Background: Oral mucositis (OM) is a painful inflammation of the oral and pharyngeal mucosa that patients receiving cancer treatments (e.g., chemotherapy and radiation therapy) frequently experience. OM often requires escalating doses of opioids and interferes with oral intake and nutrition. See Fast Fact #121, Fast Fact #130, and Fast Fact #450 for more information on OM. Standard topical agents (e.g., lidocaine, “magic mouthwash,” doxepin, and morphine rinse) provide only brief relief and can blunt taste or the gag reflex. This Fast Fact reviews the mechanism, evidence, and practical use of methylene blue (MB), which has emerged as an inexpensive topical option for refractory OM pain.

Pharmacology/mechanism: MB is a thiazine dye long used for methemoglobinemia and as a surgical marker. In OM, it is thought to produce analgesia by inhibition of peripheral voltage-gated sodium channels, suppression of nitric oxide-mediated inflammation, and chemical neurolysis of exposed mucosal nerve endings; this neurolytic action may also explain the prolonged duration of relief compared with topical anesthetics like lidocaine (1-3). Because MB does not produce numbing or true local anesthesia of the oral mucosa, it leaves taste perception and the gag reflex intact (4,5).

Evidence: Nearly all published data for OM involve adults. A randomized phase 2 trial (n=60) compared three MB concentrations (0.025%, 0.05%, 0.1%) plus conventional therapy to conventional therapy alone. All MB groups showed a significant reduction in pain scores by day 2, with improved oral function and no serious adverse events; the 0.05% group showed the greatest numerical effect (4). In a retrospective, single-site cohort (n=243), mean pain scores fell from 7.7 to 2.51 (p<0.0001), with most patients responding within 4 doses; the benefit was consistent across cancer types, treatment modalities, and concentrations (5). In a head and neck radiation cohort (n=58), median pain fell from 8 to 2 with relief lasting ≥6 hours per dose, and 36% of patients with pre-existing feeding tubes resumed oral intake (6). Evidence is maturing: an open-label, non-randomized controlled study (n=43) comparing 0.05% MB to standard-of-care mouthwash (comprised of diphenhydramine, lidocaine, aluminum hydroxide, magnesium hydroxide, and simethicone) in hospitalized patients found significant pain reduction in both groups. A systematic review and meta-analysis concluded that MB is an effective and well-tolerated option for OM pain management induced by chemotherapy and radiotherapy (7,8). Pediatric data are limited to case reports and topical MB applied directly to OM lesions before laser therapy (9,10).

Dosing & administration: The most common MB concentration is 0.05%. To achieve this concentration, pharmacists must dilute the commercially available MB 1% injectable solution (10 mg/mL) with sterile water or saline– 1:20 for 0.05% (0.5 mg/mL). It is dispensed in a light-protected container. Because the concentration of MB for OM is not commercially available, it must be compounded by a pharmacist, which can affect both its availability and consistency. Adults swish ~10 mL for 2-5 minutes (per published protocols) and then expectorate (do not swallow). Dose interval is every 6 hours. Since this is a relatively long time to swish a medication, patient selection is key. Most respond to MB within 4 doses, and use continues as needed through the OM episode (4-6). Per a published case report, 3-5 mL of the same mixture every 4 hours might be a reasonable dose in children (11). 

Adverse effects & cautions: The most common adverse effect is transient burning with the first dose. Temporary blue staining of the mouth, saliva, and urine may alarm the patient, but it is harmless. Clinicians should proactively inform patients about it. No serious adverse events have been reported across studies (4-6). MB is contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficiency due to the risk of hemolysis. Most recommend G6PD screening in patient populations with higher prevalence of G6PD deficiency — patients of African, Mediterranean, Middle Eastern, and Southeast Asian descent — before prescribing it (12-14). MB is a potent reversible MAO-A inhibitor and carries an FDA warning for serotonin syndrome when combined with serotonergic drugs (e.g., SSRIs, SNRIs, and certain opioids). However, systemic absorption from swish-and-spit is minimal, and no cases of serotonin syndrome have been reported in OM studies. Clinicians should weigh the risk in patients on serotonergic agents and confer with clinical pharmacists (15). Use with caution in pregnancy because of concerns about teratogenicity (16). Efficacy in esophageal mucositis beyond the reach of the rinse is poor (5).

Cost: MB is inexpensive as a stock solution, with an average wholesale price of $31.25 per mL for a 50 mg/10mL vial (17). Compounding costs vary by pharmacy and can affect overall affordability (4,5). Given that MB is not yet FDA-approved for OM, it is unlikely to routinely be covered by insurance.

