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					A STUDY OF TOOTH WHITENING: SAFETY, EFFICACY AND MECHANISM OF ACTION

Gerard Kugel

A STUDY OF TOOTH WHITENING: SAFETY, EFFICACY AND MECHANISM OF ACTION

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A STUDY OF TOOTH WHITENING: SAFETY, EFFICACY AND MECHANISM OF ACTION

Dipartimento di Scienze Odontostomatologiche Università di Siena Viale Bracci 53100 Siena
Prepared for the graduate committee on June 13, 2004

Gerard Kugel Boston, MA, USA

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The present thesis is respectfully submitted to Prof Piero Tosi, Rector of the University of Siena, to Prof Alberto Auteri, Dean of the Faculty of Medicine, University of Siena, to Prof Egidio Bertelli, vice-Dean of the Faculty of Medicine and Director of the Department of Dental Science, and to Prof Marco Ferrari, Pro-Rector for international affairs and President of Dental School, University of Siena. Graduate Committee: Promotor
Committee Prof. Dr Marco Ferrari Prof. Dr C.L. Davidson Prof. Dr F. Tay Prof. Dr Toledano Prof. Dr Balleri

This thesis was prepared at Tufts University School of Dental Medicine, Boston MA, USA and at the School of Dentistry University of Siena, Italy.
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Contents
Chapters 1
2 Introduction A Novel Low Dose Tooth-Whitening Delivery System
Efficacy and Safety: A Randomized and Controlled Clinical Trial

3

Concentration and Dose Response
Clinical Trial Evaluating the Peroxide Concentration Response of a Polyethylene strip Delivery System over 28 Day

4

Light activated Tooth Whitening
Clinical Evaluation of a 35% Hydrogen Peroxide In-Office Whitening System

5

Chemical Vs Light activated Tooth Whitening Clinical Evaluation of Chemical And Light-Activated Tooth Whitening Systems

6

Tooth whitening and its Effect on Enamel and Dentin
Daily Use of Whitening Strips on Tetracycline Stained Teeth: Comparative Results after Two Months

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Long Term Hydrogen Peroxide Exposure and its Effect on Dentin
Comparative Study of 6.5% Hydrogen Peroxide Bleaching Strips on Tetracycline Stain: Clinical Response after Six Months Daily Use

8

Paint on delivery systems
A clinical Comparison of two Paint on Whitening Systems

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Maintenance of Whitening Clinical Study to Evaluate the Maintenance of Whitening after Bleaching Treatment

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10

Intrapulpal Temperatures with Light Activated Whitening
Effects of a Light Activated Bleaching System on Pulp Chamber Temperature in Vitro

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Effect of Tooth Whitening on Enamel
An exploratory study using SEM to evaluate the enamel surface effects in vivo of a 6% hydrogen peroxide strip bleaching system with that of a 2.5% chlorite tray bleaching system

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Summary and Conclusions

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Chapter 1

INTRODUCTION
The dental profession has succeeded in reducing caries and periodontal diseases and as a result dental problems have decrease to the point where esthetic improvements are now more attainable 1. One of the fastest growing areas of esthetic dentistry today is the management of the discolored and hypoplastic dentition. The demand for an improved appearance and a whiter smile has made tooth whitening a very popular dental procedure. Tooth whitening, sometimes referred to as ―bleaching‖, offers a conservative treatment option for discolored teeth in comparison to resin bonded composites, porcelain veneers or crowns
2,3

. Candidates for

whitening procedures include patients whose teeth are stained by aging, chromogenic foods, endodontic treatment, tetracycline use and smoking or use of other tobacco products. Success of the treatment depends on type, intensity and location of the discoloration and a careful diagnosis by the practitioner.

History of Tooth Whitening
Many attempts to find an effective bleaching method have been made through out the history of dentistry. The desire to have whiter teeth dates back at least 2000 years ago. During the first century the Romans physicians claimed the use of urine, especially Portuguese, to brush the teeth would whiten the teeth 4. Barber-surgeons used a solution of nitric acid to lighten the teeth after using a course metal file to abrade the enamel 4, practice until late eighteenth century.

In 1895 it was reported the combination use of pyrozone 25% and electricity to bleach the endodontically treated teeth 5. Later on, in 1916, it was stated the use of hypochloric acid to treat endemic fluorosis 6. In 1939 it was advocated the use of 30% hydrogen peroxide, ether 6

and heat to treat fluorosis staining 7. In 1966, it was promoted the combination use of hydrochloric acid and hydrogen peroxide to remove ―brown stain from mottled teeth‖ due to a chronic endemic dental fluorosis 8. The early efforts to whiten teeth relied on the assumption that the process involved the removal of extrinsic enamel stain. The mechanism of action was poorly understood.

It was only on 1970 that Cohen and Parkins first published a method for bleaching the discolored dentin of young adults with cystic fibrosis who has undergone tetracycline treatment
9

. This publication indicated that the mechanism of tooth whitening using hydrogen peroxide

involves penetration to the dentin. In 1976, Nutting and Poe introduced the walking bleach technique, which uses 35% hydrogen peroxide and sodium perborate for nonvital teeth bleaching10. The breakthrough in tooth whitening was in 1989 when Haywood and Heymann published the nightguard vital bleaching technique
11

. This is procedure is still widely used

among the dental community as the take-home bleaching system.

Tooth Whitening Systems
Tooth whitening with various concentrations of peroxide has been demonstrated to be safe and effective in a variety of regimens, including in-office procedures, dentist-prescribed and supervised home treatments and over the counter system approaches in the United States offer some form of tooth whitening system.
12

. Most dental practices

A) Take- home System The most common regimen is the at-home use for 2 to 4 weeks, based on the color of the teeth at the start of whitening
13,11

.The use of hydrogen peroxide for removing intrinsic stains from

vital teeth has been used for many years. Haywood and Heymann published the first article describing night guard vital bleaching in 1989
11

. A tray is fabricated from a model of the

patient’s teeth using a soft plastic nightguard. This tray is the loaded with carbamide peroxide 7

gel and seated over the teeth for approximately 2 hours. concentrations are 10% to 22% carbamide peroxide.

The most commonly prescribed

The advantage of the take-home systems is the decreased cost when compared to the in office bleaching options. The major disadvantages associated with take-home systems are: (a) they require significant patient compliance with the number of applications usually involving 1-2 hours twice a day or overnight wear, and (b) the entire treatment usually takes at least four weeks.

B) In-Office System The most acceptable applications involve are in-office techniques, dentist prescribed take-home systems or a combination of both. The in-office bleaching technique generally employs a 15%, 30% or 35% hydrogen peroxide bleaching agent (heated or non-heated).

The advantages of the in-office procedure are: (a) it requires minimal patient compliance, and (b) immediate results are attainable. The disadvantages to this treatment are: (a) chair-time requirement, and (b) cost to the patient. It is important to note that this procedure usually requires multiple office visits.

C) Combination Technique By combining the two techniques (in-office and take-home), there is a reduction in the amount of time and the need for repeated office visits as well as the expense associated with in-office bleaching as a stand-alone technique
14

. The combined technique increases overall success

and patient satisfaction. This procedure involves the use of a high concentration of hydrogen peroxide (35%) delivered chair side for one hour followed by a take home regimen of 5days. This is often followed by an additional chair side application. 15

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D) Whitening Strips A new method involves using a 5.3% hydrogen peroxide-impregnated polyethylene strip (CrestWhitestrips) for 30 minutes twice daily. This method is recommended for maintaining already whitened teeth. It can also be a good option to patients who cannot afford the cost of other whitening treatment or who do not have the time for multiple dental visits for tray fabrication teeth 13.
13

. It was published in 2002 the use of the whitening strips for tetracycline stained

Development of this flexible, polyethylene whitening strips allows for consistent bleaching using shorter contact times. Fixing the daily strip regimen at 30 minutes per day, a randomized, double blind, a double placebo-controlled clinical study was conducted to evaluate the effects of increasing the dosing regimen on tooth shade
17

. Also, an in vitro study explored the impact of

varying concentration of carbamide peroxide ranging from 0.4% to 10% on bleaching efficacy and the impact of increasing hydrogen peroxide concentration on bleaching strip efficacy and tolerability under clinical conditions
18

. These studies demonstrated that a modest increase in

peroxide concentration on a flexible bleaching strip results in increased whitening effectiveness, without adversely impacting on overall tolerability.

