Design of Studies to Evaluate Plaque Control Agents

Journal of Dental Research http://jdr.sagepub.com/

Design of Studies to Evaluate Plaque Control Agents Stuart L. Fischman J DENT RES 1979 58: 2389 DOI: 10.1177/00220345790580120903 The online version of this article can be found at: http://jdr.sagepub.com/content/58/12/2389

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Design of Studies to Evaluate Plaque Control Agents STUART L. FISCHMAN School of Dentistry, State University of New York, Buffalo, New York, and Erie County Medical Center, Buffalo, New York

The importance of plaque in the etiology of periodontal diseases is reviewed. A survey is also presented of the various indices for scoring plaque in clinical trials. Variations in the clinical design, type of population studied, and difficulty in scoring gingival plaque are reviewed. A survey is presented of some recent published studies of plaqueinhibiting agents. J Dent Res 58(12):2389-2395, December 1979

Importance of plaque. Dental plaque has been defined as the soft, tenacious bacterial deposit which forms on the surface of a tooth. W. D. Miller' is generally credited with being the first person to describe bacterial plaque on teeth, but he did not appreciate the significance of the material, and it therefore received little attention for several decades. Bibby2 and Stephan3 presented some of the initial evidence of the pathogenicity of dental plaque. The importance of dental plaque in the development of dental caries stimulated a number of studies on the bacteriology and biochemistry of dental plaque and on its structure, flora, and rate of development. It is only recently that the significance of dental plaque for gingival health has been appreciated. L6e and his coworkers4 demonstrated a close correlation between the formation of plaque and the development of gingivitis. About ten years ago, Loe5 stated that: "Recent clinical and experimental research on the association between bacterial plaque and caries and marginal periodontal disease has concluded that natural mechanisms do not adequately clean the human dentition. The control of plaque must, therefore, be based on active removal of soft deposits. It is concluded that although quite recent experiments on the use of antibacterial

agents appear quite promising, mechanical tooth cleansing must still be regarded as a most effective means of controlling dental plaque." Microbial dental plaque is the primary cause of gingivitis in man. A cause and effect relationship between dental plaque and gingivitis has been established experimentally in longitudinal studies. Furthermore, sustained removal of dental plaque for several days predictably results in the resolution of gingivitis. Except in acute necrotizing ulcerative gingivitis, the response of periodontal tissues to plaque does not result from bacterial invasion, but rather from the diffusion of microbial products into the tissues via the junctional and pocket epithelia. Subsequent destruction of parts of the gingival tissues appears to be due mainly to host-mediated phenomena. Dental plaque, therefore, causes gingivitis which may later, through various path modifiers, progress to the development of periodontitis. Control of microbial plaque accumulation is the means by which preventive programs can be made effective. There is probably a low level of plaque accumulation that is not consistent with long-term periodontal health, but the amount that can be tolerated varies from one individual to another. In some persons, a small amount of plaque may cause severe disease, while in others, heavy plaque for decades will produce no major periodontal problem; however, neither the average "tolerable" level nor the variability has been established. The current consensus regarding the epidemiology, etiology, and prevention of periodontal diseases has been reported by the World Health Organization.6 It has been observed that a strong inverse correlation exists between the prevalence and severity of periodontal disease and the level of oral hygiene, regardless of 2389