Summary: MB for OM has not yet been incorporated into major professional society guidelines, and most data come from a single institution; however, a recent systematic review strengthens its role as part of a multimodal strategy for refractory OM.  

References 

1. Roldan CJ, Nouri K, Chai T, Huh B. Methylene blue for the treatment of intractable pain associated with oral mucositis. Pain Pract. 2017;17(8):1115-1121. doi:10.1111/papr.12566.
2. Lee SW, Moon SW, Park JS, et al. Methylene blue induces an analgesic effect by significantly decreasing neural firing rates and improves pain behaviors in rats. Biochem Biophys Res Commun. 2021; 541:36-42. doi:10.1016/j.bbrc.2021.01.008.
3. Lee SW, Han HC. Methylene blue application to lessen pain: its analgesic effect and mechanism. Front Neurosci. 2021; 15:663650. doi:10.3389/fnins.2021.663650.
4. Roldan CJ, Huh B, Song J, et al. Methylene blue for intractable pain from oral mucositis related to cancer treatment: a randomized phase 2 clinical trial. BMC Med. 2022; 20(1):377. doi:10.1186/s12916-022-02579-8.
5. Roldan CJ, Chung M, Feng L, et al. Methylene blue for the treatment of intractable pain from oral mucositis related to cancer treatment: an uncontrolled cohort. J Natl Compr Canc Netw. 2021; 19(5):521-527. doi:10.6004/jnccn.2020.7651.
6. Roldan CJ, Rosenthal DI, Koyyalagunta D, Feng L, Warner K. Methylene blue for the treatment of radiation-induced oral mucositis during head and neck cancer treatment: an uncontrolled cohort. Cancers. 2023;15(15):3994. doi:10.3390/cancers15153994.
7. Karow J, Mackey RM, Olson E, et al. Methylene blue mouthwash for oral mucositis pain in cancer: an open-label, non-randomized study. J Pain Palliat Care Pharmacother. Published online April 11, 2026. doi:10.1080/15360288.2026.2655779.
8. Rondelli E, Romiti E, Gavlasova D, et al. Methylene blue in chemoradiotherapy-induced oral mucositis: systematic review and meta-analysis. J Cancer Res Ther. 2026; 22(1):13-19. doi:10.4103/jcrt.jcrt_2347_25.
9. Lavaee F, Amanati A, Ramzi M, et al. Evaluation of the effect of photodynamic therapy on chemotherapy induced oral mucositis. Photodiagnosis Photodyn Ther. 2020; 30:101653. doi:10.1016/j.pdpdt.2020.101653.
10. Ribeiro da Silva VC, da Motta Silveira FM, et al. Photodynamic therapy for treatment of oral mucositis: Pilot study with pediatric patients undergoing chemotherapy. Photodiagnosis Photodyn Ther. 2018; 21:115-120. 
11. Oso T, Roldan CJ. Methylene blue for the treatment of oral mucositis associated with cancer treatment in a pediatric patient. Pediatr Blood Cancer. Published online April 24, 2023. doi:10.1002/pbc.30375.
12. Youngster I, Arcavi L, Schechmaster R, et al. Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug Saf. 2010; 33(9):713-726. doi:10.2165/11536520-000000000-00000.
13. Belfield KD, Tichy EM. Review and drug therapy implications of glucose-6-phosphate dehydrogenase deficiency. Am J Health Syst Pharm. 2018; 75(3):97-104. doi:10.2146/ajhp160961.
14. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008; 371(9606):64-74. doi:10.1016/S0140-6736(08)60073-2.
15. Methylene blue injection [prescribing information]. US Food and Drug Administration. Updated April 2, 2026. Accessed June 29, 2026.
16. Iolascon A, Bianchi P, Andolfo I, et al. Recommendations for diagnosis and treatment of methemoglobinemia. Am J Hematol. 2021; 96(12):1666-1678. doi:10.1002/ajh.26340.
17. Smith BA, Robinson R, Most AK. From Theory to Therapy: Methylene Blue’s Emerging Role in the Management of Septic Shock. J Pharm Pract. 2026; 39(1):57-66. doi:10.1177/08971900251350554.

Conflicts of interest: None to report.
All authors attest that they verified all content and references; if they used large language models, it was only for searching content, grammar-related purposes, or formatting.
Authors’ affiliations: Icahn School of Medicine at Mount Sinai, New York, NY.
Version history: originally edited by Sean Marks MD, first electronically published in September 2026.