November 1, 2000
by Leeann Donnelly, Dip. DH, Hannu S. Larjava, DDS, Ph.D, Dip. Peri
ABSTRACT: There are questions as to whether chlorhexidine and fluoride can be used together. The purpose of this paper is to determine if chlorhexidine (CHX) and fluoride (Fl) when combined could be used as a powerful tool for the prevention of caries and gingivitis. A search over a 25-year period was conducted to locate studies about the mechanisms of action for CHX and Fl, the rationale for combining chlorhexidine and fluoride, and the interactions between CHX and Fl. In addition, studies describing the effects of combinations of CHX and sodium fluoride (NaF) at different concentrations, the effects on acid production associated with dental plaque, and the effects on CHX and Fl together in reducing gingivitis were also located. The search resulted in approximately 50 articles. Additional articles were obtained through article references. The objective of this study was to prepare a literature review on the rationale for combining chlorhexidine and fluoride. There is clinical evidence that a combination of CHX and Fl exhibits a decrease in caries production and gingival inflammation. When used together topically in the same vehicle CHX and NaF do not decrease the presence of free ionized Fl nor reduce the availability of CHX below therapeutic levels. When CHX and NaF have been combined at different concentrations, all plaque samples showed greater inhibitory effects of plaque regrowth and lower colony-forming units than when the agents were used separately. Clinically significant and useful reductions in gingival inflammation have been shown when CHX and NaF are combined and used with regular oral hygiene practices. From this review of the literature, it is apparent that CHX and Fl (specifically NaF) can be combined without losing their individual properties. For certain high-risk groups these formulations may be essential to oral health. Suitable products and the importance of sequence and timing in their application must be recognized by dentists and dental hygienists.
Extensive research has been conducted to determine methods for reducing or eliminating caries and gingivitis. These two common diseases are associated with dental plaque. Chemical adjuncts to mechanical plaque debridement have been investigated to aid in the control of dental plaque formation. One of the most studied and effective agents for the prevention of caries is fluoride (Fl). Chlorhexidine (CHX) has proven to be the most powerful chemical adjunct to reduce gingivitis. Chlorhexidine has also been used to reduce the number of Streptococcus mutans for caries prevention. It would seem of value to combine these two agents in controlling tooth decay and gingivitis. Fluoride and chlorhexidine combinations have been tested in toothpastes, gels, rinses, sprays and varnishes.3,5,6,8,9,12-14,16-18,22,26-28 At present, commercial combination products are not available in North America. There are questions as to whether CHX and Fl can be used together because of their ionic properties. The purpose of this literature review is to determine if CHX and Fl when combined could be used as a powerful tool for the prevention of caries and gingivitis for those individuals for whom conventional therapy is not effective.
BACKGROUND OF CHLORHEXIDINE AND FLUORIDE
Chlorhexidine is an antimicrobial and a cationic bisbiguanide that in its active form has the unique ability to be adsorbed to oral tissues such as hydroxyapatite, tooth surfaces, oral mucosa and salivary mucins for extended periods of time, and then be released later when its concentration in the oral cavity is reduced.24,25 This extended binding and slow release allows the antimicrobial to reduce bacterial recolonization for about 24 hours.24,25 While retained in the oral cavity, CHX also appears to be adsorbed onto the bacterial cell surface due to the cell surface negative charge at physiologic pH.4 Upon binding to the bacterial cell, CHX can disrupt the cytoplasmic membrane, damaging the permeability barrier, thus allowing the drug entrance to the cytoplasm where it causes a precipitation of its cellular contents (Table 1).11 CHX has been studied and found to be effective against Gram positive and negative bacteria, fungi, yeast and both facultative aerobic and anaerobic flora.7 Due to its bactericidal effects on these microorganisms it has been studied extensively for its use in the medical and dental fields.