E) Light Activated Whitening Systems The introduction of light activated devices such as Plasma arc, Light Emitting Diodes (LED), Argon lasers, metal halide and xenon-halogen lights by dental manufacturers have helped create a public demand for the light enhanced tooth whitening systems.

Controversial papers were published evaluating the efficacy of light activated bleaching agents in 2002. The first article reported positive results19. The other articles concluded the opposite findings
20, 21

. These articles either maintained

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or questioned the results

23

.

The dental

profession still needs more evidence of its effectiveness in order to provide better and more 9

efficient treatment. The high demand for ―up to date‖ dental office by patients and clinicians stimulates manufacturers to inundate the dental profession with advertisements emphasizing that light activated tooth whitening is ―the state of the art‖ and should be part of the armamentarium of the office, with not clear evidence of its usefulness.

The use of hydrogen peroxide (H202) for bleaching teeth has been evident with use of heat or not 24. In order to gain treatment time, clinicians have attempted to accelerate the degradation of H202 by using heat or light. Cohen and Parkins introduced a technique for bleaching discolored teeth using hydrogen peroxide and a hand-held heating source 9.

Recent in vitro study has shown that the use of intense lights does elevate temperature of the bleaching material and as a result caused an increase in intrapulpal temperature. This may have an impact on post bleaching tooth sensitivity and pulpal health 25 . Another research in vitro has verified that the use of laser-activated hydrogen peroxide did not produce any perceivable colour change 26. Light-activated chair side bleaching systems probably offer the benefit of being less time-consuming while producing faster results.

The assumption is that clinically tolerable levels of heat will speed the breakdown of H2O2 tooth bleaching chemicals and this accelerated H2O2 breakdown will cause teeth to lighten more rapidly per unit time. In a recent study the decomposition of hydrogen peroxide was measured by the amount of oxygen released. The data from this study indicated that at temperatures of up to 85º C accelerated decomposition of the 35% H2O2 was minimal when compared to the control gel 20.

The use of light activated bleaching system to accelerate the bleaching process is still on question and more evidence needs to be gathered in order to make a more precise assertion of its effectiveness. 10

F) Toothpaste Many types of toothpaste are available in the market as tooth whitening products, but only a small number of them show stain removal ability and effectiveness. Most of these toothpastes do not contain bleaching agents in their formulation. The ones that do have very low bleach concentration and contact times relatively too short to be effective
27

. Whitening toothpastes

contain mild abrasives to remove surface stains. The peroxide content in the toothpastes are very low (1% or less), also the exposures of the toothpastes on the tooth is minimal hence any whitening minimal 28.

G) Over the Counter Products Easy availability of over the counter whitening products has made whitening of teeth more popular amongst people of all ages. There are different types of over the counter products like whitening dentifrices, tray based, whitening strips and the recently introduced brush applications. The latest inclusion to OTC products is a Brush technique. This technique is nontray based paint on application. Gingival irritation can be prevented due to the ease in application. Over the counter bleaching kit requires the consumer to use either a

prefabricated tray or fabricate their own semi-molded tray then fill it with supplied bleaching agents. These types are less than ideal because the trays are not custom fitted and the formulation is not sophisticated as those dispensed by the dentist 29.

Mechanism of Action
Many studies have been conducted to evaluate the effectiveness of various bleaching materials and techniques
27, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 15, 41, 42

. The brightening effect of the carbamide

peroxide and hydrogen peroxide or of both in a combined technique was reported during the above investigations.

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The exact mechanism of action is not completely understood. Hydrogen peroxide diffuses through the organic matrix of the enamel and dentin 43, 44, 45. Because the radicals have unpaired electrons, they are extremely electrophylic and unstable and will attack most other organic molecules to achieve stability, generating other radicals. These radicals can react with most unsaturated bonds, resulting in disruption of electron conjugation and a change in the absorption energy of the organic molecules in tooth enamel. Simpler molecules that reflect less light are formed, creating a successful whitening action. This process occurs when the oxidizing agent (hydrogen peroxide) reacts with organic material in the spaces between the inorganic salts in tooth enamel 46.

Bleaching Penetration
Enamel is the most dense tissue of the body a study conducted by Bartelstone in 1951 showed the penetration of I-131 through enamel to dentin which diffused to pulp
47

. Carbamide peroxide

breaks down into hydrogen peroxide, carbon dioxide urea and ammonia. Some of the by products penetrate the dentinal tubules reaching the pulp causing reversible pulpitis
43, 48

. Some

of the pulpal enzymes are sensitive to hydrogen peroxide along with heat. However, in vital bleaching the amount peroxide reaching pulp compared to amount of H2O2 required to cause this damage is very low
44

. Gokay et al a higher peroxide diffusion was seen in teeth with

restorations using a high concentration of carbamide peroxide compared to using a lower concentration 48.

In vitro data using extracted human teeth have demonstrated that a 10% carbamide peroxide gel can change the color of dentin over time 49. In this study teeth were sectioned and placed on glass slides. The teeth were sealed at the cut surfaces and bleached for 10 days. Digital photos were taken from marked areas and lightness values determined.

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Sensitivity is generally mild and transient. Sensitivity occurs earlier in treatment and decreases as treatment continues. This might occurs due to the close contact of gel to the tooth and disappearance may be due to sensory accommodation 50.

Tooth Discoloration: External – Internal Staining
Tooth discolorations can be superficial changes that affect the enamel surface, or can be deeper staining which affects the entire tooth structure. It is essential for the dentist to identify the type of discoloration in the patient’s tooth, diagnose the cause and define the appropriate treatment plan. Tooth discoloration in vital teeth can result from aging, tobacco use,

chromogenic foods, medications and pulpal pathology 51.

Superficial discolorations are usually caused by the staining effects of certain foods, beverages, or tobacco products. Tea, coffee, red wine, cola and smoking or chewing tobacco usually result in yellow, brown or black staining with pits, fissures, grooves and enamel defects retaining even more of the pigmenting effects. Yellow-brown stains are usually external and from accumulation of environmental colorants to an irregularly formed enamel matrix. Conversely, internal staining results from improper calcification and/or hypoplasia.

More severe discolorations result from systematically prescribed medication during tooth formation, intake of excessive amount of fluoride during enamel formation and calcification, different systemic conditions, dental conditions and/or treatment and aging. In 1956,

Schwachman and Schuster first reported tooth discoloration caused by incorporation of systemic tetracycline into tooth structure
52

. Tetracycline discoloration occurs with the systemic

intake of tetracycline during tooth formation (second trimester in uterus to 8 years of age). The discoloration of the permanent dentition depends on the amount and duration of tetracycline use
53

. The portion of the tooth, color and severity of the stains can be determined by the stage of

the tooth development at the time of the drug administration. Tetracycline is incorporated into 13

dentin during tooth calcification intra and post partum, probably through chelation with calcium forming tetracycline orthophosphate
54

. It can be deposited in fetal tooth buds when

administered in the third trimester of pregnancy or by a child during the development of the tooth (between ages 3 to 4 months and 7 to 8 years)
55, 56

. Colors may vary intensity of gray,

blue, brown and yellow. The different banding can also be attributed to the variations of the tetracycline derivates

Tetracycline staining is complex, and may necessitate extensive esthetic intervention. Vital bleaching with professional tray or strip systems can yield an evident improvement in appearance within a few weeks. While non-invasive, treatment may need to continue over an extended period. Some individuals will show favorable response after 3-4 months, after which treatment may be discontinued. Duration may be difficult to predict, given the variable clinical manifestations of tetracycline staining. Practitioners and patients should be advised that optimal bleaching of tetracycline staining may necessitate extended daily at-home treatment over a period of 3-6 months. The costs, risks, and benefits of the various treatment options must be considered as part of overall patient management
57, 58

. Excessive systemic fluoride during

enamel matrix formation and calcification can result in a defective matrix and improper calcification known as endemic enamel fluorosis or mottled enamel presents bilaterally with white chalky spots, yellow or brown staining
59,60

.

