Historically speaking

People had understood the need for oral cleanliness for a very long time before we had any concept of plaque and its connection to mouth diseases. According to Chinese medicine, mouth washing was initially mentioned as a recommended practice around 2700 B.C. for the treatment of gum disorders. The printed reference was to rinse with a child's pee. According to descriptions in many nations over the years, cleaning the mouth with urine became commonplace.^[9] The ancient Egyptians and Romans also popularised the use of mouthwashes as a supplement to other oral hygiene practices. From 40 to 90 A.D. While Hippocrates is known to have prescribed mouth washing with a mixture of alum, salt, and vinegar in the ancient period, D. Pedanius Dioscorides, a Greek physician, recommended a mixture of olive juice, pomegranate seeds, wine, and gum myrrh for the treatment of halitosis.^[10]

Willoughby D. Miller, a dentist with microbiology training, was the first to advocate using an antibacterial mouthwash with phenolic chemicals to treat gingival irritation in the 1880s. He evaluated a large variety of antiseptics, at different dilutions, for their ability to stop the growth or kill oral germs as a skilled bacteriologist working under Robert Koch. He calculated the shortest amount of time needed to kill the organism by knowing the maximum time of contact between the antiseptic and the bacteria in the mouth cavity. Additionally, he distinguished between a bacteriostatic and a bactericidal effect and established that using an antibacterial mouthwash after brushing the teeth had both eliminated oral debris and decreased the bacterial burden.

The American Dental Association (ADA) endorses that mouthwashes be effective at changing microbiology by eradicating pathogens selectively without having any adverse effects on the healthy commensals in our mouths.^[9] According to evidence, using anti-plaque and anti-gingivitis mouthwashes twice a day for a prolonged period of time, specifically 0.12% CHX gluconate and essential oils with methyl salicylate that are approved by the ADA's Council on Dental Therapeutics.^[11], ^[12]

Chlorhexidine mouthwash

Due to its broad anti-microbial spectrum, chlorhexidine (CHX) gluconate is a widely used mouthwash and is regarded as the "gold standard". CHX interferes with bacterial cell osmosis and weakens the bacterial cell wall. Furthermore, the bacterial uptake of CHX is quick, which makes it easier for the cell wall to tear and ultimately the cytoplasmic membrane to rupture, leading to cell death. Its use as a therapeutic drug is constrained, nonetheless, by a variety of local adverse effects that Lindhe et al. reported. The precipitation of salivary proteins and organic salts causes a number of adverse effects, including tooth discoloration, changed taste perception, mucosal irritation, parotid edema, and a greater degree of supra-gingival calculus formation.^[18]

The recommended daily dose of chlorhexidine in mouthwashes is 20 mg, which is equivalent to 15 ml of mouthwash containing 0.12% chlorhexidine or 10 ml of mouthwash containing 0.2% chlorhexidine (20 mg). Although 30-second rinse times are suggested as being effective and pleasant, 60-second rinse intervals are also indicated.^[19] Chlorhexidine di-gluconate (0.2%) inactivated more than 99.9% of the SARS-CoV-2 virus in just 30 seconds of limited contact. Compared to povidone-iodine administered for 30 and 60 seconds, this had superior efficacy. In terms of the proportion of the virus they were able to inactivate, both mouth washes performed similarly, albeit chlorhexidine showed a better relative shift in Ct values.^[20]

The ability of CHX to adsorb (adhere to) anionic substrates like hydroxy apatite, pellicle, salivary glycoproteins, and mucosa is what gives it its remarkable antiplaque potency. Using radioactively labeled CHX, Bonesvoll et al.^[21] found that when a person washed with 10 ml of a 0.2% CHX solution for 1 minute, about 30% of the medication was still present. In the following 8 to 12 hours, the bound CHX was released, and throughout the following 24 hours, very low amounts of CHX could be detected in saliva. The medication's retention sites allow for a gradual release of the antibiotic, which prolongs the bactericidal effect.^[22]

It is well recognized that antibiotic use is linked to the emergence of microbial resistance. Subgingival plaque has established resistance to long-term medication therapy, according to observations made on patients who received systemic tetracycline for a prolonged period of time by Korman S^[23] and others.^[24] With regard to CHX, this has not been proven, and Gjermo proposed that although human bacteria did not acquire resistance after CHX therapy, the strains were less sensitive to the medication. A tiny amount of the industrial chemical para-chloroaniline (PCA) has been discovered in CHX products. It develops as a breakdown product when CHX is exposed to high temperatures or has a long shelf life. Researchers have found that Hibiclens, which contains 4% CHX, creates between 19 and 51 mg of PCA per liter.^[25] This is only half the level that the FDA has specified as allowed. This can be avoided by keeping CHX solutions in dark, chilled bottles. Both the FDA and the United Kingdom have established a limit of 100 mg/liter for PCA as acceptable.^[26] Williams et al. ^[25], ^[27] found PCA as mildly genotoxic, although Thompson et al.^[28] using the same test reported it to be negative. There haven't been any reports of an increase in cancer incidence in Europe after 20 years of oral CHX use.

