An explorative single-arm clinical study to assess craving in patients with alcohol use disorder using Virtual Reality exposure (CRAVE)—study protocol

Alcohol use disorder (AUD) is a severe disorder leading to a substantial burden of disease with worldwide 3 million deaths per year [1]. Current treatment approaches yield unsatisfactory long-term effects with relapse rates up to 85% [2]. Both the individual and their environment are strongly affected by the disorder. Including all cost components (direct and indirect cost estimates of e.g., health care, unemployment or premature mortality) associated to harmful alcohol use, the costs would equal about 2,6% of the Gross Domestic Product (GDP) in the examined countries [3]. Alcohol craving as the strong desire to drink, is a major predictor for relapse and a main diagnostic criterion [4, 5]. Craving is associated with psychological and physiological responses [6] and can be intentionally induced by confronting patients with alcohol-related cues according to the cue-reactivity paradigm [7], such as a bar or a glass of wine.

The intentional presentation of such conditioned, contextualized cues is used as part of „Cue Exposure Therapy “ (CET) in Cognitive Behavioral Therapy (CBT), aiming to enable patients to identify and handle individual relapse risks [8]. Cue Exposure Therapy has shown substantial clinical effects, although recent meta-analyses emphasized the small number and questionable quality of existing trials [9, 10]. Although it is an effective strategy, CET for patients with AUD has not yet been established in clinical routine, because of the high organizational, timely and financial costs [8]: a) actors need to be available, b) to assure realistic settings, real bars have to be visited or laboratory-based bars have to be created and c) the change between different contexts is limited [11]. Virtual Reality (VR) is a new technology that is currently developing rapidly across several fields, and VR-based therapies are about to become a major component of digital mental health [12, 13]. Using e.g., head-mounted displays (HMD) patients can immerse into a computer-generated 3D world, where realistic spatial and social interactions are possible in real-time [14]. VR interventions can be used for both therapeutic and diagnostic approaches and have been established for various psychiatric indications such as anxiety disorders (e.g., specific phobias, social anxiety disorder) and post-traumatic stress disorder. [13, 15]. Innovative approaches including virtual avatars in the therapy of psychotic disorders show promising results [12]. Furthermore, VR applications have received increasing attention in the field of substance use disorders (SUD) [16, 17]. VR yields several advantages compared to in vivo exposure: it enhances practicability of CET, allows comparability between treatment providers and offers high ecological validity by using multimodal dynamic stimuli in an immersive environment [15, 18].

The assessment of craving in VR paradigms can provide a basis for the development of an effective exposure therapy, allowing to understand which contextual cues elicit pronounced cue reactivity and should therefore be used for habituation and extinction learning in cue exposure therapy. Additionally, craving assessment can serve as an individually tailored diagnostic tool helping to identify high-risk situations and automatic responses. Studies on craving assessment in patients with AUD show that different alcohol-associated VR-scenarios successfully induce craving [17]. Interestingly, a recent study showed that craving was significantly related to the sense of presence, meaning the perceived ecological validity of the virtual environment, underlining the importance of a realistic, high-end 3D VR environment [19]. However, apart from one study using electroencephalography (EEG, [20]) only subjective craving parameters (e.g., visual analogue scales, VAS) were used [16]. VAS are the international standard but have several disadvantages: They rely on subjective reports and the assumption that patients with AUD can perceive and specify their own craving. VAS are also biased with respect to social desirability, meaning that individuals may not answer completely truthfully, but with respect to what is socially acceptable.

Psychophysiological parameters of craving (e.g., changes in electrodermal activity, pupil size and heart rate) are well established in studying physiological cue reactivity [6]. A recent meta-analysis confirmed the link between cue-induced craving and psychophysiological cue reactivity to alcohol use and relapse [7]. Considering specific physiological parameters, a review with 33 included studies confirmed the association between reactive HRV to alcohol cues and craving, faster relapse and negative mood [21]. High frequency HRV (HF-HRV), which reflects parasympathetic activity, has been shown to be increased by alcohol-related cues [22, 23]. Furthermore, a pilot study assessing pupil reactivity to alcohol-related and neutral cues as a predictor for relapse, showed that alcohol-dependent patients reacting with greater pupillary dilation were more prone to relapse at a 4-month follow-up [24].

Apart from one older study which examined electroencephalographic correlates of craving in a small cohort of 20 patients [20], physiological parameters have not been used as outcomes for VR-exposure in patients with AUD, yet [16]. In VR-studies on methamphetamine use disorder physiological data (heart rate variability, eye tracking, electrodermal activity) were able to discriminate between patients and healthy controls [25, 26].

The planned study we present here, aims to assess if VR exposure can induce craving, being intentionally induced by different VR scenarios, with help of subjective and objective parameters.

This is the first study examining change in several psychophysiological craving parameters in patients with AUD using VR exposure.

Results shall lead to a better understanding of the induction of craving in VR cue exposure as well as the link between subjective and physiological parameters. This could offer new diagnostic and therapeutic perspectives, e.g., providing a basis for future biofeedback training in VR exposure therapy. Since evidence on the effectiveness of CET in AUD is still limited [9, 10] and the role of habit learning in addictive disorders has been discussed (e.g. Hogarth et al. [43]), it would be valuable to discriminate subgroups with pronounced cue-reactivity who could potentially profit even more from this treatment. On an exploratory basis, the comparison between craving levels in the bar versus home situation will help to define contexts with pronounced craving, helping to better understand the role of social cues in inducing craving. As regards the direct benefit for patients, the VR experience in this study and future VR application can be an individually tailored tool to identify high-risk situations and practice coping skills.

This study is limited by a single-arm design: The study design does not allow a comparison of the elicited craving between patients and healthy controls. This would have changed the focus and research question of the study but would certainly be of interest for further studies in this field.