Fluorosis usually

Systemic conditions can also cause tooth discolorations. Amelogenesis imperfecta may result in hypoplasia or hypocalcification with yellow or brown stains and dentinogenesis imperfecta with brownish violet, yellowish or gray discolorations
61

. Hypoplasia or hypocalcification can

occur with clefting of the lip and palate or with acquired illnesses such as cerebral palsy, serious renal damage and severe allergies
46

. Blue, brownish or green tooth discolorations may be

caused by destruction of an excessive number of blood-cell erythrocytes in erythroblastosis fetalis a result of Rh-factor incompatibility between mother and fetus 46, 61. 14

Patients with porphyria, a rare condition that causes an excess production of pigment, may result in a red, purplish-brown or brownish tooth discoloration
46, 62, 63

. Dental caries, discolored

acrylic or restorations (made of composite, amalgam and/or metal), pins, posts and other materials employed in the dental environment can have an adverse effect on tooth coloration resulting in a darkened shade of the patient’s dentition. Aging usually brings thinning of the

enamel, loss of the translucent enamel layer, and formation of secondary dentin. The combination of less enamel and more darkened, opaque dentin creates an older-looking darker tooth 46.

Tooth Whitening Protocol
Tooth whitening, when used with professional supervision, can be safe and effective. A complete oral examination (with a review of the patient’s medical and dental history) and an updated set of periapical radiographs are necessary before planning any bleaching procedure. It is very important to determine the severity and cause of the tooth’s discoloration because it will allow the dental clinician to specify which treatment plan options are to be used. Discolorations due to medications will need longer and more persistent treatment than stains that occurred from aging, smoking or eating habits. Existence of carious lesions, restorations, endodontic treatment, pulpal anatomy and any periapical pathology must be determined during the clinical and radiographic examination before the onset of the bleaching procedure Different pulp size teeth may have different rates of response to bleaching
39 64

.

.

Existence of

caries, microcracks in enamel, exposed dentin and open margins in existing restorations must also be taken into consideration before treatment. Restorations that are not properly sealed and untreated carious lesions can lead to extensive sensitivity and should be treated before beginning any bleaching treatment 46.

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Tooth sensitivity and gingival irritation have always been a concern when tooth whitening is used. Both in-office and take-home bleaching procedures have been reported to induce sensitivity to a significant number of patients
65

. Tooth whitening is generally well tolerated.

Some patients may experience tooth sensitivity and mild oral mucosa irritation; however, these symptoms are generally mild and are alleviated at the end of treatment. Tolerability may be impacted by tray design, poor compliance or product ingestion. Tray thickness may contribute to poor compliance by causing occlusal interferences or jaw pain 13.

Detailed clinical and radiographic examination, fabrication of a custom-fitted, well- adapted mouth guard, careful selection of the tooth whitening material and proper patient instruction can significantly decrease the possibility of tooth sensitivity or gingival irritation during the take-home treatment. The tray fabrication technique should include ―scalloping‖ of the tray material to the gingival line to reduce the exposure of excess bleaching agent onto the soft tissues.

The thickness of the tray material (0.040‖ is recommended) is also important to prevent patient discomfort and other problems associated with the temporo mandibular joint (TMJ). The design of the tray (with reservoirs or without reservoirs) will be a determinant of the type of tooth whitening material to be used. Selection of the product to be used should be based on the concentration of active ingredient, viscosity and other salient features.

Teeth that have composite or amalgam restorations and are being treated with 10% carbamide peroxide demonstrated increased microleakage in the restorations, according to a study which evaluated the microleakage of previously restored Class II restoratives after exposure to 10% carbamide peroxide. Microleakage of previously restored Class II restoratives after exposure to 10% carbamide peroxide 66.

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The immediate placement of composite resin on bleached teeth has been controversial. According to a study evaluating the shear bond strength of composite restorations placed on bleached and non bleached teeth, there was no statistically significant difference when the composites were placed at 24 hours, 48 hours, 4 or 6 days
67

. A different study, evaluating the

effects of take home bleaching systems on enamel surfaces, suggests that a period of 4 days must elapse before bonding to a tooth bleached with a peroxide material, while no delay is necessary for a non-peroxide based bleaching system 68.

Most authors and tooth whitener manufacturers recommend the use of reservoirs during bleaching tray fabrication, in order to increase the effectiveness of the tooth whitening material
11

. Clinical studies examined the role of reservoirs reveal that the presence or absence

bleaching solution reservoirs in the bleaching tray did not increase the success of take-home bleaching with 10% carbamide peroxide gel
69

. Tooth whitening products pH differs in a range

of 4.0 to 7.5, with more acidic pH in materials with higher peroxide concentration. It is important that these materials have a relatively neutral pH, because root resorption, enamel demineralization and erosion may occur with pH less than 5.2
70

. Dental lasers have been used

for tooth whitening. Currently the argon laser is the most commonly used laser for power bleaching 71. There is not enough evidence to support safety and efficacy of laser bleaching 72.

Bleaching Side Effects
Toxicology FDA has approved hydrogen peroxide and carbamide peroxide to be used for debriding oral wounds. Even though bleaching is a longer process than debridment, in vitro toxicological evaluation of bleaching agents like 10% carbamide peroxide or 4% hydrogen peroxide was lower or comparable to commonly used dental materials like eugenol, dentifrices ,mouth rinses and composites 12.

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Studies have shown that daily exposure of carbamide peroxide should not exceed 10mg/kg

73

.

Li and Matis found that the average amount of bleaching agent used is 502mg per application. Even if the patient swallows all the gel, it would not exceed more than 8.37mg /kg 12 . Therefore the safety factor of the bleaching agent is high.

Oral Side Effects The mucosal irritation mostly occurs due to ill fitting trays, improper application of bleaching gel or using it for longer time than prescribed. Schulte J and others showed that the group with the overnight exposure to the bleaching gel subjects had mucosal irritation
74

. The soft tissue

irritation generally is minimal and is resolved either by adjustment of the bleaching tray, or shortly after cessation of the treatment 75.

Tooth Sensitivity Studies have shown that sensitivity occurs in 55 to 75% of the treatment groups. The placebo groups also experienced 20-30% sensitivity. One study reported tooth sensitivity of about 15 % wearing only the bleaching tray 76,77. The development of tooth sensitivity can be a multifactorial phenomenon. If the whitening tray is fabricated from a thick material, it can result in an appliance producing minor orthodontic movements
78

. Allergies and chemical sensitivity to the composition of the tray or the bleaching
79

gel. And the free radical formation of the whitening gel tooth brushing during participation in a clinical trial
77

.It can also result from overzealous

. Glycerine which is used to carry the active

ingredient can absorb water therefore can have a dehydration effect, hence resulting in sensitivity. 78,79.

Summary
In summary, although tooth whitening is one of the most popular dental procedures it is also one of the least understood. We are still unclear as to its mechanism of action. There is little data of 18

the effects of both concentration and dose on outcome. The techniques for measuring color change have been brought into question. The cause(s) of sensitivity are not clear nor are the issues of long tern exposure to hydrogen peroxide. The issue of rebound in color has not been well examined and issues related to maintenance of the whitening effect are also poorly understood

Most recently there has been a push to find ways to accelerate as well as improve the delivery of the whitening process. These include the application of a number of different light sources believed to accelerate the breakdown of peroxide and thus speed up the whitening process. The research in this area has been controversial with publications having quite different conclusions as to the efficacy of light activated bleaching. In an effort to improve the delivery systems both polyethylene strips and paint-on whitening products have been introduced. The efficacy of the paint-on products has been questioned and little research on these products can be found

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33) Jones AH, Diaz-Arnold AM, Vargas MA, Cobb DS: Colorimetric assessment of laser and home bleaching techniques. J Esth Den 11(2):87-94, 1999. 34) Haywood VB: Nightguard vital bleaching: a history and product update. 1. Esthet Dent Update 2(4):63-66, 1991. 35) Haywood VB: Nightguard vital bleaching: a history and product update. II. Esthet Dent Update 2(5):82-85, 1991. 36) Haywood VB, Heymann HO: Nightguard vital bleaching: how safe is it? Quintessence Int 22:515-523, 1991. 37) Haywood VB: Bleaching of vital and nonvital teeth. Current Opin Dent 142-149, March 1992. 38) Haywood VB: The Food and Drug Administration and its influence on home bleaching. Curr Opin Cosm Dent 12-8, 1993. 39) Haywood VB. Considerations and variations of dentist-prescribed, home-applied vital tooth-bleaching techniques. [Review] [27 refs] Compendium. Suppl 17:S616-21, 1994. 40) Nathanson D, Parra C: Bleaching vital teeth: a review and clinical study. Compend Contin Educ Dent 8(7):490-497, 1987.

