Oral lichen planus (OLP) is a chronic inflammatory disease of the mucosa of the oral cavity based on T-cell mediated autoimmune process. The estimated prevalence of OLP in the general population is 3.6% and the spectrum of disease presentation includes the following types: papular, reticular, atrophic, blistering, erosive and plaque. Being a chronic disease, the management of OPL is mainly related to the elimination of precipitating or provoking factors and relief of symptoms (15). Topical steroids remain the first-line treatment for OLP, while systemic steroids are reserved for acute exacerbation and in case of unresponsiveness to topical formulations. This class of drugs exerts its anti-inflammatory action by causing a reduction in pro-inflammatory cytokines and immune cells at the site of inflammation (16). However, these drugs are not devoid of adverse events (AEs). The most common is the occurrence of oral candidiasis, observed in about 25%–55% of patients. Other recognized local adverse effects include burning mouth, hypogeusia, oral hairy leucoplakia and hypersensitivity reactions to the drug. Systemic adverse effects are rare, but not unavoidable. These side events are related to systemic absorption of the drug and the consequent inhibition of the hypothalamic-pituitary-adrenal axis and secondary adrenal insufficiency (17).

In this scenario the use of benzydamine for OLP may represent an interesting new strategy to be employed in a multimodal approach to reduce symptoms. Given its role in reducing anti-inflammatory cytokines production and modulating the inflammatory status, different formulations of benzydamine may play an adjuvant role in the management of OPL. In addition, reducing the local transmission of painful stimuli may help relieve pain due to oral lesions. Moreover, thanks to its anti-microbial and anti-fungal properties benzydamine may reduce the burden of oral candidiasis caused by topical oral corticosteroids. Therefore, the design of new clinical trials aimed at evaluating the auxiliary and adjuvant role of benzydamine in the treatment of OPL could be very interesting.

Burning mouth syndrome (BMS) is defined as an intraoral burning or dysesthetic sensation, recurring for more than 2 h per day and for more than 3 months, without evident causative lesions during the clinical examination. Although the etiology remains unknown, there are increasing evidences underlying a neuropathic genesis of pain in BMS caused by peripheral and central nervous system changes (18). So far, no consensus has been achieved about the best treatment of BMS. Most commonly used therapeutic approach includes tricyclic antidepressants, α-lipoic acid, clonazepam, and cognitive-behavioural therapy (19). According to a network metanalysis (20) aimed at evaluating as primary outcome pain relief or burning sensation, only clonazepam is likely to reduce the pain of BMS when compared with placebo.

The efficacy of benzydamine for oral pain relief was evaluated in a randomized controlled trial involving patients with idiopathic BMS. Thirty patients were randomly assigned to one of 3 management modalities: oral rinse solution of benzydamine 0.15% 3 times a day for 4 weeks, placebo 3 times a day for 4 weeks or any kind of treatment. The study showed no significant differences between the groups (21).

Nevertheless, there is still a strong rationale for further evaluating the use of benzydamine in this setting. Benzydamine is known to block Na+ channels expressed in sensory neurons, and therefore attenuate nociceptor excitability by preventing the generation and propagation of action potentials through block of Na+ channels (7). In the light of these data and the neuropathic genesis of pain observed in BMS, new trials aimed at evaluating the efficacy of benzydamine as a potential additional weapon in relief pain of BMS patients could provide new clinical evidence on clinical indications other than inflammatory conditions of the throat and the mouth.

Postoperative sore throat (POST) represents one of the most common side effects after endotracheal intubation for any surgical reason. The estimated overall incidence ranges from 22% to 62% in the adult population, while from 24% to 44% in the pediatric population. The peak incidence of POST is reported between 2 and 4 h after extubation (22). POST is induced by direct mucosal inflammation caused by the mechanical trauma of endotracheal intubation. Recognized risk factors of POST include the presence of upper respiratory tract infection, duration of anaesthesia, intubation without neuromuscular blockers, number of intubation attempts, high cuff pressure, and the anaesthesiologist's experience (22).