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whether the disease is measured in terms of variety of material scored in plaque indices. A large number of indices have been gingivitis, periodontitis, or alveolar bone destruction. The amount of plaque present developed and used for scoring the area of on the tooth surfaces reflects the equili- the tooth covered by plaque. Because brium between the rate of plaque forma- plaque is colorless, it is usually visualized tion and the frequency and thoroughness by staining prior to scoring. Plaque is then of its removal. The findings of many surveys defined, in an operational sense, as "stainhave repeatedly substantiated the role of able material," because it usually includes microbial plaque as the principal etiologic pellicle as well as bacterial deposits. These methods generally rely on non-linear meaagent in periodontal diseases. At present, plaque is most effectively surements and should be treated as scores eliminated by mechanical means such as assigned on an arbitrary scale. brushing and flossing. However, plaque I should now like to review some of the control by these means is time-consuming indices in more general use for estimating and can be used effectively only by patients dental plaque in vivo and in situ. A more who are above average in dental knowledge, extensive summary was published following motivation, and manual dexterity. An anti- the symposium at the 1975 IADR meeting.9 The widely used Green and Vermillion plaque chemotherapeutic agent contained in an easy-to-use, palatable vehicle would "Oral Hygiene Index"10 scores "debris," make effective oral hygiene easily achievable. of which plaque is one component. Debris Such an agent could drastically reduce is defined as the "soft foreign matter loosely the prevalence of periodontal disease while attached to the teeth." It consists of mucin, augmenting the reduction of dental caries bacteria, and food. The surface area covered by debris is estimated by running a No. 23 already generated by fluorides. Clinical trials, in the context of this Explorer along the tooth surface being paper, are carefully controlled investiga- examined (Table 1). tions, employing a wide range of procedures TABLE 1 to test preventive or therapeutic methods ORAL HYGIENE INDEX10 and to define the maximum effectiveness under the best possible conditions, before O = No debris or stain present. and after they are used in the community. 1 = Soft debris covering not more than onethird of the tooth surface being examined. 2 = Soft debris covering more than one-third Review of indices. not more than two-thirds of the exposed but The choice of an index system to be surface. used in connection with clinical testing must tooth 3 = Soft debris covering more than two-thirds the of be decided in terms of the objectives of the exposed tooth surface. trial, the size of the population, the period In studies of groups of relatively small of the study, and the type and extent of changes anticipated. Indices for the amounts of plaque, the criteria of this Oral measurement of soft accumulations on Hygiene Index have usually proved too teeth were reviewed at the 1973 Confer- crude for demonstration of significant ence on Clinical Trials of Agents used in differences between study and control the prevention and treatment of periodontal groups. When plaque is evaluated in reladiseases. The deliberations of the conference tion to prevalence and severity of gingivitis, were published in a 1974 supplement to the only the amount of plaque in contact with the gingival margin is of critical importance. Journal of Periodontal Research.7 One method, proposed by Silness and Plaque weight is the most quantitative method of plaque assessment. Plaque de- Loe, 11 includes a consideration of plaque posits on teeth can be weighed in a wet thickness as well as area (Table 2). The Plaque Index scores consider only differences in or dry state, after careful standardized removal of the material. Alternatively, the thickness of the soft deposit in the plaque can be collected on foil or mylar gingival areas of the tooth surfaces with strips attached to the teeth and weighed no attention paid to the coronal extension following removal. Lobene8 has noted of the plaque. The assessment of plaque a poor correlation between plaque indices is made on top of calculus deposits, fillings, and plaque weight, probably due to the and crowns. Downloaded from jdr.sagepub.com by guest on July 9, 2011 For personal use only. No other uses without permission.

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STUDIES TO E VAL UA TE PLAQUE CONTROL

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FISCHMAN TABLE 2 PLAQUE INDEX11

0 = This score is given when the gingival area of the tooth surface is literally free of plaque. The surface is tested by running a pointed probe across the tooth surface at the entrance of the gingival crevice after the tooth has been properly dried. If no soft matter adheres to the point of the probe, the area is considered clean. 1 = This score is given when no plaque can be observed in situ by the unaided eye. However, the plaque is made visible on the point of the probe after it has been moved across the tooth surface at the entrance of the gingival crevice. 2 = This score is given when the gingival area is covered with a thin to moderately thick layer of plaque. The deposit is visible to the naked eye. 3 = Heavy accumulation of soft matter, the thickness of which fills out the niche produced by the gingival margin and the tooth surface. The interdental area is stuffed with soft debris.

The prototype for plaque indices was introduced by Ramfjord as part of his periodontal disease index. The technique, as modified by Schick and Ash,12 has been used for several studies. The modification consists of examining the facial and lingual surfaces of six selected teeth and restricting the scoring of plaque to the gingival half of the interproximal surfaces (Table 3). TABLE 3 MODIFIED PLAQUE INDEX (SCHICK-ASH) 12 0 = Absence of dental plaque. 1 = Dental plaque in the interproximal or at the gingival margin covering less than one-third of the gingival half of the facial or lingual surface. 2 = Dental plaque covering more than one-third, but less than two-thirds of the gingival half of the facial or lingual surface. 3 = Dental plaque covering two-thirds or more of the gingival half of the facial or gingival surface of the tooth.