41) Kugel G, Perry R, Papathanasiou, Kastali S: Combined in-office and at-home bleaching
system: An evaluation1. JDR 77:957, abstract #2604, 1998. 42) Deliperi S., Bardwell D.N., Papathanasiou A. Clinical Evaluation of a Combined InOffice and Take-Home Bleaching System. JADA The Journal of the American Dental Association, May 2004, vol. 135, no. 5,pp. 628-634 43) Bowles WH, Ugwuneri Z: Pulp chamber penetration by hydrogen peroxide following vital bleaching procedures. J Endod 13:375-377, 1987. 44) Bowles WH, Thompson LR: Vital bleaching: the effect of heat and hydrogen peroxide on pulpal enzymes. J End 12:108-112, 1986. 45) Fuss A, Szajkis S, Tagger M: Tublar permeability to calcium hydroxide and the bleaching agents. J Endod 15:362-364, 1989. 46) Goldstein RE, Garber DA: Complete dental bleaching. Quintessence books 1995. 47) Bartelstone HJ. Radioiodine Penetration through Intact Enamel with Uptake by Bloodstream and Thyroid Gland. Journal of Dental Research October 1951; 728-733 48) Gokay O, Tuncbilek M,Ertan R. Penetration of the pulp chamber by carbamide peroxide bleaching agents on teeth restored with composite resin. J of Endodontics 2000; 27; 92-94 49) McCaslin A.J., Haywood V.B., Potter B.J., Dickinson G.L., Russell C.M. Assessing Dentin Color Changes From Nightguard Vital Bleaching .JADA. The Journal of the American Dental Association, October 1999, vol. 130, no. 10,pp. 1485-1490

22

50) Michael G Jorgensen, William B. Carroll. Incidence of tooth sensitivity after home whitening treatment. JADA vol.133 August 2002 ;1076-1082 51) Blankenau R. Goldstein RE. Haywood VB. The current status of vital tooth whitening techniques. Compendium of Continuing Education in Dentistry. 20(8):781-4, 786, 788 passim; quiz 796, 1999 Aug. 52) Schwachman H, Schuster A: The tetracyclines applied pharmacology. Pediat Clin North Am 3:295, 1956. 53) Christensen GJ: Bleaching vital tetracycline stained teeth. Quintessence Int.1978 Jun: 9(6): 13-9 54) Mello HS. The mechanism of tetracycline staining in primary and permanent teeth. J Dent Child 1967; 34(6): 478

55) Moffitt JM, Cooley RO, Olsen NH, et al. Prediction of tetracycline-induced tooth discoloration. J Am Dent Assoc 1974; 88:547-552 56) Mull MM. The tetracycline and the teeth. Dent Abstr 1967; 12:346-350 57) Haywood VB, Leonard RH, Dickinson GL. Efficacy of six months of nightguard vital bleaching of tetracycline-stained teeth. J Esthet Dent. 9: 13-9, 1997 58) Kugel G, Aboushala A, Zhou X, Gerlach RW. Daily use of strips on tetracycline-stained teeth: comparative results after 2 months. Comp of Cont Edu in Dent. Jan 2002; 23 (1A): 2934 59) Stewart RE et al: Pediatric Dentistry. St Louis, CV Mosby Co., p.87, 1982. 60) Swift EJ: A method for bleaching discolored vital teeth. Quint Int 19:607, 1988. 61) Shafer WG, Hine MK, Levy BL: A textbook of Oral Pathology, 3rd Ed. Philadelphia, Saunders, 1974. 62) Jordan RE, Boksman L: Conservative vital bleaching treatment of discolored dentition. Comp Cont Ed Dent 5(10):803-808, 1984. 63) Faunce F. Management of discolored teeth. [Review] [30 refs] Dental Clinics of North America.27(4):657-70, Oct. 1983 . 64) Nathanson D, Parra C. Bleaching vital teeth: a review and a clinical study. Compendium 1987; 8:490-8 65) Nathanson D: Vital tooth bleaching: sensitivity and pulpal considerations. J Am Dent Assoc., 128(Suppl): 41S-44S, 1997. 66) Bardwell D, Habib C, Kugel G, Mehta N, Leone L: Microleakage of previously restored Class II restoratives after exposure to 10% carbamide peroxide. JDR 2000 Special Issue Vol.79, abstract 306.

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67) P. Yu, A. Aboushala, D. Bardwell. Effect of bleaching on Composite Resin Shear Bond Strength In Vitro. JDR 1999 Vol.78 special issue, abstract #1445

68) MacKay M., Perry R., Swift E., Varga M. S. Effects of the two home bleaching systems
on Enamel surfaces. JDR 1997 special issue abstract #1405. 69) Javaheri DS, Janis JN: The efficacy of reservoirs in bleaching trays. Operative Dentistry, 2000, 25, 149-151. 70) Price RBT, Sedarous M, Hiltz G: The pH of tooth-whitening products. J Can Den Ass, Sept. 2000, Vol. 66, No. 8, 421-426. 71) Sun G: The role of lasers in Cosmetic Dentistry Dental Clinics of North America, Vol. 44, No 4, Oct. 2000, 831-849. 72) Blankenau R, Goldstein R, Haywood V: The current status of vital tooth whitening techniques. Compendium of Continuing Education in Dentistry, Aug 1999, Vol. 20, No 8, 781794. 73) DahlJE, Becher R. Acute Toxicity of carbamide peroxide and commercially available tooth bleaching agent in rats; Journal of dental Research 1995; 74: 710-714 74) Schulte J,Morrissette D,Gasior E,Czajewski,M. Clinical Changes on the Gingiva as a result of at-home bleaching. Compendium 1993, VolXIV, no.11; 1362-1371 75) Haywood VB, Leonard RH, Chauncy NF, Brunson WD. Effectiveness, Side Effects and Long Term Status of Nightguard Vital Bleaching. JADA, September 1994 ,vol.125pg 12191226 76) Haywood VB, Caughman FW,Frazier KB,Myers ML. Tray delivery of potassium nitratefluoride to reduce bleaching sensitivity. Quintessence International ,vol32,no.2,2001;105-108 77) Michael G Jorgensen, William B. Carroll. Incidence of tooth sensitivity after home whitening treatment. JADA vol.133 August 2002 ;1076-1082 78) Pohjola R,Browning WD, Hackman ST, Michael ML, Downey MC. Sensitivity and Tooth Whitening Agents. Journal of esthetic and Restorative dentistry 2002; vol2, no.2; 85-91, 2002 79) Leonard RH, Haywood VB, Phillips C. Risk factors for developing tooth sensitivity and gingival irritation associated with nightguard vital bleaching. Quintessence International; 1997 vol. 28 no. 8; 527-534

24

Chapter 2

A Novel Low Dose Tooth-Whitening Delivery System
Efficacy and Safety: A Randomized and Controlled Clinical Trial

Abstract
A randomized, single-center, double-blind, parallel-group, placebo controlled trial evaluated the whitening efficacy and safety of 2-week, twice daily use of a 5.3% hydrogen peroxide toothbleaching gel delivered on polyethylene film. Efficacy was based on change in Vita® shade scores from baseline to the end of treatment. Thirty-three patients in each group completed treatment. Use of the peroxide-containing gel led to a mean change in baseline Vita® shade score of –3.70 ± 0.35, compared with a change of –0.87± 0.24 after use of a placebo gel. After adjustment for baseline scores, the mean difference in shade change between the peroxide gel–treated group and placebo-treated group was –2.85 ± 0.41 (P < 0.0001). Both treatments were generally well tolerated. The strips offer ease of use, comfort, and shorter duration of wear compared with other at-home bleaching systems.

