Methylene blue for intractable pain from oral mucositis related to cancer treatment: a randomized phase 2 clinical trial

Abstract

Background: Oral mucositis (OM) in patients receiving cancer therapy is thus far not well managed with standard approaches. We aimed to assess the safety and effectiveness of methylene blue (MB) oral rinse for OM pain in patients receiving cancer therapy.

Methods: In this randomized, single-blind phase 2 clinical trial, patients were randomized to one of four arms: MB 0.025%+conventional therapy (CTx) (n = 15), MB 0.05%+CTx (n = 14), MB 0.1%+CTx (n = 15), or CTx alone (n = 16). Intervention groups received MB oral rinse every 6 h for 2 days with outcomes measured at days 1-2; safety was evaluated up to 30 days. The primary outcome measured change in the pain numeric rating scale (0-10) from baseline to day 2. Secondary outcome measured change in oral function burden scores from baseline to day 2, World Health Organization OM grades, morphine equivalent daily doses, and adverse events. The trial was registered with ClinicalTrials.gov ID: NCT03469284.

Results: Sixty patients (mean age 43, range 22-62 years) completed the study. Compared with those who received CTx alone, those who received MB had a significant reduction of pain scores at day 2 of treatment (mean ± SD); 0.025%: 5.2 ± 2.9, 0.05%: 4.5 ± 2.9, 0.1%: 5.15 ± 2.6) and reduction of oral function burden scores (0.025%: 2.5 ± 1.55, 0.05%: 2.8 ± 1.7, 0.1%: 2.9 ± 1.60). No serious adverse events were noted, but eight patients reported burning sensation of the oral cavity with the first dose, and this caused one patient to discontinue therapy.

Conclusions: MB oral rinse showed significant pain reduction and improved oral functioning with minimal adverse effects.

Trial registration: ClinicalTrials.gov ID: NCT03469284.

Keywords: Cancer therapy; Methylene blue Oral Rinse; Oral mucositis.

Conflict of interest statement

Carlos Roldan MD is currently applying for a patent on the use of Methylene blue for oral pain in mucositis associated to cancer therapy. The application process is not depending on the content of the manuscript. The rest of the authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Flowchart of patients included in the trial. MB, methylene blue; CTx, conventional therapy

Fig. 2

Changes in numeric rating scale (NRS) of pain scores over the first 2 days of treatment. Mean reduction in numeric pain scores at day 2 after the start of treatment were significantly or marginally better in patients who received conventional therapy plus methylene blue (MB) oral rinse at three different concentrations than in patients who received conventional therapy alone (Tukey pairwise comparison; P = 0.0071, P = 0.0506, P = 0.0114)

Fig. 3

Mean pain numeric rating scale score reductions from baseline to day 2 by treatment arm. Mean pain numeric rating scale scores before and after treatment are shown for patients who received conventional therapy alone and those who received conventional therapy plus methylene blue (MB) oral rinse at three different concentrations. Lines indicate 95% confidence intervals of the mean

Fig. 4

Changes in oral functioning burden scores over the first 2 days of treatment. Mean oral functioning burden scores at day 2 after the start of treatment were significantly better in patients who received conventional therapy plus methylene blue (MB) oral rinse at three different concentrations than in patients who received conventional therapy alone (Tukey pairwise comparison; (P = 0.0171, P = 0.0038, P = 0.0019)

Fig. 5

Mean oral functioning burden score reductions from baseline to day 2 by treatment arm. Mean oral functioning burden scores before and after treatment are shown for patients who received conventional therapy alone and those who received conventional therapy plus methylene blue (MB) oral rinse at three different concentrations. Lines indicate 95% confidence intervals of the mean