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Original Investigation |

Association of the Sweet-Liking Phenotype and Craving for Alcohol With the Response to Naltrexone Treatment in Alcohol Dependence A Randomized Clinical Trial ONLINE FIRST

James C. Garbutt, MD1,2; Alexey B. Kampov-Polevoy, MD, PhD1,2; Linda S. Kalka-Juhl, MEd1; Robert J. Gallop, PhD3
[+] Author Affiliations
1Department of Psychiatry, University of North Carolina at Chapel Hill
2Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill
3Applied Statistics Program, Department of Mathematics, West Chester University, West Chester, Pennsylvania
JAMA Psychiatry. Published online September 14, 2016. doi:10.1001/jamapsychiatry.2016.2157
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Importance  Identification of moderators of the response to naltrexone hydrochloride treatment for alcohol dependence could improve clinical care for patients with alcohol use disorders.

Objective  To investigate the preliminary finding that the sweet-liking (SL) phenotype interacts with a high level of craving for alcohol and is associated with an improved response to naltrexone in alcohol dependence.

Design, Setting, and Participants  This 12-week double-blind, randomized, placebo-controlled clinical trial was conducted from February 1, 2010, to April 30, 2012, in an academic outpatient medical center. Eighty actively drinking patients were randomized by the SL (n = 22) or the sweet-disliking (SDL) (n = 58) phenotype and by pretreatment high (n = 40) or low (n = 40) craving for alcohol, with high craving defined as greater than the median. Patients and staff were blinded to categorization. Patients were excluded for unstable medical or psychiatric illness, including dependence on drugs other than nicotine. Four patients (2 in the placebo arm and 2 in the naltrexone arm) stopped medication therapy because of adverse effects. Data were analyzed from January 15, 2013, to May 15, 2016, based on intention to treat.

Interventions  Oral naltrexone hydrochloride, 50 mg/d, or daily placebo with weekly to biweekly brief counseling.

Main Outcomes and Measures  The a priori hypothesis tested SL/SDL phenotype, pretreatment craving, and their interaction as moderators of frequency of abstinent and heavy drinking days during treatment, assessed with the timeline follow-back method.

Results  Eighty patients were randomized (57 men [71%]; 23 women [29%]; mean [SD] age, 47.0 [8.6] years). A nonsignificant effect of naltrexone on heavy drinking was noted (4.8 fewer heavy drinking days; Cohen d = 0.45; 95% CI, −0.01 to 0.90; F1,67 = 3.52; P = .07). The SL phenotype moderated the effect of naltrexone on heavy drinking (6.1 fewer heavy drinking days; Cohen d = 0.58; 95% CI, 0.12-1.03; F1,67 = 5.65; P = .02) and abstinence (10.0 more abstinent days; Cohen d = 0.57; 95% CI, 0.11-1.02; F1,67 = 5.36; P = .02), and high craving moderated heavy drinking (7.1 fewer heavy drinking days; Cohen d = 0.66; 95% CI, 0.20-1.11; F1,67 = 7.37; P = .008). The combination of the SL phenotype and high craving was associated with a strong response to naltrexone, with 17.1 fewer heavy drinking days (Cohen d = 1.07; 95% CI, 0.58-1.54; F1,67 = 19.33; P < .001) and 28.8 more abstinent days (Cohen d = 0.72; 95% CI, 0.25-1.17; F1,67 = 8.73; P = .004) compared with placebo.

Conclusions and Relevance  The SL phenotype and a high craving for alcohol independently and particularly in combination are associated with a positive response to naltrexone. The SL/SDL phenotype and a high craving for alcohol merit further investigation as factors to identify patients with alcohol dependence who are responsive to naltrexone.

Trial Registration  clinicaltrials.gov Identifier: NCT01296646

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Figure 1.
CONSORT Diagram

Active treatment consisted of naltrexone hydrochloride, 50 mg/d. LFT indicates liver function tests; SDL, sweet-disliking phenotype; and SL, sweet-liking phenotype.

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Figure 2.
Effect of Naltrexone Hydrochloride or Placebo on Percentage of Heavy Drinking Days

Heavy drinking days are defined as at least 5 standard drinks (defined as 360 mL of beer, 150 mL of wine, or 45 mL of liquor) per day for men and at least 4 standard drinks per day for women. Results are stratified by the sweet-liking (SL) phenotype and high alcohol craving status. Individuals with the SL phenotype and high craving for alcohol demonstrate a robust reduction in heavy drinking with naltrexone compared with placebo treatment in this analysis using weekly drinking measures. SDL indicates sweet-disliking phenotype.

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Figure 3.
Effect of Naltrexone Hydrochloride or Placebo on Percentage of Abstinent Days

Results are stratified by the sweet-liking (SL) phenotype and high alcohol craving status. Individuals with the SL phenotype and high craving for alcohol demonstrate a robust increase in abstinent days with naltrexone compared with placebo in this analysis using weekly drinking measures. SDL indicates sweet-disliking phenotype.

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