While the general population perceives mucositis as soreness and inflammation of the mouth or gut, the cancer patient experiences it as one of the most dreaded and debilitating side effects of therapy. Mucositis can be painful, but especially oral mucositis (OM) stands as a prevalent adverse consequence of cancer treatment impacting the oral, pharyngeal, and esophageal mucosa [1]. The etiology and severity of OM lesions exhibit variability contingent upon the modality of treatment employed. For individuals undergoing chemotherapy, the incidence of OM approximates 40%, with a proportional increase noted in accordance with the chemotherapy agent and the number of therapy cycles [2]. In contrast, patients subjected to radiation therapy (RT) targeting the head and neck region present with an OM incidence exceeding 80%, a figure that may approach 100% among those undergoing modified fractionation and/or concurrent chemotherapy approaches [3]. The clinical spectrum of OM encompasses progressive oral pain, dysphagia, and odynophagia. Concurrently, patients may experience a diminished tolerance for oral intake, precipitating dehydration, sarcopenia, weight loss, and overall debilitation. The concomitant burden of unplanned hospitalizations, necessitating enteral hydration and nutrition via gastric feeding tubes, engenders heightened healthcare costs and jeopardizes the continuity of cancer treatment, compromising the outcome of oncologic patients [4].

Despite the advent of promising preventative strategies, their clinical efficacy remains circumscribed [5]. Attenuation of pain emerges as a paramount objective, holding a pivotal role in cancer treatment. Conventional palliative modalities encompass topical anesthetics, mucosal protective agents, corticosteroids, antihistamine mouthwashes, systemic opioids, non-steroidal anti-inflammatory drugs, and adjuvant analgesics such as gabapentin [6]. Nevertheless, the recurrent recourse to escalating doses of systemic opioids, inclusive of intravenous administration and patient-controlled analgesia devices, persists as a commonplace response to refractory OM pain, notwithstanding adequate safety standards [7]. Drawing upon its structural properties, topical methylene blue solution has garnered attention for its therapeutic utility across diverse cutaneous pain syndromes, such as anal fissures and genital herpes. As an oral rinse, it has demonstrated efficacy in ameliorating pain intensity and reducing opioid requisites vis-à-vis conventional therapy alone for individuals afflicted by oropharyngeal mucositis secondary to various cancer treatments [8]. The analgesic efficacy of methylene blue is attributed to its multifaceted modulation of nociceptive pathways, encompassing peripheral neurolysis, inhibition of nitric oxide synthetase, guanylyl cyclase, and histamine, culminating in an overarching antinociceptive effect [9].

The study in which this narrative review is based on looked to further substantiate the proposition that methylene blue mouthwash represents a viable and safe adjunctive therapeutic option for mitigating OM-associated pain in patients afflicted by head and neck cancer (HNC) undergoing RT, either as a standalone modality or in conjunction with concurrent chemotherapy.

Statistical analysis

Summary statistics, including the mean, standard deviation, median, and range, were provided for continuous variables such as age, NRS, and OF, and frequency counts and percentages are provided for categorical variables such as gender. The chi-square test was used to evaluate the association between categorical variables. The Wilcoxon signed-rank test was used to evaluate the change in pain scores from before to after treatment. The Wilcoxon rank sum test was used to evaluate the difference in continuous variables. A boxplot was generated as a visual aid to show the changes of continuous variable between patient groups.

Participants and therapeutic agent

This study included patients of any age, sex, HNC diagnosis, and stage of disease. All patients were receiving radiation therapy alone, or in combination treatment modalities. Completion of the follow-up was defined as an adequate medical records documentation from the initial use of MBOR to its discontinuation. The therapeutic mix was a dilution at 0.05% in water or normal saline solution, provided by institutional compounding pharmacy.

Outcome measures

The study measured patient-self reported numerical rating scale (NRS) scores for oral pain using a scale from 0 (no pain) to 10 (worst possible pain). It also measured changes in oral function burden (OFB) based on an assessment tool on a 7-point scale from 0 (normal) to 6 (total inability to eat, swallow, or talk, with each category scored as unable = 2, difficult = 1, and able = 0 and summed). Both the NRS and OFB scores were tabulated before starting MBOR, immediately after the first use, and until pain control was achieved (Table 1). Information was obtained from the medical records. Notes from patients’ diaries were frequently documented on the medical encounters.