The "Navy Plaque Index"13 employs a scoring system that gives greater weight to plaque in the immediate gingival area. The tooth is separated into three major zones: the occlusal, the middle, and the gingival zones. The gingival zone lies apical to an imaginary line connecting the crests

of the interdental papillae and roughly parallels the marginal gingiva. This area is subdivided into a mesial, distal, and middle zone, with each having a small area, not exceeding 1 mm, adjacent to the gingival tissue. The occlusal zone is coronal to the

JDent Res December 1979

contact area or height of contour. The middle zone extends between the occlusal and gingival zones and is divided into mesial and distal areas. By assigning each area a score of one, more emphasis is placed on plaque adjacent to the gingival tissues, inasmuch as the surface area is much smaller. Perhaps the most widely used index is Turesky's modification14 of the QuigleyHein index (Fig. 4). TABLE 4 MODIFIED PLAQUE INDEX (TURESKY)14 0 = No plaque. 1 = Separate flecks of plaque at the cervical margin of the tooth. 2 = A thin continuous band of plaque (up to 1 mm) at the cervical margin. 3 = A band of plaque wider than 1 mm but covering less than one-third of the crown. 4 = Plaque covering at least one-third but less than two-thirds of the crown. 5 = Plaque covering two-thirds or more of the crown.

Recommendations. The selection of the appropriate index depends on the nature of the agent or procedure to be tested and the goal of the study. For studies designed to evaluate the effectiveness of agents that alter the development of plaque and its relation to gingival disease, two indices are recommended. The Schick and Ash modification of Ramfjord's index12 and Turesky's modification of the Quigley-Hein index14 are the methods of choice. These indices are recommended because they emphasize the difference in plaque accumulation in the gingival third of the tooth. For measurement of plaque thickness, the index proposed by Silness and Lell1 remains unchallenged. There are, unfortunately, few data on examiner standardization with this index and its correlation with plaque weight and gingivitis in large studies. The amount of plaque present on tooth surfaces at a given time reflects an equilibrium between the rate of plaque formation and the rate of removal. Plaque scores and the correlation between plaque and gingivitis may thus be largely invalidated by an extra cleaning of the teeth before an oral examination. Plaque indices measure the current amount of plaque resulting from recent oral hygiene activities

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rather than the usual amounts of microbial deposits. No index yet described includes subgingival plaque scores. This means that, even with a plaque score index of zero, there may be microbial colonization on the root surface in connection with the periodontal pocket. Although plaque is clearly recognized as the etiologic agent in gingivitis, demonstration of in vivo plaque reduction will not, a priori, guarantee a corresponding reduction of periodontal disease. To prove a therapeutic effect, it is necessary to demonstrate activity related to a recognized disease state. Thus, an effective plaque control agent must prevent or reduce gingival disease in a patient population. Our attention is next directed to a suitable index for measuring gingival health. The Gingival Index proposed by Loe and Silness15 is the most widely used measure of gingival health (Table 5). It is frequently used in conjunction with plaque scores to determine the clinical efficacy of plaque-inhibiting agents. TABLE 5 GINGIVAL INDEX1 5 O = Absence of inflammation. 1 = Mild inflammation. There is slight change in color and little change in texture. No bleeding on probing. 2 = Moderate inflammation. There is moderate glazing, redness, edema, and hypertrophy. There is bleeding on probing. 3 - Severe inflammation. There is marked redness and hypertrophy, a tendency to spontaneous bleeding, and ulceration.

