Discussion
alcohol-dependent, thirst, substance dependence
ALCOHOL EFFECTS, EMA, DRUG EFFECT
Regarding the primary endpoint of this clinical trial, we were unable to demonstrate a statistically significant overall effect of naltrexone on cWFA. However, in exploratory analyses separating the first (“ascending”) and the second (“plateau”) half of the VWR time span, we found that naltrexone significantly reduced cWFA in the former, but not the latter.The null finding concerning the predefined primary endpoint can be best explained by the observation that naltrexone did not affect WFA during the plateau phase of the experiment. Reasons to explain this are discussed below. By design of the study, the major proportion of work was performed during the plateau phase (see Fig. We were surprised by how strongly the naltrexone effect on WFA depended on the low- versus high-demand ASA interval. We suggest interpreting this result with respect to the differing reward contingencies and incentive components driving WFA. First, we discuss results of the ascending phase, where we assumed that WFA would be positively reinforced such that work rapidly increases BrAC, this exposure resulting in pleasant subjective perceptions, which then promote further work (see introduction). Our experimental control was confined to the first of these three elements, preventing conclusions on causal relations between the others. However, the finding that cWFA was positively associated with concurrent changes in subjective stimulation and wellbeing is at least compatible with the notion that positive consequences of alcohol exposure gained some control over behavior, as in positive reinforcement. Interestingly, the same association was also observed during the second session in subjects threated with placebo, but not in the naltrexone group, suggesting that naltrexone-treated participants might have worked less for alcohol because of attenuated positive reinforcement. Such an interpretation is in line with previous studies describing that naltrexone reduces the rewarding feelings caused by alcohol in social drinkers [Our finding of a statistically significant medication effect during the ascending phase is noteworthy, since these results were obtained with a parallel-group design in a relatively small sample of nondependent subjects. Naltrexone’s effect on low-demand cWFA was significantly related to its blood levels, supporting a conclusion that that the attenuation of WFA was truly caused by the drug. Nine previous laboratory studies investigated naltrexone’s effect on free-access ASA [The observation that naltrexone treatment altered only laboratory behavior, but not the subjects’ real-life drinking, alcohol craving, or blood parameters of alcohol consumption is an ambiguous finding. Since naltrexone undoubtfully helps to reduce drinking, this could mean that the TESMA, designed as a screening tool, actually is more sensitive than mere clinical observation, detecting a real drug effect already in a small sample within a short time. Our sample may have also been motivated to reduce their drinking despite their non-treatment-seeking status. Participants reduced their average grams of alcohol per drinking day, percent drinking days, and percent binge days as a function of treatment with both naltrexone and placebo. The reduction from baseline associated with naltrexone treatment reached significance for percent drinking days and binge days (Table Discussing reasons why a naltrexone effect was not detected during the high-demand ASA phase is more difficult. From a statistical point of view, the reason might simply be that the SEM of the outcome variable steadily increased over time, averaging ~25 at the end of the ascending phase and 75 towards the end of the experiment, while its group difference remained largely unchanged throughout the plateau phase (see Fig. Two more conceptual interpretations of the results during the high-demand ASA phase refer again to the reward contingencies and incentive components driving WFA. As outlined in the introduction, we assume that WFA during that period was negatively reinforced. This notion is supported by scorings of subjective alcohol “desire”, which can be interpreted as dissatisfaction with the perceived alcohol effects. “Desire” slopes correlated positively with WFA during the plateau-, but not during the ascending phase, which implies that subjects used WFA to fight unpleasant feelings caused by falling BrAC, i.e., negative reinforcement. In this light, the absent naltrexone effect might match recent findings in clinical trials. While naltrexone reduces heavy drinking in alcohol-dependent patients [Yet another interpretation of the high-demand phase refers to the motivation to work. Continuing to work for alcohol despite long periods without getting rewarded can be interpreted as an expression of alcohol “wanting.” This pathological motivation is thought to specifically characterize subjects with substance dependence [While naltrexone treatment affected cWFA, it did not change the peak or mean BrAC.To make the above-described differences in reward contingencies possible, we critically depended on the use of i.v. administration. While increasing BrACs to induce positive reinforcement can be easily achieved by oral administration, obtaining experimental control over falling BrAC is much harder. With the TESMA, the infusion rate is adapted immediately after each reward in order to decrease BrAC at a steady slope of −0.8 mg/dL per minute; nearly four times faster than the ~12–15 mg/dL per hour observed after oral ingestion. BrAC is closely related to arterial blood concentration [Regarding the A118G polymorphism of the OPRM1 gene, G-allele carriers were slightly, but not statistically significantly, more responsive to naltrexone treatment than AA subjects, which is in line with a prior study employing free-access i.v. ASA [Some fundamental methodological goals of the TESMA paradigm were also accomplished. We demonstrated test-retest reliability for cWFA and cWFS. The fact that cWFA was significantly greater than cWFS indicates that, by design, alcohol was the “primary” reward and that the subjects’ effort was not driven by nonspecific reasons such as boredom or thirst. Their work resulted in substantial alcohol exposure with peak BrAC before treatment averaging 117 ± 23 mg/dL, and 91 % of all subjects reaching binge levels above 80 mg/dL. This peak exposure compares well with that reported by previous studies using i.v. alcohol administration [A specific strength of our study is that it was registered with the European Medicines Agency, rigorously complied with all regulations of good clinical practice as defined by the international conference of harmonization of (GCP-ICH) and still was finished in a single center within a relatively short time of 1 year and ten months. The mandatory results reporting was uploaded at the EMA website [Limitations included that, due to ethical concerns, we could not include alcohol-dependent subjects, which may partly explain why we observed only ambiguous effects of naltrexone treatment on real-life drinking. Second, females were grossly underrepresented, requiring further studies to examine gender-specific effects in our paradigm. Third, highly educated individuals were overrepresented; therefore, it remains unclear whether our results can be generalized to the general population. In addition, working for alcohol precluded more frequent measurements of subjective effects, which would have been desirable to strengthen our conclusions on drinking motivations.We conclude that the TESMA is a safe and practical method that has the potential to enable quick and efficient screening of new drugs for their efficacy to attenuate alcohol consumption under conditions of positive reinforcement of drinking. It probably also provides a condition of negative reinforcement, and for the first time, provides experimental evidence suggesting that naltrexone’s effect might depend on reward contingency. This result, however, requires confirmation by studies where timing and progressive-ratio work schedules are specifically devised to investigate negative reinforcement, and which include alcohol-dependent patients.