to help curb alcoholism, and the research community has remained interested in determining specific factors that may predict the efficacy of treatments such as naltrexone.

While the SNP OPRM1 A118G has demonstrated some predictive value, results have been inconsistent, with some believing that smoking status could prove a stronger predictor of naltrexone response than the OPRM1 allele. However, this relationship had yet to be comprehensively evaluated. The fact that nicotine use is considerably higher in alcoholics compared with the general population also made smokers an ideal target for assessing naltrexone effectiveness.

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The primary outcome in this study ( Identifier: NCT00920829) was percent of heavy drinking days per month, with drinks per day and percent of days drinking serving as secondary outcomes.  Percent change in disialo carbohydrate-deficient transferrin (%dCDT), an independent biomarker of alcohol use, was used to confirm participants’ verbal reports of alcohol consumption patterns. In the original 16-week trial, 146 individuals (69.2% men) meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for alcohol use disorder were randomized by SNP genotype as well as nicotine use and then assigned to either naltrexone 50 mg/d or placebo.

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In patients taking naltrexone who also used nicotine, there was a significant interaction between naltrexone and nicotine in decreasing percent of heavy drinking days (P =.003) throughout the trial. Smokers demonstrated significantly reduced percent of heavy drinking days on naltrexone vs placebo (P =.0001, Cohen’s d =0.89), while non-smokers exhibited no difference between treatments (P =.95, d =0.02). The team saw similar results in reduction of percent of days drinking for nicotine users on naltrexone (P =.016, d =0.62) vs non-users (P =.34, d =-0.19), as well as drinks per day reduction in smokers (P =.0001, d =0.72) vs non-smokers (P =.94, d =0.02). The %dCDT also paralleled these reported percent of heavy drinking days reductions in nicotine users taking naltrexone (d range, 0.3 to 0.9), thus confirming the superior efficacy of naltrexone vs placebo in smokers with alcohol use disorder.

The investigators noted several study limitations, including the lack of initial stratification by nicotine use, unequal numbers of nicotine users and non-users, lack of further characterization of nicotine dependence level, and lack of daily nicotine use patient recordings or urine cotinine level confirmation.

These findings should serve as confirmation of earlier hypotheses that nicotine may indeed be a more useful predictor of naltrexone response in individuals with alcohol use disorder compared with genetic factors such as the OPRM1 SNP previously identified.

For clinicians, this may impact the choice of patients as candidates for naltrexone-aided alcohol intake reduction based on their status as nicotine users.

Disclosures: Dr Anton has been a consultant for Alkermes, Eli Lilly, Novartis, Lundbeck, Glaxo Smith Kline, Roche, Techmira, Indivior, and Laboratorio Farmaceutico CT. He also received grant funding from Eli Lilly. He is a chair and participant in the Alcohol Clinical Trials Initiative (ACTIVE) that has received support from Abbvie, Alkermes, Amygdala, Arbor, Ethypharm, Glaxo Smith Kline, Indivior, Janssen, Eli Lilly, Lundbeck, Otsuka, Pfizer, and Schering. Dr Schacht has been a consultant for Laboratorio Farmaceutico CT. All other authors report no biomedical conflict of interests.


Anton RF, Latham PK, Voronin KE, et al. Nicotine-use/smoking is associated with the efficacy of naltrexone in the treatment of alcohol dependence [published February 12, 2018]. Alcohol Clin Exp Res. doi:10.1111/acer.13601