Study design. In general, there have been two sets of clinical trials of anti-plaque agents -those involving "restricted oral hygiene" or "no-brushing" studies and those permitting normal oral hygiene practices by the participants. The "no-brushing" studies followed the now-classic procedure reported by Loe4 to demonstrate experimental gingivitis in man. Subjects would refrain from brushing for a relatively short period of time (e.g., 14 days). During this period they would use either an experimental agent or a control agent, usually in mouthrinse form. At regular intervals, plaque would be scored,

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and the results of various treatment regimens compared. Various reasons justify this no-brushing regimen. Primarily, the studies have been designed to screen the gingivitis-preventing potential of known plaque inhibitors. The restriction of normal oral hygiene fosters the rapid development of gingivitis and permits a shorter and more easily managed clinical trial. Further, the use of a dentifrice in clinical trials of mouthrinses creates questions of chemical compatibility. For example, the ionic detergents present in dentifrices have the ability to bind quaternary ammonium substances and thus decrease their bioavailability. In a variation of this closed-end nobrushing regimen, we have used an open-end or end point technique. 16 Subjects refrained from brushing and were examined at regular intervals until a predetermined, but readily reversible, level of gingivitis was reached. The time taken to reach this end point was an indication of the gingivitis-preventing activity of the agent. Since any active agent would be recommended for use in a brushing population, it must be demonstrated to be effective in a population practicing at least normal oral hygiene. As will be discussed later, many agents shown to be effective gingivitis inhibitors in no-brushing studies have not been able to produce statistically or clinically significant reductions in gingival disease when used by brushing subjects. Another variable is the use of a dental prophylaxis (scaling and polishing) prior to the study. Plaque studies have usually been done on subjects rendered plaquefree at the start of the study by a thorough polishing of the teeth. They have measured the inhibition of plaque formation, rather than the removal of pre-existing plaque. In a clinical sense, then, these agents would likely be prescribed by the dentist for use following a thorough professional prophylaxis. They would not be dispensed ad libitum to the general population, most of whom receive no regular professional care. The significance of the prophylaxis procedure was demonstrated in a trial which we reported a few years ago. 1 7

Review of published studies. With an understanding of the variables

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in design of clinical experiments, we will now proceed to review briefly some recent studies of plaque-inhibiting agents. Johnson and Rozanis have recently reviewed the chemotherapeutic methods for plaque control.1 8 In their article they note: "A review of the pertinent literature, enlightening in many ways, often is frustrating because of the difficulty in trying to compare the results reported by independent investigators. In assessing the potential benefits, sometimes just clinical evaluations are performed, while in other experiments a battery of fairly sophisticated laboratory tests is conducted. The situation is confused further by the selection of the population to be studied. In some instances, volunteers with excellent oral hygiene and minimal, if any, dental disease comprise the control and experimental groups. In other experiments, the agents are administered in the presence of caries, gingivitis, and/or periodontitis. Finally, the participants of an investigation may or may not be required to abstain from mechanical oral hygiene procedures during the course of the experiment." The most frequently reported antiplaque agents fall into the following groups: bisbiguanides, antibiotics, quaternary ammonium compounds, enzymes, iodine, fluoride, and xylitol. Bisbiguanides have been studied extensively. The major agent investigated has been chlorhexidine. Chlorhexidine is adsorbed onto tooth surfaces and salivary mucin and is then slowly released in active form. It is this property of substantivity that apparently gives chlorhexidine its impressive antiplaque properties. Chlorhexidine appears to be significantly effective, reducing plaque in both brushing and no-brushing studies. There are conflicting data regarding its efficacy in a dentifrice formulation. Chlorhexidine does not seem to be effective against subgingival plaque and established periodontitis. The major adverse effect reported has been a discoloration of dental restorations, teeth, and the tongue. It also has a very bitter taste. Alexidine, also known as QR-7 1 1, has been shown to produce a statistically significant reduction in plaque. Staining of the teeth has also been reported. Antibiotics have also been evaluated as

plaque control agents. The ideal antibiotic, which has a very narrow spectrum directed toward plaque-forming organisms, but is not in general use against systemic disease, is not toxic or allergenic, and is retained in the tissues for a considerable period of time, apparently does not exist. The agents evaluated have been spiramycin, vancomycin, kanamycin, tetracycline, niddamycin, penicillin, and erythromycin. The consensus of the present literature would indicate that vancomycin is a useful therapeutic agent in situations in which it is necessary to remove substantial amounts of plaque for relatively short periods of time. Tetracycline has been shown to be possibly useful as an adjunct to the treatment of certain specialized types of periodontal disease. Quaternary ammonium compounds have also been tested. The major agents evaluated are cetylpyridinium chloride (CPC) and domiphen bromide. In several reported studies, there was a decrease in plaque accumulation but no significant reduction in the gingival index. This may be due to the reduction of supragingival plaque, but a lack of effect on subgingival organisms. Other agents reviewed by Johnson and Rozanis include enzymes, dextranase, iodine, chloride, and xylitol. Studies suggested that xylitol not only was a noncariogenic sugar substitute, but may have had an antiplaque effect as well. However, recent studies suggesting the possibility of xylitol toxicity in experimental animals have eliminated this agent from current one

investigation.

