BackgroundLow dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN.MethodsSystematic literature searches were conducted in MEDLINE,Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results.ResultsThree studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life. One study reported baseline erythrocyte sedimentation rate (ESR) predicted LDN response (≥30% reduction in fibromyalgia symptoms) and a second study showed plasma concentrations of inflammatory biomarkers were lower after LDN treatment. To our knowledge, there are no brain imaging studies reporting the effect of LDN in patients with fibromyalgia. All studies were based on small sample sizes, were restricted to women and the risk of bias was assessed to be high. There is also some evidence of publication bias.ConclusionThe strength of evidence from randomized controlled trials to support the use of LDN among patients with fibromyalgia is low. Two small studies suggest ESR and cytokines may be involved in the mechanism by which LDN exerts its effects. Two trials (INNOVA and FINAL) are currently in progress, but further work is needed among men and different ethnic groups.