Introduction
Tooth whitening is one of the most widely accepted esthetic procedures today, with treatment options that include in-office procedures, dentist prescribed home-applied systems, over-thecounter (OTC) bleaching kits, and a host of whitening dentifrices. Peroxides have been used for tooth bleaching for more than 100 years, and at-home nightguard vital bleaching, which involves use of a 10% carbamide peroxide gel in a custom-fitted tray, has met with much success since its introduction in 1989.1 The safety and efficacy of carbamide peroxide bleaching agents is well documented, and currently six products have been approved by the American Dental Association for home whitening.2 25

Tooth discoloration in vital teeth can result from chromogenic foods, tobacco products, medications such as tetracycline and fluoride, pulp pathology, and aging.2 Concentrations of up to 35% peroxide have been used to resolve discoloration. The most research has been conducted on 10% carbamide peroxide, which produces substantial lightening of treated teeth after 2 to 6 weeks of treatment,
3, 4

although a period as long as 6 months may be required for

stubborn stains, such as those caused by tetracycline or nicotine.5 After treatment, the whitening effect may persist for 3 or more years.

Tooth-whitening agents are remarkably well tolerated; the main adverse events are generally mild and transient tooth sensitivity and gingival irritation.6 Nevertheless, poor compliance and product ingestion are problems that are encountered with whitening therapy. Many of these are associated with the delivery trays, even custom-fitted ones, used in most at-home regimens. Tray insertion and removal can lead to sensitivity and gum irritation, and tray thickness is believed to contribute to poor compliance and development of occlusal interferences.

One alternative to the rigid delivery tray is a polyethylene strip with a hydrogen peroxide (H2O2)– containing tooth-whitening gel (Crest® Whitestrips™, a). In this article we report preliminary results from a randomized, placebo-controlled clinical trial that evaluated the whitening efficacy and safety of the 2-week, twice-daily use of a peroxide tooth-whitening gel delivered on a polyethylene film.

Materials and Methods Study Population
Seventy adults in good general health were selected for the study. To be included, participants had to have (1) a minimum of 16 natural teeth, including 4 maxillary anterior teeth; and (2) at least 3 maxillary teeth gradable at Vita®,b shade A2 or darker. Patients with obvious periodontal 26

disease (as evidenced by purulent exudate, tooth mobility, or other signs), oral pathoses requiring prompt treatment, active untreated dental caries, dentinal hypersensitivity, or who had tetracycline stain, dental fluorosis, or atypical non uniform stain were excluded from the study. Previous participation in a professional or home-use vital bleaching trial, participation in a dentifrice-whitening trial in the past year, or having fixed orthodontic appliances on the anterior teeth were further reasons for exclusion. All participants provided written informed consent and agreed to delay any elective dentistry (including dental prophylaxis) and to refrain from using any other than the assigned dentifrices or toothbrushes during the study.

Study Design
The study was a randomized, placebo-controlled, double-blind, parallel-group trial. Subject eligibility and an average Vita® shade score for each participant were determined at the screening visit (visit 1). At the baseline visit (visit 2), participants were stratified on the basis of their screening Vita® shade average score and gender, and randomized to either the placebo or the active treatment group with a block-randomization protocol. Baseline tooth color and safety assessments (described below) were performed. These assessments were repeated at the end of the 2-week treatment period (visit 3).

Treatment
The active treatment product consisted of a polyethylene film with a tooth-whitening gel containing 5.3% H2O2, supplied as strips for anterior teeth. Polyethylene film with a placebo tooth-whitening gel served as the control. Except for the presence of peroxide, test products were identical in composition and packaging. Study participants applied the strips twice daily to the maxillary anterior teeth for 30 minutes at home and brushed normally twice a day with Crest®,a toothpaste and provided toothbrushes.

27

Efficacy Assessment Efficacy was assessed as the change in Vita® shade tooth color between baseline and end-oftreatment visits. Up to six teeth from among the maxillary incisors and cuspids were selected at baseline on the basis of shade (minimum Vita® shade score of A2) and access for grading. At a minimum, the four maxillary incisor teeth were graded at baseline for each subject. The Vita® shade guide has been used successfully in clinical studies to gauge the efficacy of tooth whitening products.7,8 All assessments were made by a standardized, trained, and calibrated examiner, and performed in the same operatory throughout the study. All examinations were performed blinded as to treatment assignment.

Safety Assessment Extensive safety evaluations were performed to establish the absence of irreversible side effects associated with the use of the tooth-whitening gel. Assessments were performed at baseline and at the end of treatment and included the following: 1. Oral soft-tissue (OST) examination—this consisted of a visual examination of the oral cavity and perioral area, including gingiva (free and attached), hard and soft palate, oropharynx/uvula, buccal mucosa, tongue, floor of mouth, labial mucosa,

mucobuccal/mucolabial folds, and lips. 2. Oral hard-tissue examination—a visual and tactile examination was performed of the dentition and restorations. 3. Dentinal hypersensitivity—this parameter was assessed by questioning participants about tooth hypersensitivity to thermal, air, or other stimuli. 4. Löe and Silness gingival index (GI)—the GI was an assessment of periodontal health that evaluated the severity of gingivitis on the basis of color, consistency, and bleeding on probing (BOP). Six gingival areas on each Ramfjord tooth (tooth Nos. 3, 9, 12, 19, 25, and 28) were scored from 0 to 3, and an average score for each participant was derived 28

by dividing the sum of individual scores by the number of evaluable sites. Scoring criteria were as follows: 0—normal gingiva; 1—mild inflammation (slight color changes and edema; no BOP); 2—moderate inflammation (redness, edema, and glazing; BOP); 3— severe inflammation (marked redness, edema, ulceration; tendency toward spontaneous bleeding); 8—ungradable site; 9—missing tooth. 5. Silness and Löe plaque index (PI)—the PI was an assessment of the plaque deposit at the gingival area of the tooth. Dental plaque was scored on the facial, lingual, mesial, and distal surfaces of the Ramfjord teeth at 6 sites per tooth, in both arches (with a maximum of 36 sites). An average PI score was obtained for each participant, by dividing the sum of individual scores by the number of gradable sites. Scoring criteria were as follows: 0—no plaque/debris; 1—film of plaque adherent to free gingival margin and adjacent tooth area and seen in situ only after probing; 2—gingival area visibly covered with a thin to moderately thick layer of plaque; 3—abundant soft matter within the gingival pocket or on the tooth and gingival margin; 8—ungradable site; 9—missing tooth.

Analysis
Effectiveness was determined by measuring the change in Vita® shade codes from baseline to end of treatment for each evaluable tooth for the active group (Figures 2A and 2B). Shade scores were ordered from 1 to 16 according to the brightness grouping recommended by the manufacturer. Using this ranking, B-1 represented a score of ―1,‖ while C-4 represented a score of ―16.‖ A decrease in Vita®shade numeric code represented an increase in tooth whiteness. All adverse events related to OST, hard tissue, and dentinal hypersensitivity were summarized. Analysis of covariance was used to compare the mean Vita® shade score change from baseline between the active and placebo groups at the end of the 2-week treatment period. Baseline Vita® shade score was included as a covariate in the model.

29

RESULTS
Demographic and Baseline Characteristics The peroxide-treated and placebo groups were comparable with respect to age, sex, and race distribution (Table 1). Baseline Vita® shade scores were similar for the two treatment groups. Scores were 8.18 (D-4 to A-3) and 8.28 (D-4 to A-3), and, on average, ranged from A-2 to C-4 and from A-2 to A-4 in the active and placebo groups, respectively. Sixty four percent of teeth treated in the active group started at scores of C-2 or whiter.

Efficacy Table 2 summarizes the Vita® shade scores in the 2 treatment groups at the end of the 2- week treatment period. Data were evaluated for 33 participants in each group. After treatment with the peroxide-containing gel, the average score declined from 8.18 at baseline to 4.55, which was a change of –3.7 ± 0.35, representing an average increase in tooth whiteness of approximately 4 Vita® shades. By contrast, the placebo group experienced a Vita® shade score change of only – 0.87 ± 0.24. After adjustment for baseline scores, the mean difference in shade change between the peroxide gel–treated group and placebo-treated group was –2.85 ± 0.41 (P < 0.0001).

