Capsaicin is commonly administered topically to treat chronic pain associated with osteoarthritis, rheumatoid arthritis, diabetic neuropathy and nondiabetic peripheral neuropathy (10,31). The pain-relieving effects of low-dose topical capsaicin (0.025, 0.050 and 0.075%) were also demonstrated in conditions such as oral neuropathic pain and trigeminal neuralgia (32-34). These capsaicin cream formulations are also available over the counter (35). However, the efficacy of lower doses appears to be moderate and patient compliance with this therapy is often hindered by the need for daily repetitive application and the potential for irritation, which can manifest as sensations of burning, stinging or itching (31,36). Therefore, products containing higher concentrations of capsaicin were suggested to relieve pain after a single topical application (37). Higher capsaicin doses may desensitize cutaneous and subcutaneous receptors, resulting in reduced responsiveness to various sensory stimuli (3).

Several studies have tested the effectiveness of 8% capsaicin patch in managing orofacial neuropathic pain. In a case report, Sayanlar et al (38) revealed that a single application of the 8% capsaicin topical patch on a patient diagnosed with trigeminal postherpetic neuralgia demonstrated a substantial effect on reducing the pain level and area. Gaul and Resch (39) reported the effectiveness and safety of the application of 8% capsaicin patch in the treatment of four cases of neuropathic pain in the head and facial region caused by surgery or herpes zoster infection. Sustained reduction in pain was noted in three of the patients; however, two of them required repeated applications of capsaicin (39). Similarly, Martinez et al (40) reported the success of repeated applications of 8% capsaicin patch in managing pain in two patients with trigeminal neuralgia. These three studies have used a similar method, which was applying 8% capsaicin for 60 min in the painful area and ensuring eye protection such as using safety goggles, a compress and plaster, and eye dressing and cream (38-40).

Burning mouth syndrome (BMS) is a chronic neuropathic pain common in post-menopausal women (41). Several studies have explored the effectiveness of capsaicin in managing BMS symptoms using capsaicin therapies in different durations (ranging from 1 month to 1 year), concentrations (0.01, 0.02, 0.025 and 0.25%), and forms (capsule, gel and mouth rinse). All of these studies have reported that capsaicin successfully relieved BMS-related pain and discomfort (42-45). A study found no significant difference in the effectiveness of 0.01 and 0.025% capsaicin gels in reducing BMS symptoms, which indicates that the 0.01% gel is adequate to activate the analgesic effect of capsaicin for BMS (44).

Capsaicin in chili peppers was once proposed as a component that could cause ulcers, particularly in the gastrointestinal tract (46,47). However, later studies have found that it acted contrarily, i.e., capsaicin helps in preventing and relieving ulcers by inhibiting gastric acid secretion and stimulating mucus secretions and blood flow (47).

Despite studies discussing the effect of capsaicin on gastric or intestinal ulcers, published studies involving capsaicin and oral ulcers are limited. A study on 11 patients who underwent chemotherapy or radiotherapy reported the significant analgesic effect of orally administered capsaicin on oral mucositis pain; however, the effect was temporary in most patients (48). In an animal study, Jiang et al (49) reported a healing rate of 97.8% on the oral ulcer model in rats after 7 days of treatment with 0.05% capsaicin candy, which was significantly higher than those in groups receiving a placebo and dexamethasone. The study also reported a high inflammatory effect of capsaicin, as it reduces the expression of TNF-α and IL-6(49). This finding holds significance in the treatment of oral ulcers and needs further investigation.

TMDs are considered neuropathic and idiopathic pain disorders (50,51). In a randomized controlled study involving 30 patients with unilateral pain in the temporomandibular joint area, Winocur et al (52) found no significant difference in the pain relief effect between the group using 0.025% capsaicin cream four times a day and the placebo group, despite the significant improvement in pain parameters throughout the experiment (4 weeks). Later, Campbell et al (53) demonstrated that a higher concentration of capsaicin (8% cream) was effective in relieving pain in patients with TMDs, despite the shorter experiment duration (1 week). However, the authors also reported that the finding may be biased by the small sample size and inclusion of female subjects only due to funding and difficulty in participant recruitment (53).

Tanaka et al (55) found that a 500-ppm capsaicin diet reduced the incidence and multiplicity of tongue dysplasia on 4-NQO-induced tongue tumorigenesis in male rats. In another in vivo study, Mohamed and AlQarni (58) experimentally induced hamster buccal pouch carcinogenesis and demonstrated that capsaicin-treated hamsters exhibited slower cell proliferation and reduced incidence and severity of oral epithelial dysplasia.

