Methylene blue in chemoradiotherapy-induced oral mucositis: Systematic review and meta-analysis

Oral mucositis (OM) is a frequent and debilitating side effect of chemotherapy and radiotherapy, affecting up to 80% of patients receiving high-dose regimens or head and neck radiation. It severely compromises oral function, quality of life, and treatment adherence, often necessitating opioid analgesia and nutritional support. Methylene blue (MB), known for its anti-inflammatory and analgesic properties, has recently emerged as a potential therapeutic agent for OM pain.

This systematic review aimed to evaluate the analgesic efficacy of methylene blue in the management of chemotherapy- and radiotherapy-induced OM, either as a topical oral rinse or as a photosensitizer in photodynamic therapy (PDT).

Following PROSPERO registration (CRD42024594258), we conducted a comprehensive search of five databases up to September 2024. Studies were eligible if they included cancer patients with chemotherapy- or radiotherapy-induced OM treated with MB. Data extraction and quality assessment were performed independently by two reviewers following PRISMA guidelines. Pain reduction was the primary outcome. A random-effects meta-analysis using inverse variance weighting was conducted; heterogeneity was assessed with I2 statistics.

Out of 137 screened records, 6 studies comprising 9 treatment groups and 432 patients met inclusion criteria. MB was administered either as an oral rinse alone (7 groups) or in combination with laser therapy (2 groups). The pooled mean reduction in pain was -4.81 points on a 0-10 scale (95% CI -5.57 to -4.05; P < 0.001). Subgroup analysis showed a mean change of -5.01 with oral rinse alone and -3.80 with the combination, with no significant difference between the two strategies (P = 0.30). Sensitivity analyses confirmed the robustness of these findings.

Methylene blue appears to be a safe and effective option for pain relief in OM, with significant reductions in pain scores observed across studies. Its simplicity, affordability, and favorable safety profile make it a promising adjunctive therapy. Larger randomized trials are needed to validate these findings and explore long-term outcomes.