Bis-biguanides, Alexidine-based mouthwash

Alexidine, a bis-biguanide chemically linked to chlorhexidine, has demonstrated promise in reducing plaque and gingivitis in both animal research and brief clinical trials. Over the course of a six-month study, two groups used a placebo and twice-daily washings with 0.035% alexidine. Plaque levels in the alexidine group significantly dropped over the course of the study. At 30 and 90 days, gingivitis was less severe, but not at 180 days, and tooth discoloration was still visible. Additionally, there were some cases of taste disturbance. In later research, plaque significantly decreased during a 60-day period, but gingivitis did not. There have been no additional studies reported since alexidine did not appear to have any advantages over chlorhexidine.^[14]

Bis-pyridines-based mouthwash

In the 1980s, octenidine dihydrochloride (OCT), a novel antibacterial cationic surfactant molecule, was created at the Sterling-Winthrop Research Institute in Rensselaer, New York. By attaching to negatively charged microbial surfaces and clinging tenaciously to lipid components, it breaks the cell membrane of fungus, bacteria, and yeast. There is a lack of information about secondary pharmacodynamics, drug interactions, metabolism, and microbiological resistance.

It is not believed that Octenidine dihydrochloride (OCT) accumulates in the body because it is flushed out with feces. It is more effective in-vitro against numerous bacterial and fungal species, giving it a wide range of activity than chlorhexidine (CHX), polyvinylpyrrolidone-iodine (PVP-I), poly-hexamethylene biguanide (PHMB), and triclosan. Its efficacy is pH-dependent. There was a statistically significant reduction in oral microbial growth after its treatment in all ten studies that looked at it (P= 0.05 to 0.001).^[29] There were eight studies that examined OCT and CHX for their effects on oral microbial development, and seven of them found it to be more effective than CHX.^[29]

Tooth stain was a commonly associated complaint with OCT use. The other side effects, which varied in frequency across the trials included, included poor mucosal tolerance, altered taste, tongue dorsum discoloration, bitter aftertaste, minor tongue tingling, and altered flavor.

Halogens-iodine, iodophor-based mouthwash

Iodine has long been utilized topically in medicine due to its well-known antiseptic and antibacterial qualities. Iodine's bactericidal impact is controlled by its chemical makeup. A povidone-iodine preparation (polyvinylpyrrolidone) that offers 10% of the iodine as free iodine and a 2% aqueous I2-KI in 53% glycerol solution have both been recommended for use in clinical settings. The latter formulation has largely been investigated as an anti-microbial and has been shown to minimize buccal lesions in experimental animals by more than 70%.^[9]

Because it possesses oxidizing capabilities, hydrogen peroxide has some minor antiseptic qualities. It has mostly been utilised as a wound-cleansing agent despite being relatively unstable. The molecule is quickly broken down into H2O and O2 by the catalase enzyme, which is found in bacteria and tissue fluids. A unique rinse made up of 5% povidone-iodine (PVP-I2) and 1.5% hydrogen peroxide has been created using a combination of the aforementioned ingredients. Despite the fact that this mouthwash is relatively new and has not undergone the rigorous testing of those described earlier, initial in-vitro and in-vivo data suggest that it is capable. ^[30]

Fluoride mouth rinses

Bibby^[31] and Cheyne^[32] autonomously reported in 1942 that topical application of fluorides to teeth is useful in reducing caries. Sodium fluoride and stannous fluoride are the two compounds most extensively studied. Shannon^[33] performed widespread laboratory studies on a stannous fluoride at the USAF School of Aerospace Medicine. Swerdloff and Shannon^[34] demonstrated the practicability of using the stannous fluoride mouth rinse as a part of a school preventive dentistry camp. Although they worked with a small group of children, they were able to detect an apparent benefit and could establish the safety of the technique.

Through a clinical trial, the anti-caries benefit of sodium fluoride mouthwash was assessed. Two examiners independently observed caries reductions of 33% and 43% in DMFS scores for the group using the stannous fluoride mouth rinse.^[35] According to the findings of a separate research project carried out in South Africa, the application of sodium fluoride at a concentration of 0.2% over the course of a period of six years led to a reduction in the number of cases of dental caries.^[36] The use of mouthwash containing 0.2% sodium fluoride on a weekly basis led to a 52.2% reduction in the average DMFT score in a research project that included 750 children from the United States.^[37]

Heavy metal salt-based mouthwash

Heavy metal salts have a long history of use as powerful antibacterial agents. When 0.5% zinc citrate or zinc chloride is added to mouthwash, it has an effect by attaching to the surface of oral bacteria, affecting adhesion, changing metabolic processes, and slowing the growth of the bacteria. Recent research has demonstrated zinc's contribution to decreasing plaque development. Up to this point, there have only been brief investigations on zinc salts in mouthwash.

