There is considerable data supporting the use of the opiate antagonist naltrexone in the treatment of alcohol dependence.1-3
Naltrexone is FDA-approved for the treatment of alcoholism and has been shown to either reduce the priming effect or reward (stimulation) effect of alcohol.4-8
Also, in clinical treatment studies, naltrexone has been found to enhance abstinence 9
to reduce drinks per drinking day, 1-2
to reduce craving 3
and to enhance resistance (reduce urge and impulse) to drink.1,10
Unfortunately, not all studies with naltrexone have been positive. 11-12
In addition, a meta-analysis of 27 randomized controlled trials of naltrexone reported that while short-term treatment with naltrexone decreased relapse, the number of patients needed to be treated in order to achieve a better outcome over placebo response was 7.13
This number needed to treat for a positive effect of naltrexone over placebo was recently confirmed in a large multi-site trail, the COMBINE Study.14
This evidence suggests that not everyone responds to treatment with naltrexone. It is not clear whether naltrexone works by blocking cue-induced reinforcement as suggested by some animal 15-16
and human 17-18
studies, or if it works primarily on blocking alcohol's pharmacological reward properties. 4, 19-21
The relative lack of robust data in regards to the medication treatment of alcohol dependence has led to the idea of combining medications to improve treatment outcomes. The rationale is to utilize medications that target multiple neurotransmitter systems thought to be involved in alcoholism. One such study was the above-mentioned COMBINE Study in which naltrexone alone, acamprosate alone, or the combination of the two medications was evaluated.14
Unfortunately, while there was no increased efficacy from the combination of the medications in this study, at least one smaller study suggested efficacy of combined naltrexone/acamprosate. 22
While not FDA-approved, there is evidence for the potential clinical utility of 5HT3 antagonist drugs in the treatment of alcoholism. 23-24
Ondansetron is a 5HT3 antagonist that has been found to have potential clinical utility in terms of animal studies 25
and human clinical laboratory paradigms. 24,26
In clinical trials, Sellers et al. 27
reported a greater reduction in drinks per drinking day in a subgroup of subjects treated with low dose ondansetron (0.25mg BID) compared to placebo or high dose ondansetron (2.0mg BID) and Johnson et al. 28
found that ondansetron (4 ug/kg) reduced drinks per drinking day and increased abstinent days in early onset alcoholics but not in late onset alcoholics.
Secondary to the possible synergistic mechanisms on decreasing alcohol use, the combination of naltrexone and ondansetron has been studied in preclinical and clinical studies. Both rats and mice evaluated in a limited access paradigm had a greater reduction in alcohol intake when both medications were given together versus either medication alone. 29
In addition, an 8-week study in 20 early onset alcoholics showed a significant difference in drinks per day between subjects who received naltrexone in combination with ondansetron and those who received placebo. 30
It has been thought that human alcohol-cue based laboratory paradigms might provide useful transitional data between animal laboratory support for potential alcohol treatment medications and clinical trials. 4,19,21
However, the study of medication effects on alcohol-cue response in the clinical laboratory is difficult secondary to the variability of subjective response (e.g. craving) to cues, and the variability in objective peripheral measures of autonomic arousal and response such as heart rate changes, salivary output, etc. 31
In addition, these subjective and peripheral measures provide more distal and only correlative information as to what might be happening in the brain of the addicted/dependent individual. This has lead us and others to seek a more proximal brain signal of alcohol-cue induced urges to drink and reward salience in which to explore medication effects as a potential predictor of treatment utility.
Several brain-imaging technologies have been refined and applied to the study of brain activation during presentation of drug-related cues. Recent studies have indicated that similar findings may be emerging during the presentation of alcohol cues.32-37
While imaging studies have begun to shed light on the areas of the brain involved in alcohol craving, data regarding the impact of drug treatments on these structures are lacking.
An area of cue-stimulated activation noted by our group has been the ventral striatum. 35
The mesolimbic dopamine pathway that projects from the ventral tegmental area (VTA) to a structure within the ventral striatum, the nucleus accumbens (Nac), has been implicated as a major site for the reinforcing actions of many addictive drugs including ethanol 38-42
and that naltrexone has been shown to block this effect. 15-16,43
Therefore, the goal of the current study was to 1) replicate our previous findings that alcoholics have differential brain activation to alcohol cues compared to social drinkers, especially in the ventral striatum and 2) explore, in a double-blind, placebo-controlled fashion, the effect of naltrexone, ondansetron, or the combination of the medications on cue-induced craving and ventral striatum activation. A priori hypotheses were that participants treated with naltrexone or ondansetron would have lower ventral striatum activation to alcohol cues compared to placebo-treated participants and that the combination of naltrexone and ondansetron would have a greater reduction in cue-induced craving and ventral striatum activation as compared to participants treated with naltrexone or ondansetron alone.