Although uncontrolled oral pain is the final pathway to failed therapy in OM, current efforts seem to focus on the prevention and correction of the histological damage. Overall, the use of non-opioid systemic analgesics in this population is of limited use due to factors such thrombocytopenia, neutropenia, inability to use the oral route, renal and liver failure, presence of other comorbidities and polypharmacy, which can preclude the use of non-steroidal anti-inflammatory drugs and acetaminophen. Despite common side effects and well documented risk, the mainstay of managing pain in OM has usually relied on the use of opioid analgesics, frequently, using a patient-controlled analgesia device. Methylene blue oral rinse (MBOR) is emerging as a safe, effective, inexpensive, and widely available alternative which has been studied in clinical trials and reported in observational studies such as the one currently described. This study included patients of any age, sex, head and neck cancer diagnosis, stage of disease, as well as any combination of modalities for cancer treatment. All patients had uncontrolled pain from OM despite conventional treatment including, coating and anesthetic agents in oral rinses and systemic analgesics of all kinds.

Procedures

Patients are instructed to swish and gargle the MBOR mix every 6 hours until pain control is achieved (Figure 1). Detailed instructions are given about safety, toxicity, side effects, and precautions. Patients are advised to keep a diary of pain levels before and after oral rinsing, and medications used and their effect on their ability to eat and talk. Since MBOR is not commercially available, it must be mixed at a compounding pharmacy.

Clinical efficacy

The findings of this study underscored the safety and efficacy of 0.05% MBOR in OM pain associated with RT or combined chemotherapy and RT for HNC. Notably, the substantial reduction in mean NRS pain scores post-MBOR administration (mean reduction of 5.53; P<0.0001) attests to its analgesic potency, surpassing that of conventional rinses and systemic analgesics (Figure 2). Furthermore, objective assessment via OFB scores revealed a noteworthy mean reduction (mean reduction of -3.03; P<0.0001), further corroborating its clinical efficacy (Figure 3).

Therapeutic percutaneous feeding tube utilization

While the clinical indications for percutaneous endoscopic gastrostomy (PEG) tubes are multifactorial, their necessity signifies the magnitude of RT or chemo-RT toxicity [10]. Published data has shown that as many as 60% to 70% of patients receiving treatment with RT for advanced HNC will benefit from a feeding tube at some point during their treatment [11]. Notably, in this study a subset of patients previously reliant on PEG tubes, transitioned to oral feedings following MBOR-induced pain alleviation. Additionally, the low proportion of patients necessitating PEG tube insertion despite MBOR usage underscores its potential to mitigate severe malnourishment (Figure 4).

Topical mechanism of methylene blue

Methylene blue's topical analgesic properties have been harnessed across various tegument pain syndromes [12], attributed to its inhibition of peripheral axons, antioxidant, and anti-inflammatory effects [13]. Mechanistically, when utilized as an oral rinse, methylene blue is postulated to denature nociceptive nerve endings within OM lesions, inhibit the nitric oxide inflammatory pathway, and block N-methyl-D-aspartate receptors [14-16].

Safety profile of MBOR

During the reported study few patients reported mild and transient adverse events. Three of them experienced oral burning sensation during their first treatment. One patient discontinued use of the mix because of the pharmacy’s compounding cost (Table 3).

MBOR is emerging as a safe, effective, inexpensive, and widely available alternative, which has been studied in clinical trials and reported in observational studies. Despite concerns surrounding ionization effects on radiated tissue [17], when topically applied and in such low concentrations, an ionization effect had not been reported and was not a concern to the participating radiation oncologists on the reported study.

MBOR's topical application at low concentrations presents negligible systemic absorption and minimal risk of pharmacologic interactions or toxicity. If ingested, MB has rapid absorption which can reach peak plasma concentration in less than 2 hours [18]. Fortunately, the plasma concentration is calculated to be 100-fold less than an equivalent dose if intravenously administrated [19]. Therefore, based on the pharmacokinetics of methylene blue, it is projected that if ingested at diluted concentrations, the plasma levels of methylene blue can reach negligible levels and therefore present a low risk from pharmacologic interactions or systemic toxicity. If swallowed, patients might observe transient greenish discoloration of the feces and urine until clearance is accomplished. Although, broncho aspiration of MBOR has not been reported. Due to the clinical complexity of some patients with HNC, a speech pathologist recommendation must be followed.

Advantages and disadvantages of MBOR

Distinct from other topical agents, MBOR lacks local anesthesia properties, thus preserving gag reflex and taste sensation. Moreover, its potential for cumulative analgesic effect distinguishes it from short-acting oral rinses. However, its inability to access compromised mucosa in the esophagus and larynx poses limitations to its efficacy (Table 2).

Limitations

The study listed inadequacies in data acquisition that could not be addressed owing to the retrospective nature of the study. The discrepancy in the size of the comparison groups and the inability to address patient compliance.

Our narrative advocates for the integration of MBOR as a safe, efficacious, and cost-effective adjunctive therapy for refractory OM pain during RT for HNC. Its accessibility, low-risk profile, and potential to reduce opioid utilization and PEG tube dependency underscore its clinical utility. Large prospective randomized controlled trials are warranted to fully delineate and better evaluate MBOR efficacy.