Testing pharmacotherapies for alcohol use disorder with cue exposure paradigms: A systematic review and quantitative synthesis of human laboratory trial methodology

Abstract

Alcohol cue exposure is a widely used experimental paradigm for screening pharmacotherapies for alcohol use disorder (AUD). Medication-related reductions in cue-reactivity signal early efficacy and inform medications development. Yet, across trials, the design of cue exposure, parameter testing, and outcome reporting is heterogeneous. This systematic review is a quantitative synthesis of trial methodologies and effect size estimation for AUD medication-related craving and psychophysiological outcomes under the cue exposure paradigm. A PubMed search was conducted on January 3, 2022 based on identified pharmacotherapies for peer-reviewed articles reported in English. Study-level characteristics, including sample descriptors, paradigm design, analytic approach, and Cochrane Risk of Bias, along with descriptive statistics for cue-exposure outcomes, were coded by two independent raters. Study-level effect sizes were estimated for craving and psychophysiological outcomes separately and sample-level effect sizes were calculated for each medication. Thirty-six trials, comprising 1640 participants and testing 19 different medications satisfied eligibility criteria. All studies reported on biological sex (71% male participants on average). The exposure paradigms implemented used in vivo (n = 26), visual (n = 8), and audio script (n = 2) cues. Some trials included means for craving by medication condition in text (k = 7) or figures (k = 18). The quantitative synthesis included 63 effect sizes (craving k_es = 47; psychophysiological k_es = 16) from 28 unique randomized trials testing 15 medications for effects on cue reactivity. For cue-induced craving, eight medications (k_es range: 1-12) demonstrated small-to-medium effects (Cohen's d range: |0.24-0.64|) compared to placebo, with individuals randomized to receive medication reporting lower craving following cue exposure. Recommendations are provided to promote further consilience, so that the utility of cue exposure paradigms can be maximized in the development of effective AUD pharmacotherapies. Future work should explore the predictive utility of medication-related reductions in cue-reactivity on clinical outcomes.

Keywords: alcohol use disorder; cue-reactivity; medications; pharmacotherapy; systematic review.

Figure 1.

PRISMA flow diagram for systematic review on alcohol use disorder medication studies using the alcohol cue exposure paradigm.

Figure 2.

Effect sizes for medication versus placebo on self-reported cue-induced craving. k_es indicates the number of outcomes contributing to each effect size. Medication effect sizes were averaged across craving outcomes and studies. Single RCT indicates that only one randomized controlled trial contributed to the estimated effect size, while multiple RCTs indicate that multiple trials contributed. A negative effect size reflects a medication condition with reduced cue-induced craving than placebo. Cohen’s d > ∣0.20∣ suggests small effect size, d > ∣0.50∣ suggests medium effect size, and d > ∣0.80∣ suggests large effect size.

Figure 3.

Effect sizes for medication versus placebo on physiological outcomes. k_es indicates the number of outcomes contributing to each effect size. Medication effect sizes were averaged across physiological outcomes and studies. Single RCT indicates that only one randomized controlled trial contributed to the estimated effect size, while multiple RCTs indicate that multiple trials contributed. A negative effect size reflects a medication condition with reduced physiological response than placebo. Cohen’s d > ∣0.20∣ suggests small effect size, d > ∣0.50∣ suggests medium effect size, and d > ∣0.80∣ suggests large effect size.

Figure 4.

Study-level effect sizes for medication versus placebo on self-reported cue-induced craving. If two or more study-level outcomes on craving were reported, averaged effect sizes (SE) were presented. A negative effect size reflects a medication condition with reduced cue-induced craving than placebo. Cohen’s d > ∣0.20∣ suggests small effect size, d > ∣0.50∣ suggests medium effect size, and d > ∣0.80∣ suggests large effect size.

Figure 5.

Sample-level statistical reporting on craving by medication condition outcomes across cue exposure trials.