Fluoride anion is used most commonly in the prevention of dental caries to strengthen tooth structure.10 During tooth development and to some degree also in the oral cavity, fluoroapatite is formed when fluoride is present. Fluoroapatite resists acid demineralization significantly better than hydroxyapatite. However, fluoride has other effects against cariogenic microorganisms (Table 1). In its ionic form it has the ability to be toxic to Streptococcus mutans (S. mutans) at high concentrations, and at low concentrations it can exert an antienzymatic effect on the organism.10 Inhibition of these enzymes decreases the ability of S. mutans to produce acid and to transport and store glucose and its analogues.10
RATIONALE TO COMBINE CHLORHEXIDINE AND FLUORIDE
Many preparations of CHX or fluoride are available for the prevention of gingivitis and caries (Table 2). Luoma et al.16 states that “clinical observations indicate single chemical agents used in prevention of dental diseases exert their action merely or predominately against either caries or gingivitis.” McDermid et al.18 has proposed that a combination of an anticaries and antiplaque agent may be useful and provide an additive protective effect if each agent acts at a different site. A potentially useful combination of CHX in any oral hygiene product with the addition of fluoride could be beneficial in reducing caries increments.29 Since there can be an inhibitory effect on acid production and plaque formation by CHX, it may reduce the cariogenic challenge enough for fluoride to act more effectively.27 There is evidence that, when used together for caries prevention, CHX and Fl provide additive benefits and together may prove valuable in the prevention of oral diseases.12 A number of studies have been conducted on the effects of combining CHX and fluoride in the same vehicle and their interactions with one another (Table 2).5,6,12-17,21,22 In spite of their opposite charges they have been shown to be successfully incorporated into the same vehicle without affecting their individual activity.5,6,12-17,21,27,28 It appears that there is more damage to the outer structures of S. mutans by the combination of CHX and fluoride than by each agent alone.20 It has been speculated that a combination of CHX and fluoride could exhibit a decrease in caries production and gingival inflammation.6 There is clinical evidence that this is possible.16 It has been shown that, when used together topically, sodium fluoride (NaF) and CHX in the same vehicle do not decrease the presence of free ionized fluoride or its protective action on enamel,6,16 nor reduce the availability of CHX below therapeutic levels.6,19
Chlorhexidine, a strong cationic compound, has the ability to form low-solubility salts with anions such as sulphate, phosphate and chloride24,25 which can make it a difficult agent to incorporate into dental products without losing its antiseptic properties through interactions with other ingredients.2 A fluoride used commonly in toothpaste, monofluorophosphate (MFP), was studied for its possible compatibility in formulations with CHX.2 Results from this study showed that when clinically relevant concentrations of 0.2% CHX and 8.0% MFP were used, a visible precipitate formed in all samples.2 This eliminated a large portion of the free CHX, leading the authors to conclude that MFP and CHX are not compatible.2 In a study by Dolles et al.,5 it was found that when 2.0% CHX and 0.1% NaF were used together in a toothpaste, the NaF could be fully recovered, leading to the conclusion that ingredients other than the NaF were interacting and binding with the CHX. Sodium lauryl sulphate, a detergent commo
nly used in dentifrices, was studied for its compatibility with CHX and also found to react with and render CHX ineffective.1 The time intervals of 3 to 120 minutes between use of CHX and sodium lauryl sulphate also showed that use of the two agents at a 3 minute interval did not decrease the plaque index and in fact the two agents need to be used at least 30 minutes apart or preferably greater that 120 minutes apart.1 It is apparent that ingredients in toothpaste which are anionic such as sodium lauryl sulphate and MFP can have adverse affects on CHX both before and after its use. This may be due to ionic interactions21 but to date no such interactions have been found with NaF and CHX.12
