OBJECTIVES: To determine the effectiveness of systemic pharmacotherapeutic interventions compared to placebo in burning mouth syndrome (BMS) randomized controlled trials (RCTs) based on the core outcome domains recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT). METHODS: A systematic literature review of RCTs, concerning systemic pharmacotherapeutic interventions for BMS, published from January 1994 through October 2019, and meta-analysis was performed. RESULTS: Fourteen RCTs (n = 734 participants) were included. Of those, nine were eligible for the quantitative assessment due to the availability/homogeneity of data for at least one of the IMMPACT domains. Pain intensity was the only domain reported in all RCTs. Weighted mean changes in pain intensity, based on visual analogue scale (ΔVAS), were reported in three RCTs at 6 ± 2 weeks and only one RCT at 10+ weeks follow-ups. Quantitative assessment, based on ΔVAS, yielded very low evidence for the effectiveness of alpha-lipoic acid and clonazepam, low evidence for effectiveness of trazodone and melatonin, and moderate evidence for herbal compounds. CONCLUSIONS: Based on the RCTs studied, variable levels of evidence exist that suggest that select pharmacological interventions are associated with improved symptoms. However, the underreporting of IMMPACT domains in BMS RCTs restricts the multidimensional assessment of systemic interventions outcomes. Standardized outcome measures need to be applied to future RCTs to improve understanding of intervention outcomes.