Conclusions. In this presentation, I have attempted to review the importance of plaque in the etiology of periodontal diseases and to survey the various indices for scoring plaque in clinical trials. Variations in clinical design, including the use of brushing, the type of population studied, and the difficulty in scoring subgingival plaque have been discussed. It would appear that for clinical studies, the recommendation by consensus is to score plaque by the Schick-Ash or modified Quigley-Hein index and to relate this to gingival health, as scored by the Loe-Silness index.

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REFERENCES MILLER, W. D.: The Presence of Bacterial Plaque on the Surface of Teeth and Their Significance, Dental Cosmos 44:425-446, 1902. BIBBY, B. G.: Neglected Factors in the Study of Dental Caries, JADA 22:222-239, 1935. STEPHAN, R. M.: Hydrogen-ion Concentration of the Dental Plaque, J Dent Res 17: 251-256, 1938. LOE, H.; THEILADE, E.; and JENSEN, S. B.: Experimental Gingivitis in Man, J Periodont 36:177-187, 1965. LOE, H.: A Review of the Prevention and Control of Plaque in: Dental Plaque. W. D. McHugh (ed.), Edinburgh: E. S. Livingstone, Ltd., 1970, pp. 259-270. World Health Organization: Epidemiology, Etiology, and Prevention of Periodontal Diseases, Geneva, 1978, Technical report series 621. CHILTON, N. (ed.): International Conference on Clinical Trials of Agents Used in the Prevention/Treatment of Periodontal Diseases, JPerio Res 9:Suppl. 14, 1974. LOBENE, R.: A Clinical Study of the Effect of Dextranase in Human Dental Plaque, JADA 82:132-135, 1970. ROSS, N. and CIANCIO, S. (eds.): Clinical Research in Pharmacology, Second Symposium of the Pharmacology, Therapeutics, and Toxicology Group, IADR, New York: Lever Bros. Co., 1975.

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10. GREENE, J. and VERMILLION, J.: The Simplified Oral Hygiene Index, JADA 68: 7-13, 1964. 11. SILNESS, J. and LOE, H.: Periodontal Disease in Pregnancy, Acta Odont Scand 22:121-135, 1964. 12. SCHICK, R. and ASH, M.: Evaluation of the Vertical Method of Toothbrushing, J Periodont 32:346-353, 1961. 13. ELLIOTT, J.; BOWERS, G.; CLAMMER, B.; and ROVELSTAD, G.: Evaluation of an Oral Physiotherapy Center in the Reduction of Bacterial Plaque and Periodontal Disease, JPeriodont 43:221-224, 1972. 14. TURESKY, S.; GILMORE, N.; and GLICKMAN, I.: Reduced Plaque Formation by the Chloromethyl Analogue of Vitamin C, JPeriodont 41:4143, 1970. 15. LOBE, H., and SILNESS, J.: Periodontal Disease in Pregnancy, Acta Odont Scand 21:533-551, 1964. 16. FISCHMAN, S.; CANCRO, L.; PADER, M.; BOLTON, S.; and PICOZZI, A.: A New Method for Assessing Inhibition of Gingivitis by Potential Therapeutic Agents, J Periodont 44:5 35-539, 1973 . 17. FISCHMAN, S.; PICOZZI, A.; CANCRO, L.; and PADER, M.: Influence of a Chlorhexidine and a Zinc Mouthrinse on Gingivitis, J Periodont 46:710-714, 1975. 18. JOHNSON, R. and ROZANIS, J.: A Review of Chemotherapeutic Plaque Control, Oral Surg, Oral Med, Oral Path 47:136-141, 1979.

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