Due to the apparent compatibility of CHX and NaF, a combination of the two may be effective in caries prevention (Table 2).28 Over a two year period, Luoma et al.16 tested a 0.05% CHX and 0.044% NaF mouthrinse and toothpaste on schoolchildren and found there to be a 53% reduction in caries increment. In this study, interproximal caries were decreased by 73.2%, vestibular/lingual by 66.3% and occlusal caries by 15.3%, showing that significant caries reduction could be obtained with the exception of fissure caries.16 Ullsfoss et al.27 found that when a 0.2% CHX mouthrinse was used twice daily along with a 0.05% NaF mouthrinse once daily on children where the premolars were fitted with orthodontic bands scheduled for extraction, the fluoride rinse alone did not totally prevent caries but the CHX and NaF rinses used together were more effective. The reduction of lesion depth and mineral loss of the teeth examined by microradiographic data showed the lesions to be in the same range as sound enamel. Another study using dentifrices has shown a trend toward decreased caries incidence with subjects using 2.0% CHX and 0.1% NaF together compared with subjects using the agents separately. The highest number of subjects who did not have caries during the study period were from the CHX and NaF group.5 It is important to note that these dentifrices did not contain sodium lauryl sulphate.5 Contrary to these findings, use of a CHX and fluoride varnish for the prevention of proximal caries in children found the combination offered no added benefit when applied every six months when compared with a fluoride varnish alone.22
It is known that CHX and fluoride at high concentrations can produce a bactericidal effect against S. mutans, the major bacteria responsible for caries.7 Studies have shown that when CHX and NaF have been combined at different concentrations all plaque samples showed greater inhibitory effects of plaque regrowth and lower colony-forming units than when the agents were used separately (Table 2).9,18 CHX and NaF in a combination rinse form were used on subjects highly colonized by S. mutans (those with 100% detectable S. mutans at the beginning of the test period).27 After CHX and NaF rinsing only 20% of the surfaces showed colonization by S. mutans, whereas the fluoride rinse group showed 64% colonization.27 Plaque samples from this same study showed that after the CHX and NaF rinse only 53% of the samples were positive for S. mutans; whereas the fluoride group was 100% positive, demonstrating that fluoride alone did not eliminate S. mutans as effectively.27 When disinfection by a 1.0% CHX gel followed by the daily use of a 1.0% NaF gel was used to analyze the reappearance of S. mutans, it was found that S. mutans suppression was considerably longer than a placebo without fluoride.29 Even though S. mutans was not completely eradicated in this study, there was a significant decrease in the amount of recolonization by the bacterium.29 In contrast to these findings, a study by Mendieta et al.19 did show that when a 0.12% CHX and a 0.12% CHX and 0.022% NaF rinse were tested for plaque regrowth, the 0.12% CHX rinse performed better by one index than the combination rinse.
Acid production plays an important role in the process of dental caries and it has been postulated that, since CHX and fluoride can alter this process at different stages, when used together there may be a synergistic effect.18 A limitation of fluoride when used alone is that it has difficulty preventing caries formation if the plaque pH is too low.27 A way to increase the pH so that fluoride can act more effectively would be to use an agent that could reduce the acid formation of dental plaque.27 Since CHX has been shown to decrease plaque and subsequently reduce the amount of acid production, it would seem to be a worthwhile agent to use to accomplish the above proposition. Fluoride has also been shown to inhibit glycolysis and acid production, but when used together with CHX the terminal pH after glycolysis was shown to be much lower than if each agent were used alone.8,9,18,27 Mineral loss from enamel due to acid attack has also been shown to decrease when a combination of CHX and NaF have been used instead of NaF alone.27 This observation was believed to be due to decreased acid production and a pH drop for a short time of time, thus allowing available fluoride to form fluorapatite.27
As it has been shown that CHX and Fl together can have an effect on caries production, the formulations would be of even greater value if they could also reduce gingivitis (Table 2). When a 0.12% CHX and 100 ppm NaF mouthrinse was evaluated over a six week period where the subjects rinsed with the test solution or a placebo that contained neither CHX nor NaF, the results of the study showed that after six weeks the greatest decrease in gingival bleeding was found with the CHX and NaF group, but significant only for the mandibular posterior buccal and the lingual of mandibular anterior and posterior areas that can receive less attention from toothbrushing.12 Another study13 showed similar results when 0.05% CHX and 0.05% NaF at a pH of 6.0 was tested on adult subjects for a reduction in gingival inflammation along with regular oral hygiene practices. The test solution showed both significant and clinically useful reductions in gingival inflammation and added a useful component to regular oral hygiene practices and periodontal debridement for the reduction of gingival bleeding.13 With respect to area-specific reductions in gingival bleeding, it has been reported that vestibular bleeding was reduced from 63% to 14% and mesial bleeding from 59% to 39% using a toothpaste and mouthrinse with 0.05% CHX and 0.044% NaF for two years.17 The combination of CHX and Fl in toothpaste form has also been evaluated for its effect on gingivitis.28 One study showed that, six weeks into the 6 month trial the test group using a 1.0% CHX and 1000 ppm NaF toothpaste two times per day had lower gingivitis and bleeding scores than the control groups, but little additional reductions were achieved after six weeks.28