Safety Abnormal soft-tissue findings were noted at baseline and after completion of treatment. There were no new notable findings, nor was there any exacerbation of baseline pathology in any soft tissue for the 66 participants evaluated at the end of treatment. In the placebo group, one patient had slight cervical inflammation over one tooth. After treatment with peroxide-containing gel, one patient developed a minor superficial distal cervical lesion on one tooth and a second patient showed a swollen papilla between two adjacent teeth. The hard-tissue examination and dentinal hypersensitivity assessment were unremarkable. 30 Both groups experienced a

significant reduction (P < 0.0001) in gingivitis and plaque scores over the 2-week evaluation period (Table 3). After adjusting for baseline, there were no significant differences (P > 0.70) between the treatment groups in either the gingivitis or plaque scores after 2 weeks.

Discussion
This study demonstrates the efficacy and safety of a simple at-home tooth-whitening technique consisting of 5.3% H2O2 gel applied to disposable polyethylene strips. Twice-daily, 30-minute applications of the whitening strips for 2 weeks lightened discolored teeth by more than 3 Vita® shades, compared with a change of less than 1 Vita® shade in teeth treated with placebo gel. This treatment difference was highly significant after adjusting for baseline. Adverse effects after treatment were minimal and were observed in less than 10% of subjects in either treatment group. The main findings in these participants were papillary swelling, minor cervical inflammation, and a superficial cervical lesion.

Growing public interest in whiter, brighter teeth has increased demand for tooth-whitening procedures and products. More than 90% of dentists now offer an at-home whitening procedure, and 50% to 60% offer an in-office technique.
9,10

Despite their proven efficacy, these systems

suffer from certain drawbacks. In-office treatments are rarely successful in just a single visit, and 3 to 5 visits are usually needed to achieve reasonable results, making this an expensive procedure.11 Also, the higher concentrations of H2O2 (30% to 35%) used for in-office bleaching can cause chemical trauma to gingival tissue and also hold the risk of cervical root resorption. 12

Home-whitening systems provide a relatively inexpensive way to lighten discolored teeth but require patient compliance and discipline. The nightguard system, which requires patients to wear a custom-fabricated tray all night or for several hours during the day to achieve optimal results, is cumbersome and requires an average of 2 to 6 weeks of treatment. 2 Stubborn stains may require extended treatment periods of 2 to 6 months. Patient compliance with such lengthy 31

regimens is therefore a problem; in a 6-month nightguard vital bleaching study, the rate of compliance was only 60%.5 To encourage compliance, some offices recall patients on a weekly basis, which is not an efficient use of office time and also adds to the cost of the procedure. Many patients may therefore elect to have the procedure completed in the dentist’s office and will pay the extra cost.13 Thermal tooth sensitivity and gingival irritation, two common adverse effects that may occur in as many as two thirds of patients undergoing nightguard treatment, have been ascribed to tray rigidity, multiple changes of the whitening solution in a 24-hour period, soft-tissue coverage of the guard, and leakage of fluid from the guard.14 Furthermore, the system may not be favorable for use in certain patient groups. For example, patients with temporo-mandibular joint disorders can wear trays only during the day, and patients with bruxism may wear through several trays over the course oftreatment.11

A strong market also exists for OTC products, despite the fact that advertised claims for the efficacy and safety of these products remain unsubstantiated.11 Additional drawbacks of OTC systems include lack of professional supervision and poorly adapted bleaching trays, which can cause occlusal problems, joint and muscle pain, increased salivation, and discomfort during sleep with extended treatment times.2,11

The treatment described here provides an attractive alternative to current at-home whitening procedures. The polyethylene film with peroxide gel is supplied as ready-to-use strips and is easily applied by patients. This ease of use contrasts with the nightguard system, which must be custom fabricated, precisely fitted, and filled with the bleaching product at each use. In addition, successful tooth lightening with the film is observed with a much shorter duration of daily wear, and the thin film is more comfortable and better tolerated by patients. These factors favor patient acceptance of the procedure and encourage compliance with the whitening regimen.

32

Table 1—Demographic Characteristics at Baseline
Demographic Characteristic Age (years) mean range PeroxideContaining Gel (n = 35) Placebo Gel (n = 35) Overall (n = 70)

32.3 (18-66)

33.8 (22-56)

33.0 (18-66)

Sex Male Female 15 20 17 18 32 38

Race Asian Black White Hispanic 5 2 27 1 2 2 30 1 7 4 57 2

S19

Table 2—Average Shade Scores by Treatment
5.3% Peroxide Strip Placebo Strip

Baseline (n = 35)

End of Treatment (n = 33)

Change from Baseline (n = 33)

Baseline (n = 35)

End of Treatment (n = 33)

Change from Baseline (n = 33)

Mean

8.18

4.55

-3.70

8.28

7.49

-0.87

Standard Deviation

2.72

2.56

1.99

2.51

3.00

1.35

Median

7.00

3.67

-4.00

7.33

6.67

0

33

Table 3—Gingival (GI) and Plaque Index (PI) Scores at Baseline and 2 weeks

Baseline

End Of Treatment (2 weeks)

Change
(BaselineEnd of Treatment )

n

Mean

SD

Range

n

Mean

SD

Range

Mean

GI
5.3% Peroxide Strip

35 35

0.75 0.65

0.405 0.436

(0, 1.6) (0, 1.5)

33 33

0.23 0.16

0.331 0.323

(0, 1) (0, 1)

-0.52 -0.49

Placebo Strip

PI
5.3% Peroxide Strip

35

0.85

0.437

(0, 1.6)

33

0.24

0.407

(0, 1)

-0.61

Placebo Strip

35

0.76

0.450

(0, 1.3)

33

0.18

0.380

(0, 1)

-0.59

34

REFERENCES 1. Haywood VB, Heymann HO: Nightguard vital bleaching. Quintessence Int 20:173-176, 1989. 2. Haywood VB: Current status and recommendations for dentist-prescribed, at-home tooth whitening. Contemp Esthet 3(suppl 1):2-9, 1999. 3. Haywood VB, Leonard RH, Nelson CF, et al: Effectiveness, side effects, and long-term status of nightguard vital bleaching. J Am Dent Assoc 125:1219-1226, 1994. 4. Matis BA, Cochran MA, Eckert G, et al: The efficacy and safety of a 10% carbamide peroxide bleaching gel. Quintessence Int 29:555-563, 1998. 5. Haywood VB, Leonard RH, Dickinson GL: Efficacy of 6 months of nightguard vital bleaching of tetracycline stained teeth. J Esthet Dent 9:13-19, 1997. 6. Li Y: Biological properties of peroxide-containing tooth whiteners. Food Chem Toxicol 34:887-904, 1996. 7. Croll TP, Sasa IS: Carbamide peroxide bleaching of teeth with dentinogenesis imperfecta discoloration: report of a case. Quintessence Int 26:683-686, 1995. 8. Small BW: The application of and integration of at-home bleaching into private dental practice. Compend Contin Educ Dent 19:810-813, 1998. 9. Christensen GJ: Bleaching teeth: practitioner trends. J Am Dent Assoc 128:16S-18S, 1997. 10. Christensen GJ: Bleaching teeth: report of a survey. 1997. J Esthet Dent 10:16-20, 1998. 11. Blankenau R, Goldstein RE, Haywood VB: The current status of vital tooth whitening techniques. Compend Contin Educ Dent 20:781-794, 1999. 12. Barghi N: Making a clinical decision for vital tooth bleaching: at-home or in-office? Compend Contin Educ Dent 19:831-838, 1998. 13. Nash RW: In-office bleaching system for quick esthetic change. Compend Contin Educ Dent 20:986-1000, 1999. 14. Leonard RH: Efficacy, longevity, side effects, and patient perceptions of nightguard vital bleaching. Compend Contin Educ Dent 19:766-781, 1998.

35

Chapter 3 Concentration and Dose Response
Clinical Trial Evaluating the Peroxide Concentration Response of a Polyethylene strip Delivery System over 28 Day ABSTRACT
OBJECTIVES: The research evaluated the peroxide concentration whitening response following self-directed use of whitening strips over a 28-day period.

MATERIALS AND METHODS: A randomized, double-blind, parallel group clinical study was conducted. 37 healthy adult volunteers were randomly assigned to one of three groups based on tooth color at screening – 1.8% hydrogen peroxide strips (HPS), 3.3% HPS or 5.3% HPS. Subjects applied the assigned maxillary strips twice per day for 30 minutes over 28 days. Tooth color was evaluated at day 7, 14 & 28 from digital images of the maxillary 6 anterior teeth using a standard method. Treatments were compared using analysis of covariance (adjusting for baseline), or analysis of variance at a 0.05 level of significance.

