Pharmacological Management of Gambling Disorder: A Systematic Review and Network Meta-Analysis
Authors: Ioannidis Konstantinos , Del Giovane Cinzia , Tzagarakis Charidimos , Solly Jeremy E , Westwood Samuel J. , Parlatini Valeria , Bowden-Jones Henrietta , Grant Jon E , Cortese Samuele , Chamberlain Samuel R 
Published: October 2023

ABSTRACTBackgroundClinical guidelines remain unclear on which medications for gambling disorder are to be preferred in terms of efficacy and tolerability. We aimed to compare pharmacological treatments for gambling disorder in terms of efficacy and tolerability, using network meta-analysis (NMA).MethodsWe searched, up to 19 February 2024, a broad range of databases, including MEDLINE, EMBASE, PsycINFO, PubMed, CINAHL, AMED, and the Cochrane Database of Systematic Reviews, ERIC and Web of Science (including Science Citation Index Expanded (SCI-EXPANDED), Social Science Citation Index (SSCI), Conference Proceedings Citation Index-Science (CPCI-S) and Conference Proceedings Citation Index-Social Science and Humanities (CPCI-SSH)) via Web of Knowledge and the WHO International Trials Registry Platform (includingClinicalTrials.gov), for double-blind randomised controlled trials (RCTs) of medications for gambling disorder. Outcomes were gambling symptom severity and quality of life (for efficacy), and tolerability. Confidence in the network estimates was assessed using the CINeMA framework. We followed the PRISMA-NMA guidelines and pre-registered the protocol [CRD42022329520].OutcomesWe included 22 RCTs in the systematic review and 16 RCTs (n = 977 participants) in the NMA. Compared with placebo, moderate confidence evidence indicated that nalmefene [Standardized Mean Difference (SMD): −0·86; 95% confidence interval (CI: −1·32,-0·41)] reduced gambling severity, followed by naltrexone [-0·42; −0·85, 0·01)]. Nalmefene [Odds Ratio (OR): 7·55; 95%CI: 2·24-25·41] and naltrexone (7·82; 1·26-48·70) had significantly higher dropout due to side effects (lower tolerability) compared with placebo. Naltrexone (SMD: −0·50; 95%CI: −0·85,-0·14) and nalmefene (−0·36; −0·72,-0·01) were more beneficial than placebo in terms of quality of life. Olanzapine and topiramate were not more efficacious than placebo.InterpretationNalmefene and naltrexone currently have the most supportive evidence for the pharmacological treatment of gambling disorder. Further clinical trials of novel compounds, and analysis of individual participant data are needed, to strengthen the evidence base, and help tailor treatments at the individual patient level.FundingThis study was supported by unrestricted grant funds to Professor Chamberlain held at the University of Southampton, originating from the NHS.Research in ContextEvidence before this studyOver the past few decades, there has been a substantial need for evidence-based pharmacological treatments of gambling disorder. However, the benefits and safety of medications trialled to treat gambling disorder remains debateable.Before planning this study, we searched PubMed on 01.06.2022 (and again on 16.03.2024 for any new evidence) for meta-analyses of randomised controlled trials (RCTs) of pharmacological treatments for gambling disorder, using the following syntax/search terms: gambling [tiab] AND meta-analy* [tiab]. We found two recent pairwise meta-analyses assessing the efficacy and tolerability of individual medications. However, we could not find any network meta-analysis (NMA) providing evidence on the comparative efficacy and tolerability of medications used for the treatment of gambling disorder. As NMAs have been successfully used to inform treatment approaches for other conditions, the lack of NMA of pharmacological treatments for gambling disorder is an important gap.Added value of this studyWe conducted the first NMA of pharmacological treatments for gambling, based on state-of-the-art methodology for NMA. Our NMA represents the most comprehensive synthesis to date on the comparative efficacy and tolerability of pharmacological options to treat gambling disorder. Unlike previous systematic reviews and pairwise meta-analyses of head-to-head trials, we considered each treatment option separately (i.e., not as “class of medication”) and focused on clinically relevant outcomes – namely, the efficacy on gambling severity symptoms, tolerability and effects on the quality of life. We found that nalmefene and naltrexone currently have the most supportive evidence, in terms of clinical efficacy (reduction of gambling severity and improvement in quality of life), for the pharmacological treatment of gambling disorder, whereas olanzapine or topiramate had less or no supportive evidence. We also found that nalmefene and naltrexone were less well tolerated than placebo, which highlights the need for future clinical trials to broaden the evidence base.Implications of all the available evidenceEvidence from our NMA supports the use of nalmefene and naltrexone in adults with gambling disorder as the preferred first pharmacological choice for the management of gambling disorder. Our NMA should inform future guidelines and supplement clinical decision-making on the choice of treatment for adults with gambling disorder, along with available evidence on psychological options, evidence on cost-effectiveness, and patients’ preferences. Future studies should evaluate a broader range of pharmacological agents for the treatment of gambling disorder .Future research should also include individual patient data in NMA of gambling disorder medications, which will allow a wider and more reliable estimation of predictors of individual response.