A common side effect of CHX is tooth staining and this may be the reason CHX has not been incorporated into commercially-available products designed for long-term use.23 Studies of the combination of CHX and Fl have looked at the amount of tooth staining of the subjects.5,12-14,28 When used in combination, it appears the fluoride may produce a reduced effect on CHX’s propensity to cause tooth staining.5 To further support this, it has been shown that, when children rinsed or brushed with a CHX and NaF preparation, there was little or no staining of the teeth.16 The finding from this study is difficult to apply to adults since their intake of beverages such as red wine, tea and coffee, and smoking habits, all of which can propensiate the staining from CHX, were not a factor in this study involving children.13 A reason proposed for this decreased staining aside from diet and smoking is that fluoride can reduce the adsorption of CHX to oral surfaces.5 Interestingly, when a CHX and NaF gel and mouthrinse were used on patients who had received orofacial radiation and had little or no saliva, there was no staining present on the subjects’ teeth.14 The author of this study postulated that saliva
may have a contributory effect on CHX’s propensity to cause staining.14
The most common form of plaque control is toothbrushing with toothpaste.21 Numerous studies have shown that CHX and NaF can be used together in toothpaste form and result in decreased plaque, gingivitis and caries.5,6,16,17,21,28 It is important to note that, when using a mouthrinse containing CHX and a toothpaste containing NaF, it has been found in one study that the combination therapy shows greater efficacy when the CHX is used prior to toothpaste, which is the opposite order that most toothpastes and mouthrinses are commonly used.21 Of greatest importance when combining a CHX rinse with a fluoride toothpaste that contains sodium lauryl sulphate is that the two be used at least thirty minutes apart.1
Mouthrinses are another common vehicle for delivering chemical agents and many studies have shown that CHX and NaF can be formulated together to also decrease plaque, gingivitis and caries to a greater extent than the use of just one of the agents.12-14,27 Varnishes containing both CHX and NaF have also been tested but the results showed that there was no added benefit to combining the two agents into one vehicle.22 CHX and NaF gels have also been successfully formulated and have proven to be of great benefit to the prevention of dental caries and gingivitis when followed by a CHX and NaF rinse in patients who have received head and neck radiation.14 The gel prevented caries formation and also caused remineralization of incipient carious lesions, a result that was not found in the group that used just the CHX and NaF mouthrinse.14 Gingivitis was also markedly reduced in this study and no complications of oral infection were noted during the study period.14
INDICATIONS FOR USE
It appears possible and beneficial to use CHX and NaF simultaneously in the prevention of caries and gingivitis. At present, there are no commercially-available products that contain both CHX and NaF. Therefore, when combining two separate preparations of the antimicrobials, oral health professionals need to be careful to prevent antagonistic interactions with the CHX and other ingredients such sodium lauryl sulphate.1 Individuals who have shown the most benefit from the use of this combination have been those identified as having a high caries risk such as children, orofacial radiation patients and the medically-compromised.13,14,16 Daily use of the combination has been shown to be most successful, whereas when a once-weekly rinse was tested to try to increase compliance, the results did not reach clinical significance.26 For patients currently receiving little prevention of caries and/or gingivitis from their current regime, this combination may be of value, but for chronic long-term use by the average person, this recommendation is not warranted at this time.28
From the review of this literature it is apparent that, although CHX and Fl (specifically NaF) have opposite charges, they can be combined without losing their individual properties. Many authors realize that the combination of these two chemotherapeutic agents is not required for everyone, but for certain high-risk groups these formulations may be essential to the maintenance of their oral health. It is clear that commercial products that would combine CHX and NaF would be of value for the prevention of caries and gingivitis. Dentists and dental hygienists can already use the combinations, however they must apply the suitable products and recognize the importance of sequence and timing in their application (Table 3).
