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Effect of Naltrexone and Ondansetron on Alcohol Cue–Induced Activation of the Ventral Striatum in Alcohol-Dependent People

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Effect of Naltrexone and Ondansetron on Alcohol Cue–Induced Activation of the Ventral Striatum in Alcohol-Dependent People ORIGINAL ARTICLE Effect of Naltrexone and Ondansetron on Alcohol Cue–Induced Activation of the Ventral Striatum in Alcohol-Dependent People Hugh Myrick, MD; Raymond F. Anton, MD; Xingbao Li, MD; Scott Henderson, BA; Patrick K. Randall, PhD; Konstantin Voronin, MD, PhD Context: Medication for the treatment of alcoholism is double-blind randomly assigned daily dosing with 50 mg currently not particularly robust. Neuroimaging tech- of naltrexone (n=23), 0.50 mg of ondansetron hydro- niques might predict which medications could be use- chloride (n=23), the combination of the 2 medications ful in the treatment of alcohol dependence. (n=20), or matching placebos (n=24). Objective: To explore the effect of naltrexone, ondanse- Main Outcome Measures: Difference in brain blood tron hydrochloride, or the combination of these medi- oxygen level–dependent magnetic resonance when view- cations on cue-induced craving and ventral striatum ac- ing alcohol pictures vs neutral beverage pictures with a tivation. particular focus on ventral striatum activity comparison across medication groups. Self-ratings of alcohol craving. Design: Functional brain imaging was conducted dur- ing alcohol cue presentation. Results: The combination treatment decreased craving for alcohol. Naltrexone with (P=.02) or without (P=.049) Setting: Participants were recruited from the general ondansetron decreased alcohol cue–induced activation community following media advertisement. Experimen- of the ventral striatum. Ondansetron by itself was simi- tal procedures were performed in the magnetic reso- lar to naltrexone and the combination in the overall analy- nance imaging suite of a major training hospital and medi- sis but intermediate in a region-specific analysis. cal research institute. Conclusions: Consistent with animal data that suggest Patients: Ninety non–treatment-seeking alcohol- that both naltrexone and ondansetron reduce alcohol- dependent (by DSM-IV criteria) and 17 social drinking stimulated dopamine output in the ventral striatum, the (Ͻ14 drinks per week) paid volunteers recruited through current study found evidence that these medications, alone advertisements at an academic center. or in combination, could decrease alcohol cue–induced activation of the ventral striatum, consistent with their Interventions: A taste of alcohol and a series of alcohol- putative treatment efficacy. related pictures, neutral beverage pictures, and visual con- trol images were provided to volunteers after 7 days of Arch Gen Psychiatry. 2008;65(4):466-475 ONSIDERABLE DATA ARE tive. In addition, a meta-analysis of 27 ran- available to support the domized controlled trials of naltrexone Author Affiliations: Research use of the opiate antago- reported that, although short-term treat- and Development Service, nist naltrexone in the ment with naltrexone decreased relapse, Ralph H. Johnson Department treatment of alcohol de- the number of patients needed to be treated of Veterans Affairs Medical pendence.1-3 Naltrexone is approved by the to achieve a better outcome over placebo C 13 Center (Dr Myrick and US Food and Drug Administration for the response was 7. This number needed to Mr Henderson), and Alcohol treatment of alcoholism and has been treat for a positive effect of naltrexone over Research Center, Department of shown to reduce either the priming effect placebo was recently confirmed in a large Psychiatry and Behavioral or the reward (stimulation) effect of alco- multisite trial, the Combined Pharmaco- Sciences (Drs Myrick, Anton, hol.4-8 Also, in clinical treatment studies, therapies and Behavioral Interventions for Li, Randall, and Voronin and naltrexone has been found to enhance ab- Alcohol Dependence (COMBINE) Study.14 Mr Henderson), and Center for stinence,9 to reduce drinks per drinking This evidence suggests that not everyone Advanced Imaging Research 1,2 3 (Drs Myrick and Li and day, to reduce craving, and to enhance responds to treatment with naltrexone. It Mr Henderson), Medical resistance (reduce urge and impulse) to is not clear whether naltrexone works by University of South Carolina, drink.1,10 Unfortunately, not all stud- blocking cue-induced reinforcement as Charleston, South Carolina. ies11,12 with naltrexone have been posi- suggested by some animal15,16 and hu- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 4), APR 2008 WWW.ARCHGENPSYCHIATRY.COM 466 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 man17,18 studies or if it works primarily by blocking al- the presentation of alcohol cues. Although imaging stud- cohol’s pharmacologic reward properties.4,19-21 