Ip et al (56) found that increasing capsaicin doses and longer incubation periods enhanced the induction of apoptosis in NPC-TW 039 cells. Among the doses tested (0, 200, 250, 300 and 400 µM) and incubation times (12, 24, 36 and 48 h), treatment with 400 µM capsaicin resulted in the most significant decrease in cell viability, reaching nearly 65% after 48 h of treatment (56).

In another in vitro investigation focusing on oral squamous cell carcinoma of Asian origin (ORL-48), Kamaruddin et al (57) revealed that capsaicin treatment induced apoptosis, leading to apoptotic DNA fragmentation. In addition, the cell viability rate was the lowest, whereas the apoptosis rate was the highest after 72 h of treatment compared with that at 48 h (57).

Chang et al (59) investigated the interplay between apoptosis and autophagy in p53-mutated HSC-3 and p53-functional SAS cells treated with different concentrations of capsaicin. They revealed that capsaicin engaged with tumor-associated NADH oxidase (tNOX) to cause its degradation, and inhibition of sirtuin 1 (SIRT1) deacetylase activity, which enhanced unc-51-like autophagy activating kinase 1 (ULK1) acetylation and autophagy activation in p53-functional SAS cells (59). Capsaicin induced autophagy and apoptosis in p53-mutated HSC-3 cells, with autophagy inhibiting but later facilitating apoptosis. Reduced tNOX and SIRT1 levels, combined with high levels of ULK1 and c-Myc acetylation, reactivated the tumor necrosis factor-related apoptosis-inducing ligand pathway, resulting in apoptosis (59).

Huang et al (60) investigated capsaicin-induced sensitization to four chemotherapeutic agents (5-fluorouracil, cisplatin, docetaxel and doxorubicin) in oral squamous cell carcinoma (HSC-3 and SAS) and discovered that 200 µM capsaicin did not significantly induce apoptosis but caused ER stress and autophagy by suppressing ribophorin II. Furthermore, capsaicin in combination with anticancer agents sensitizes cancer cells to these agents and inhibits their viability by increasing necroptosis markers such as mixed lineage kinase domain-like protein and receptor-interacting protein kinase 3(60).

Santos et al (66) evaluated the inhibitory effects of capsaicin, dihydrocapsaicin and four synthetic capsaicinoid derivatives against Streptococcus mutans, a key contributor to cariogenic biofilm. They revealed that these compounds had a minimum inhibitory concentration (MIC) ranging from 1.25 to 5.0 µg/ml for these bacteria (66). Similarly, Gu et al (67) demonstrated the potent action of capsaicin against cariogenic bacterial strains, including S. mutans, Actinomyces viscosus, Lactobacillus and Streptococcus sanguis, by inhibiting acid production and biofilm formation. The MIC values of capsaicin were 50 µg/ml for S. mutans, A. viscosus and Lactobacillus and 25 µg/ml for S. sanguis (67). However, Doğan and Tunçer (68) reported contrasting findings: Although capsaicin did not inhibit the growth of S. mutans, it suppressed the growth of the oral probiotic Streptococcus salivarius M18 at concentrations >100 µg/ml. These discrepancies underscore the need for further studies into the nuanced effects of capsaicin, considering factors such as compound nature and concentration, and its effect on nonpathogenic oral bacteria.

Previous studies have also highlighted the efficacy of capsaicin against periodontitis-associated pathogens, notably P. gingivalis. An in vitro study by Zhou et al (13) demonstrated the inhibitory effect of capsaicin on the growth of P. gingivalis and the expression of NF-ĸB p65, indicating its potential to inhibit alveolar bone resorption. In addition, animal experimental studies, such as that by Cong et al (69), revealed that topical application of 0.075% capsaicin over the submandibular gland increased salivary secretion, which could have a significant utility in the control of microbial colonization.

Investigations into the antifungal properties of capsaicin, particularly against Candida albicans, a common cause of oral candidiasis infections, have yielded promising results (65). Nascimento et al (70) found that at the MIC of 25 µg/ml, capsaicin inhibited the growth of C. albicans. Furthermore, Omolo et al (71) highlighted greater susceptibility of C. albicans to capsaicin than certain bacterial strains. Behbehani et al (72) proposed the mechanism of capsaicin's antifungal activity, suggesting its ability to disrupt C. albicans cell wall integrity by inhibiting ergosterol biosynthesis. In addition, the combination of capsaicin and fluconazole exhibited enhanced efficacy, potentially aiding in preventing fluconazole resistance (72).

Despite studies investigating the potential antiviral properties of capsaicin, particularly against Herpes simplex virus (73), Lassa virus (74,75) and severe acute respiratory syndrome coronavirus 2(75), research on its effects on oral viruses is limited. Nevertheless, considering capsaicin's potential to inhibit the replication of certain viruses because of its ability to modulate immune and inflammatory responses (76), further related research could provide valuable insight into its therapeutic potential for viral infections in the oral cavity.