Zinc salts do not cause staining. They have anti-calculus effects at the right concentrations, but the level that can be utilized is constrained by taste. The sanguinaria products also include 0.2% zinc chloride. Numerous investigations also revealed that plaque and gingivitis might be reduced by 0.035% copper sulfate concentration. Compared to chlorhexidine, it leaves some stains but not as many. Compared to zinc, copper has a higher affinity for binding to plaque and seems to be far more effective at reducing acid formation. Additional research on copper would be necessary. Stannous fluoride is a far more potent antiplaque agent than sodium fluoride, according to a number of short-term trials highlighting the significance of the tin ion itself.^[9]

Herbal extract-based mouthwashes

Phenolic compounds – Triclosan-based mouthwashes

Triclosan TCL is an aromatic chlorinated non-ionic chemical triclosan. It has ether and phenol functional groups. It is used in consumer goods like soaps and detergents because of its antibacterial and antifungal qualities. Triclosan is a non-ionic germicide that is a bis-phenol with a broad spectrum of antibacterial activity and low toxicity. Two strategies have been developed to increase the clinical effectiveness of oral triclosan products: (1) combine it with zinc citrate to benefit from its potential antiplaque and anti-calculus properties, and (2) incorporate triclosan in a copolymer of polyvinyl methyl ether and maleic acid. At low doses, it alters the bacteria's cytoplasmic membrane's permeability, resulting in cell efflux and variations in cellular oxygen levels; at higher concentrations, it also induces protein coagulation and denaturation. Mouthwashes contain 0.3% triclosan by weight.

In the USA, triclosan was outlawed in 2016 by the Food and Drug Administration. On September 6, 2017, it was pulled from the marketplace. The possibility has been raised that triclosan might harm the thyroid and heart by upsetting the body's endocrine equilibrium.^[40]

Listerine pyrimidines – Hexetidine-based mouthwash

The cationic chemical hexetidine (C21H45N3) belongs to the class of pyrimidine derivatives. It has a broad spectrum of antibacterial activity and is effective against both Candida albicans and Gram-positive bacteria. Hexetidine had previously been used to treat cervicitis and vaginitis. Additionally, it has been suggested as a supplement for halitosis, gingivitis, and aphthous ulcers. It has a strong affinity for plaque and oral mucosa proteins. Hexetidine can eliminate up to 98% of saliva-borne pathogens immediately after rinsing, but its effectiveness is limited since bacterial counts rebound to their baseline levels after 70 to 90 minutes. There have been reports of negative effects, such as desquamation of the oral mucosa epithelium.^[40]

Quaternary ammonium compounds

Plaque modifying agents

A few products have combined a number of ingredients to deliver antibacterial and plaque-disrupting properties. Ascoxal (also known as Ascutal-T) was created as a "mucolytic" substance based on the presence of ascorbic acid, percarbonate, and copper sulphate. Numerous studies that have been published have shown that gingivitis has not progressed while plaque scores significantly decreased (over the course of a four-week period). Another mixture that has been investigated for its antiplaque and anti-gingivitis properties is urea peroxide, 11% in anhydrous glycerine gel. The capacity of urea to denaturize proteins with its antibacterial and debridement properties is combined in this more stable form of hydrogen peroxide. Two clinical studies found a temporary decline in plaque scores but not gingivitis. It makes perfect sense to combine several agents, but the ideal mix hasn't yet been discovered.^[9], ^[14]

Probiotic mouth-rinses

Probiotics are living microbes that decrease the level of bad bacteria that is detrimental to one’s oral health. They have a huge market in the pharma sector. They have already been used in the treatment of many diseases like GIT infections, UTI, Lactose intolerance, and even cancer chemotherapy, Currently, research is going on in the field of dentistry as well. Examples are lactobacillus species and Bifidobacterium species. Bifidobacterium was most effective in the reduction of S. mutans counts. S. Salivarius can be used in the reduction of halitosis. They have emerged as an alternative to biotherapeutics and can be a huge boon in the field of dentistry.^[42]

The FDA published guidelines in 2016 that describes how manufacturers can satisfy the manufacturing requirements for early clinical studies for probiotics. As of right now, no probiotic has received FDA approval as a "live biotherapeutic product". However, there are FDA-regulated foods, including nutritional supplements, that contain probiotics that are legally offered, even though it is illegal for these goods to advertise that they can treat, prevent, or alleviate any disease.^[43]