eeann Donnelly, Dip. D.H., 4th Year B.D.Sc. Student; Hannu S. Larjava, D.D.S., Ph.D., Dipl. Perio, Chair, Division of Periodontics & Dental Hygiene; Bonnie J. Craig, Dip. D.H., M.Ed., Director, Dental Hygiene Degree Completion (B.D.Sc.) Program, Faculty of Dentistry, University of British Columbia.
Oral Health welcomes this original article. Complete references available upon request.
1.Barkvoll P, Rolla G, Svendsen AK: Interaction between chlorhexidine gluconate and sodium lauryl sulfate in vivo. J Clin Periodontol 1989; 16: 593-595.
2.Barkvoll P, Rolla G, Bellagamba S: Interaction between chlorhexidine gluconate and sodium monofluorophosphate in vitro. Scand J Dent Res 1988; 96: 30-33.
3.Chikte UM, Pochee E, Rudolph MJ, Reinach SG: Evaluation of stannous fluoride and chlorhexidine sprays on plaque and gingivitis in handicapped children. J Clin Periodontol 1991;18: 281-286.
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5.Dolles OK, Bonesvoll P, Gamst ON, Gjermo P: Determination of fluoride and chlorhexidine from chlorhexidine/fluoride-containing dentifrices. Scand J Dent Res 1979; 87: 115-122.
6.Dolles OK, Gjermo P: Caries increment and gingival status during 2 years’ use of chlorhexidine-and-fluoride-containing dentifrices. Scand J Dent Res 1980; 88: 22-27.
7.Emilson C: Susceptibility of various microorganisms to chlorhexidine. Scan J Dent Res 1977; 85: 255-265.
8.Giertsen E, Scheie AA: Effects of mouthrinses with chlorhexidine and zinc ions combined with fluoride on the viability and glycolytic activity of dental plaque. Eur J Oral Sci 1995; 103: 306-312.
9.Giertsen E, Scheie AA: Effects of chlorhexidine-fluoride mouthrinses on viability, acidogenic potential, and glycolytic profile of established dental plaque. Caries Res 1995; 29: 181-187.
10.Hamilton, IR: Effects of fluoride on enzymatic regulation of bacterial carbohydrate metabolism. Caries Res 1977; (suppl 1): 262-291.
11.Hennessey T. Some antimicrobial properties of chlorhexidine. J Periodont Res 1973; 12(suppl 12):61-67.
12.Jeffcoat MK, Bray KS, Ciancio S, Dentino AR, et al.: Adjunctive use of a subgingival controlled-release chlorhexidine chip reduces probing depth and improbes attachment level compared with scaling and root planing alone. J Periodontol 1998; 69: 989-997.
13.Jenkins S, Addy M, Newcombe R: Evaluation of a mouthrinse containing chlorhexidine and fluoride as an adjunct to oral hygiene. J Clin Periodontol 1993; 20: 20-25.
14.Joyston-Bechal S, Hernaman N: The effect of a mouthrinse containing chlorhexidine and fluoride on plaque and gingival bleeding. J Clin Periodontol 1993; 20: 49-53.
15.Katz S: The use of fluoride and chlorhexidine for the prevention of radiation caries. JADA 1982; 104.
16.Luoma H, Ainamo J, Soderholm S, Meurman J, Helminen S: Reduction of enamel solubility and plaque development with chlorhexidine-fluoride solutions. Scand J Dent Res 1973; 81: 523-527.