RESULTS: Hydrogen peroxide at concentrations ranging from 1.8-5.3% resulted in significant (p < 0.05) color improvement versus baseline as early as Day 7. There was a clear

concentration-response for all color parameters (b*, L* and E*) at all timepoints, favoring the higher concentrations. While the concentration-whitening relationship approached a linear

response at Day 7, continued treatment resulted in incremental color improvement. All three peroxide concentrations were well tolerated, and no subjects discontinued early due to a treatment-related adverse event.

CLINICAL SIGNIFICANCE: Digital image analysis demonstrated a concentration gradient for whitening response following use of a low peroxide dose strip whitening system. 36

INTRODUCTION
Discoloration of the natural dentition may occur as a result of exposure to various chemicals or medicines, disease processes, and other factors.1 Much of this staining is intrinsic in nature, and a likely product of the aging process that can be readily measured as increased yellowness and decreased brightness in tooth color.2 Treatment typically involves peroxide-based vital bleaching, sometimes in combination with other esthetic dental procedures. In practice, peroxide-containing gels may be applied using a tray, strip or other barrier system, at-home over time, or in-office with gingival isolation, to assure necessary contact time for peroxide diffusion through enamel to the underlying stain.

Practiced widely since the late 1980s, vital bleaching is recognized as safe and effective. There are several contemporary reviews that support tooth whitening using peroxide-containing gels in combination with barrier systems.3-5 Some cases with extensive staining, from tetracycline or other agents, have been treated daily with peroxide for several weeks or months without significant adverse response.6,7 Post-treatment follow-up, which has now exceeded a decade in some instances, provides further evidence of safety with vital bleaching.8,9

Peroxide concentration and contact time with tooth surfaces are recognized as playing a prominent role in the clinical response seen with vital bleaching.10 Since the 1980s, use of higher peroxide concentration gels has become more commonplace, in turn, lowering recommended treatment times from several weeks to only a few days. At the extreme, very high concentrations of hydrogen peroxide in the range of 35-38% provide a basis for tooth whitening as an in-office procedure.11,12 Research on peroxide degradation in vivo, and in vitro shade measurements on extracted teeth further support a relationship between peroxide concentration and whitening.13,14

37

Although widely-accepted and plausible, there are surprisingly few peroxide concentration ranging studies in the clinical trials literature. Such evidence is largely confined to the traybased, professional bleaching systems at hydrogen peroxide-equivalent concentrations of 37%.7,15 Concentration ranging studies provide important evidence, not only of product response, but also of measurement validity in clinical trials applications. New clinical research was conducted to evaluate the effects of peroxide concentration on clinical response using one of the new selfdirected strip-based bleaching systems. Digital image analysis was used to extend the dose ranging evidence from older tray-based research to the newer strip delivery system.15

MATERIALS AND METHODS
A randomized, double-blind, parallel group clinical trial was conducted to evaluate the impact of peroxide concentration and treatment duration on whitening effectiveness. The research was conducted within a private dental practice located in western Tuscany, Italy. Following informed consent, 37 healthy adult volunteers underwent vital bleaching of the maxillary anterior teeth using a flexible polyethylene strip coated on one side with an experimental, hydrogen peroxide bleaching gel. After balancing for baseline tooth color, subjects were randomly assigned to one of three experimental groups: 1.8% hydrogen peroxide strips, 3.3% hydrogen peroxide strips or 5.3% hydrogen peroxide strips (The Procter & Gamble Company, Cincinnati, OH USA). Maxillary strips carried 0.200 mg of hydrogen peroxide gel distributed uniformly across the 9.9 cm2 strip surface. In this double-blind study, treatment groups differed only in peroxide concentration, and otherwise, were identical in appearance, aesthetics, packaging, and labeling. Usage was twice daily for 30 minutes over a 28-day period, at-home and unsupervised. Study participants returned for efficacy and safety evaluations at day 7, day 14, and day 28.

Efficacy and safety assessments were conducted at baseline and subsequent visits blind as to treatment assignment. Efficacy was assessed as change in tooth color as measured from 38

standard digital images of the maxillary anterior teeth. This objective and instrumental color measurement method had previously been used to demonstrate a peroxide concentration response for tray-based professional bleaching systems.15 Using this method, subjects were first positioned in a chin rest, retractors were inserted, and standard bilateral illumination of the arch was obtained from two 150-watt lights and linear polarizers. Images were then captured using a photographic system using a HC1000 CCD high resolution digital camera manufactured by Fuji a Fujinon A8x12BMD, 1:2.8/12-96mm zoom lens, and a personal computer. Color measurements were calibrated to known standards daily prior to use and hourly thereafter to assure proper operation. Safety was assessed by interview and clinical examination at each visit. The interview focused on tooth sensitivity or oral irritation during treatment, since these have been recognized as the most common adverse events associated with vital bleaching.16 The clinical examination, using a standard dental light, dental mirror, and gauze, evaluated the oral and perioral regions, including the gingiva (free and attached), hard and soft palate, oropharynx/uvula, buccal mucosa, tongue, floor of the mouth, labial mucosa, mucobuccal/mucolabial folds, and lips to assess any changes in oral status with treatment.

For analysis, red-green-blue values for the 6 maxillary teeth were derived with reference to calibration standards, and then, these average values were transformed to yield CIELAB tooth color values for b* (yellow – blue), L* (lightness), and a* (red – green).17 Change values were calculated for any given post-baseline visit as: b* = b*visit - b*baseline, L* = L*visit - L*baseline, a* = a*visit - a*baseline. In addition, a composite parameter, E*, was derived from the square root of the sum of the squares of the individual L*a*b* changes. Reduction in yellowness (b*) was selected a priori as the primary endpoint, because this parameter has been previously shown to correlate with subjective perception of whitening following vital bleaching.18

A paired difference t-test was used to evaluate absolute color improvement (change from baseline). Between-group efficacy comparisons were made at each time point using analysis of 39

covariance with the baseline value as the covariate. A separate model was fit for b* and L*. Treatment comparisons for E* used analysis of variance methods. All testing was two-sided at a 5% significance level without adjusting for multiple comparisons. Tolerability outcomes were tabulated by treatment.

RESULTS
Of the 37 subjects randomized, one had a baseline image that was not evaluable, one had extensive facial anterior restorations, and one had heavy, atypical extrinsic stain. Of the 34 remaining subjects, 32, 29 and 28 were present and evaluable at Days 7, 14 and 28, respectively. This sample ranged in age from 21-66 years, with mean (SD) age of 37.2 (11.4). Males (53%) and females (47%) were similarly represented in the population. Study subjects exhibited considerable diversity with respect to tooth color. At baseline, b* (yellowness) ranged from 16.2 to 22.7, L* (brightness) ranged from 66.3 to 77.2, and a* (redness) ranged from 5.9 to 9.1. Treatment groups were balanced (p > 0.18) with respect to age, gender, and tooth color at baseline.

All three treatments resulted in significant whitening, with color improvement evident as early as Day 7. For the primary response parameter, the Day 7 mean (SD) b* values were –0.44 (0.558), –0.86 (0.509), and –1.41 (0.690) in the 1.8%, 3.3% and 5.3% hydrogen peroxide strip groups, respectively, with each group differing significantly from baseline (p < 0.05) at this initial timepoint. Outcomes were generally similar for L*, as well as the composite parameter E*, with each differing significantly (p < 0.05) from baseline at Day 7. Continued use past Day 7 resulted in incremental color improvement. This was evident for the individual parameters b* and L*, as well as the composite parameter, E*.

Between-group comparisons generally favored the higher concentration groups (Table 1-3). At Day 7, the 5.3% strips exhibited significant (p < 0.05) reduction in yellowness versus the other 40

two groups, while at Day 14, both the 5.3% and 3.3% groups differed significantly (p < 0.03) from the lowest concentration 1.8% strips. These outcomes generally held (directionally or significantly) for L*, and for the composite parameter E*. At Day 7, mean (SE) E* was 1.01 (0.204), 1.66 (0.204) and 2.30 (0.214) for the 1.8%, 3.3% and 5.3% groups, respectively. All three treatments differed significantly (p < 0.05), with increasing concentration contributing to greater composite color change. Results were similar over time, though by Day 28, the composite E* for the intermediate concentration approached that seen with the higher concentration. Mean (SE) E* was 3.23 (0.272) and 3.26 (0.246) for the 3.3% and 5.3%, respectively, with these higher concentration strips not differing significantly (p = 0.944).

