Non-invasive brain stimulation paradigms in treatment of alcohol use disorder: Systematic review and network meta-analysis protocol

Background: Alcohol use disorder (AUD) is a chronic condition linked to allostatic neuroadaptations in the brain’s reward circuitry, leading to compulsive and automatized alcohol use in response to craving or negative affect. There are only a few treatment options for AUD, and their efficacy and tolerance profiles remain suboptimal. New AUD management strategies are actively being investigated, and among these, non-invasive brain stimulation (NIBS) interventions. We are planning to conduct a systematic review and network meta-analysis to simultaneously compare different NIBS strategies for AUD, and the present protocol aims to document our methodological approaches and a priori decisions. Methods and analysis: We will include only randomized controlled trials involving adults with AUD, alcohol dependence, or alcohol abuse. The primary interest outcomes of our review will concern alcohol consumption in AUD population. In trials investigating NIBS as a strategy for alcohol use reduction, we will explore the effect of NIBS on the reduction in total alcohol consumption and the number of heavy drinking days among participants. In trials in recently detoxified AUD patients where the potential of NIBS to prevent relapse is explored, the primary outcome will concern the rate of relapse. Data on craving and safety parameters will be gathered as secondary interest outcomes. At the time of submitting this protocol, four electronic databases (EMBASE, PubMed, PsycINFO, and The Cochrane Library) and three clinical trial registries (Clinical Trials, EU Trials, WHO ICTRP) were searched. The results of the searches were screened in a blinded manner by two authors using titles and abstracts, with conflicts adjudicated by a third author. The second round of selection based on full texts will be performed after the protocol submission. Data will then be extracted independently by two authors using a predefined extraction form. Risk of bias evaluation for each trial will be performed independently by two authors using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2). We will quantitatively synthesize the extracted results using mean differences and risk ratios as effect measures. Initially, a random-effects pairwise meta-analysis will be performed to compare treatment and control arms across different trials. A network meta-analysis will then be conducted. The results of the network meta-analysis will be presented as a network graph representing treatment nodes and direct comparisons, a league table with both direct and network meta-analysis (indirect or mixed) estimates, a net heat plot for inconsistency evaluation, and CINeMA evaluation of the confidence in our results. Systematic review registration: PROSPERO registration number CRD42024504362.