The role of benzydamine in this setting has been largely explored. In 1987 Mazzarella et al. (23) assessed the efficacy of benzydamine 0.3% spray over placebo in relief POST when applied just before intubation and then every 3 h for 3 days following surgical procedure. Interestingly, together with clinical assessment of objective signs and subjective reported symptoms, also cytological differences confirmed these results. Two cytological samples were obtained from each patient by brushing the vocal cord, before intubation and after extubation, and at microscopical evaluation patients receiving benzydamine presented with a statistically significant less inflamed cytology (i.e., less inflammatory cells, blood cells and foamy cells).

Chang et al. (24) demonstrated the prophylactic role of benzydamine spray on POST after intubation with a double-lumen endobronchial tube. Applied on oropharyngeal cavity before intubation, benzydamine compared with placebo reduced the onset (at 1, 6 and 24 h after surgery) and the intensity of pain according to visual analogue scale (VAS). The role of benzydamine in reducing the incidence and severity of sore throat 24 h after surgery/extubation was confirmed in a systematic review and meta-analysis of 13 randomized controlled trials involving 1,842 patients (11). On the contrary, the same purpose needs to be further explored in pediatric population (25).

Even if POST has been largely evaluated, we believe that some issues still need to be addressed. First, in case of prophylactic POST treatment benzydamine is just sprayed on endotracheal tube cuff; however, it is well known how the source of pain after intubation is represented by traumatic inflammation of the laryngeal subsites that are in direct contact with the endotracheal tube, i.e., epiglottis, posterior commissure and vocal cords. In this regard, application of the drug through laryngoscopy directly to the target areas could provide additional benefit, even considering the availability of a new drug formulation such as gel. Moreover, thinking about tonsillectomy as an extremely painful procedure and at risk of postoperative bleeding, the development of new compounds able to reduce inflammation and bleeding without gargles is really intriguing. The potential auxiliary role of a novel combination of benzydamine with fibrin glue, could be of great interest in the multimodal approach to these unmet needs.

A recent work by Ardizzoni et al. (26) demonstrated in vitro the ability of benzydamine mouthwashes to impair Candida Albicans adhesion, biofilm formation, and biofilm regrowth and persistence. Moreover, as interestingly stated by the authors counteract Candida colonization may favour oral cavity health by reducing the growth and persistence of oral pathogens such as Streptococcus mutans.

Even if not confirmed by in vivo studies, these data highlight the possibility of using benzydamine to prevent oral candidiasis, as well as to treat biofilm-related Candida infections. This application may be of particular interest in frail, elderly, and immunocompromised patients. Therefore, clinical trials to address the need of reduce oral candidiasis in the aforementioned population could potentially expand the scope of benzydamine as an adjuvant antifungal tool.

In recent years, substantial progress in the unveiling of mechanisms underlying oncogenesis has led to a significant improvement in the anti-cancer therapy scenario.

Oral toxicities of targeted therapies are not unusual in clinical practice and present peculiar features which differ from those observed with chemotherapy (27). In this setting, the best described oral toxicity is that caused by mammalian target of rapamycin inhibitors (mTORi: everolimus, temsirolimus, deferolimus) (28). Mucositis induced by mTORi represents the most prevalent and dose-limiting adverse event, with an overall incidence of any grade according to Common Terminology Criteria for Adverse Events (CTCAE) of up to 52.9% (27). Mucositis can negatively impair adherence to the cancer treatment and affect the patient's quality of life, aspects that configure it as a non-negligible toxicity. Therefore, early management and prevention are crucial and include good oral hygiene and prophylactic use of alcohol-free dexamethasone mouthwash (29).

Another novel therapeutic breakthrough is represented by antibody drug conjugates (ADCs), which combine the potent cytotoxicity of chemotherapy with the antigen-specific targeted approach of antibodies into one single molecule. For instance, in the two studies BEGONIA (NCT03742102) and Tropion PanTumor01 (NCT03401385) evaluating the ADC datopotamab-deruxtecan in advanced triple negative breast cancer, grade 3 stomatitis has been reported in 14% and 9.1% respectively.

Considering these data and taking in account that benzydamine was able to relieve symptoms of OM induced by radio-chemotherapy, it would be of great interest the possibility of studying its efficacy in patients who are treated with mTORi and ADCs.