ies have begun to shed light on the areas of the brain in- The relative lack of robust data regarding the medi- volved in alcohol craving, data regarding the impact of cation treatment of alcohol dependence has led to the idea drug treatments on these structures are lacking. of combining medications to improve treatment out- An area of cue-stimulated activation noted by our group comes. The rationale is to use medications that target mul- has been the ventral striatum.35 The mesolimbic dopa- tiple neurotransmitter systems thought to be involved in mine pathway that projects from the ventral tegmental alcoholism. One such study was the COMBINE Study in area (VTA) to a structure within the ventral striatum, the which naltrexone alone, acamprosate calcium alone, or nucleus accumbens (NAC), has been implicated as a ma- the combination of the 2 medications was evaluated.14 jor site for the reinforcing actions of many addictive drugs, Unfortunately, although no increased efficacy was found including ethanol,38-42 and naltrexone has been shown to from the combination of the medications in this study, block this effect.15,16,43 Therefore, the goals of the cur- at least 1 smaller study22 suggested efficacy of combined rent study were to (1) replicate our previous findings that naltrexone and acamprosate. individuals with alcoholism have differential brain acti- Although not approved by the US Food and Drug Ad- vation to alcohol cues compared with social drinkers, es- ministration, serotonin 3 antagonist drugs have pro- pecially in the ventral striatum, and (2) explore, in a duced evidence of their potential clinical utility in the double-blind, placebo-controlled fashion, the effect of nal- treatment of alcoholism.23,24 Ondansetron hydrochlo- trexone, ondansetron, or the combination of the medi- ride is a serotonin 3 antagonist that has been found to cations on cue-induced craving and ventral striatum ac- have potential clinical utility in terms of animal stud- tivation. A priori hypotheses were that participants treated ies25 and human clinical laboratory paradigms.24,26 In clini- with naltrexone or ondansetron would have lower ven- cal trials, Sellers et al27 reported a greater reduction in tral striatum activation to alcohol cues compared with drinks per drinking day in a subgroup of individuals placebo-treated participants and that the combination of treated with low-dose ondansetron hydrochloride (0.25 naltrexone and ondansetron would have a greater reduc- mg twice daily) compared with placebo or high-dose on- tion in cue-induced craving and ventral striatum activa- dansetron hydrochloride (2.0 mg twice daily), and tion compared with participants treated with naltrex- Johnson et al28 found that ondansetron hydrochloride (4 one or ondansetron alone. µg/kg) reduced drinks per drinking day and increased abstinent days in individuals with early-onset alcohol- METHODS ism but not in those with late-onset alcoholism. Secondary to the possible synergistic mechanisms on decreasing alcohol use, the combination of naltrexone PARTICIPANTS and ondansetron has been studied in preclinical and clini- cal studies. Both rats and mice evaluated in a limited ac- Non–treatment-seeking individuals (n=125) who met the cri- cess paradigm had a greater reduction in alcohol intake teria for alcohol dependence participated in a larger protocol that included a limited-access, bar-laboratory paradigm for which when both medications were given together vs either 4 medication alone.29 In addition, an 8-week study in 20 general methods have been previously described. From this larger study, 100 participants agreed to take part in a brain individuals with early-onset alcoholism showed a sig- imaging study. Of these 100 participants, 10 were excluded for nificant difference in drinks per day between those who the following reasons: head movement (2 participants), arti- received naltrexone in combination with ondansetron and fact (1), mechanical problems (1), incomplete craving ratings those who received placebo.30 in the scanner (5), and a positive prescan breath alcohol level It has been thought that human alcohol cue–based (1). Therefore, 90 non–treatment-seeking individuals had evalu- laboratory paradigms might provide useful transitional able data for the analysis. Non–treatment-seeking individuals data between animal laboratory support for potential al- with alcoholism, after baseline evaluation, were assigned through cohol treatment medications and clinical trials.4,19,21 How- urn randomization (using a double-dummy placebo- ever, the study of medication effects on alcohol cue re- controlled design) to 1 of 4 experimental groups: naltrexone, sponse in the clinical laboratory is difficult secondary to ondansetron, naltrexone and ondansetron, or placebo. Partici- pants received study drugs for 8 days (days 1-5 being a natural the variability of subjective response
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