17.Luoma H, Murtomaa H, Nuuja T, Nyman A, Nummikoski P, Ainamo J, Luoma AR: A simultaneous reduction of caries and gingivitis in a group of schoolchildren receiving chlorhexidine-fluoride applications. Caries Res 1978; 12: 290-298.
18.Maynard JH, Jenkins SM, Moran J, Addy M, Newcombe RG Wade WG: A 6-month home usage trial of a 1% chlorhexidine toothpaste (II). Effects on the oral microflora. J Clin Periodontol 1993; 20: 207-211.
19.McDermid AS, Marsh PD, Keevil CW, Ellwood DC: Additive inhibitory effects of combinations of fluoride and chlorhexidine on acid production by Streptococcus mutans and Streptococcus sanguis. Caries Res 1985; 19: 64-71.
20.Mendieta C, Vallcorba N, Binney A, Addy M: Comparison of 2 chlorhexidine mouthwashes on plaque regrowth in vivo and dietary staining in vitro. J Clin Periodontol 1994; 21: 296-300.
21.Meurman JH: Ultrastructure, growth, and adherence of Streptococcus mutans after treatment with chlorhexidine and fluoride. Caries Res 1988; 22: 283-287.
22.Ostela I, Karhuvaara L, Tenovuo J: Comparative antibacterial effects of chlorhexidine and stannous fluoride-amine fluoride containing dental gels against salivary Streptococci mutans. Scand J Dent Res 1991; 99: 378-383.
23.Owens J, Addy M, Faulkner J, Lockwood C, Adair R: A short-term clinical study designed to investigate the chemical plaque inhibitory properties of mouthrinses when used as adjuncts to toothpastes: applied to chlorhexidine. J Clin Periodontol 1997; 24: 732-737.
24.Petersson LG, Magnusson K, Andersson H, Deierbor
g G, Twetman S: Effect of semi-annual applications of a chlorhexidine/fluoride varnish mixture on approximal caries incidence in schoolchildren. A three-year radiographic study. Eur J Oral Sci 1998; 106: 623-627.
25.Prayitno S, Addy M: An in vitro study of factors affecting the development of staining associated with the use of chlorhexidine. J Periodontal Res 1979; 14: 397-402.
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28.Spets-Happonen S, Luoma H, Forss H, Dentala J, Alaluusua S, Juoma A-R, Gronroos L, Syvaoja S, Tapaninen H, Happonen P: Effects of a chlorhexidine-fluoride-strontium rinsing program on caries, gingivitis and some salivary bacteria among Finnish schoolchildren.. Scand J Dent Res 1991; 99: 130-138.
29.Ullsfoss BN, Ogaard B, Arends J, Ruben J, Rolla G, Afseth J: Effect of a combined chlorhexidine and NaF mouthrinse: an in vivo human caries model study. Scand J Dent Res 1994; 102: 109-112.
30.Yates R, Jenkins S, Newcombe R, Wade W, Moran J, Addy M: A 6-month home usage trial of a 1% chlorhexidine toothpaste (I). Effects on plaque, gingivitis, calculus and toothstaining. J Clin Periodontol 1993; 20: 30-138.
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Table 1: Effect of Fluoride and Chlorhexidine on Bacteria
Table 2 : Effects of Various Combinations of Fluoride and Chlorhexidine on Caries, Plaque Formation and Gingivitis in Clinical Trials
Table 3: Practical Recommendations for Combined Use of Fluoride and Chlorhexidine
1. When toothpaste containing sodium lauryl sulphate is used, CHX rinse should be used a minimum of 30 minutes before or after brushing with the toothpaste.
2. When toothpaste containing sodium fluoride and no sodium lauryl sulphate is used, brushing can immediately follow the CHX rinse.
3. When two mouthrinses are used together, use the CHX first followed by the NaF rinse. The NaF rinse can be used immediately after the CHX rinse. Brushing with regular toothpaste containing sodium lauryl sulphate is again recommended only after a minimum of 30 minutes.
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