Figure 1 illustrates the concentration response for the primary whitening parameter b* over time. (Because yellowness is removed during bleaching, negative change in b* is representative of color improvement. The graph illustrates –b* in order to be consistent with L*, where positive change represents improvement.) The linear concentration response is most evident at Day 7 across the concentration ranges tested in this research. Similar results are evident for L*, and the mathematical composite parameter E* (Figures 2-3). Overall, twice-daily use of 5.3% strips for 14 days yielded generally similar whitening (b*, L and E*) to the 3.3% strips used for 28 days.

Transient oral irritation represented the most common side effect associated with treatment. Oral irritation was reported only in the lower concentration group (25% of subjects), and the higher concentration group (36% of subjects). One subject (in the 5.3% hydrogen peroxide group) had an aphthous ulcer during treatment. Other safety findings were generally unremarkable. Most (75%) oral soft tissue findings were judged ―mild‖ in severity, with only two events (in the higher concentration group) scored as moderate. All peroxide concentrations were well tolerated overall, and none of the study participants discontinued strip use due to a product-related adverse event. 41

DISCUSSION
This double-blind clinical trial evaluated the effect of peroxide concentration on whitening response following repeated daily use of a self-directed bleaching system. In this research, hydrogen peroxide at concentrations ranging from 1.8-5.3% resulted in significant color improvement compared to baseline. This was evident for all individual L*a*b* color parameters measured in the study, as well as the mathematical composite parameter E*, beginning as early as Day 7.

Extended treatment duration past Day 7 contributed to greater observed whitening response for each of the strip concentrations. This was evident for all parameters (b*, L* and E*) measured in this study. Such results are consistent with previous research which demonstrated a favorable impact of treatment duration on tooth color in head-to-head testing comparing a popular tray and strip-based system.19 Use of hydrogen peroxide under barrier conditions at lower concentrations (~2%) is likely to require a much greater treatment duration. In this research, the observed whitening response at Day 7 with the 5.3% strips (b*, L* and E*) exceeded that achieved with the 1.8% strips at Day 28. Clinical implications with respect to compliance and other factors may suggest use of higher concentrations where possible.

The research provides clear evidence of a peroxide concentration whitening response. Whitening efficacy was greatest for the highest concentration group (5.3% hydrogen peroxide), while the intermediate concentration group had an intermediate response. Not surprisingly, this effect most approached linearity at the earliest time point (Day 7). At that time, adjusted mean b* for was –1.43, –0.84, and –0.44 in the higher, intermediate and lower concentration groups, respectively. Relative to the lowest concentration strip, this represented a 225% improvement in whitening for the 5.3% strip (a 194% increase in concentration), and a 91% improvement in whitening for the 3.3% strip (a 83% increase in concentration). As such, peroxide concentration 42

alone likely contributed the measured differences in response at that time point, results that are completely consistent with the physical chemical bleaching process.

With extended treatment, the concentration response curve flattened out especially at the two higher peroxide concentrations. At Day 28, the adjusted mean b* was 20% higher in the 5.3% group compared to the 3.3% group (a 61% difference in concentration). While sample sizes were small, there were no statistically significant differences in b*, L* or E* between the higher and intermediate concentrations at Day 28. This flattening with extended treatment may be expected in dose ranging, especially where the response substrate (intrinsic stain) is nonrenewal or slowly renewable, as it is with vital bleaching.

Despite the concentration differences (there was nearly a three-fold difference between the lowest and highest concentration tested in this research), all three strips tested in this research carried a low total amount of peroxide. The total amount of hydrogen peroxide on each predispensed strip ranged only from 3.6-10.6 mg. Relative to some tray-based systems, which may deliver up to 2 grams of bleaching gel, total peroxide delivered with any of these strips was remarkably low. This likely contributed to the low overall adverse event rate seen in this trial. All three treatments were well tolerated, with no subjects reducing or discontinuing treatment due to bleaching-related adverse events.

This new clinical research provides evidence of a concentration gradient for whitening response following use of a low peroxide dose strip whitening system. As such, this may represent a first example of concentration ranging for one of the self-directed bleaching systems. More importantly, the research also provides evidence of the sensitivity and robustness of the measurement method – in this instance – digital imaging. While previous concentration ranging research was conducted in the US on tray-based systems, this work was done in Italy, in a private dental practice using strips for peroxide delivery.15 The authors are unaware of any other 43

method (whether subjective shade assessment or objective colorimetry) that has demonstrated similar measurement sensitivity under such diverse clinical research conditions.

Concentration ranging trials, like this one, represent one of the most complex and difficult studies types in the clinical research arena. Research of this nature may be particularly exemplary of the measurement sensitivity (or lack thereof) of the clinical method used in the study. By design, the goal of this research was to distinguish both the effect of increased peroxide concentration (three treatment groups) and increased treatment duration (three posttreatment timepoints) within the constraints and variability seen with unsupervised human testing. Moreover, the research involved a degree of blinding, both with respect to the test products (identical appearing peroxide-containing strips), and clinical methods (instrumental color measurement from digital images) greater than that seen in most vital bleaching clinical trials. Despite these complexities, the research adequately differentiated multiple concentrations from low to high over time. With b* as an endpoint, the study demonstrated a nearly linear concentration response relationship, with measured efficacy differences at Day 7 that reasonably modeled the real concentration differences between groups. As such, the research provides important evidence of the validity of this method and endpoint for practicerelevant evaluation of vital bleaching technologies.

44

Tables and Figures

Table 1 Table 2 Table 3

Adjusted Mean b* and ANCOVA Treatment Comparisons Adjusted Mean L* and ANCOVA Treatment Comparisons Mean E* and ANOVA Treatment Comparisons

Figure 1 Figure 2 Figure 3

Peroxide Concentration on Strip and Adjusted Mean –b* at 7, 14 & 28 Days Peroxide Concentration on Strip and Adjusted Mean L* at 7, 14 & 28 Days Peroxide Concentration on Strip and Adjusted Mean E*at 7, 14 & 28 Days

45

Table 1 Adjusted Mean b* and ANCOVA Treatment Comparisons Evaluable Subjects (N=34) Visit/Group Day 7 1.8% H2O2 3.3% H2O2 5.3% H2O2 Day 14 1.8% H2O2 3.3% H2O2 5.3% H2O2 Day 28 1.8% H2O2 3.3% H2O2 5.3% H2O2
a

Adjusted Mean Change From Baseline (SE)a -0.44 (0.181) -0.84 (0.182) -1.43 (0.195) -1.02 (0.203) -1.77 (0.245) -1.99 (0.240) -1.23 (0.284) -1.91 (0.272) -2.30 (0.251)

Two-Sided p-Value 3.3% H2O2 0.122 5.3% H2O2 0.001 0.041

0.026

0.006 0.525

0.094

0.010 0.308

Means adjusted for baseline b*

46

Table 2 Adjusted Mean L* and ANCOVA Treatment Comparisons Evaluable Subjects (N=34) Visit/Group Day 7 1.8% H2O2 3.3% H2O2 5.3% H2O2 Day 14 1.8% H2O2 3.3% H2O2 5.3% H2O2 Day 28 1.8% H2O2 3.3% H2O2 5.3% H2O2
a

Adjusted Mean Change From Baseline (SE)a 0.74 (0.281) 1.07 (0.287) 1.31 (0.297) 1.20 (0.203) 1.32 (0.249) 1.86 (0.240) 1.28 (0.318) 2.03 (0.302) 2.15 (0.275)

Two-Sided p-Value 3.3% H2O2 0.423 5.3% H2O2 0.175 0.580

0.717

0.051 0.140

0.100

0.051 0.776

Means adjusted for baseline L*

47

Table 3 Mean E* and ANOVA Treatment Comparisons Evaluable Subjects (N=34) Visit/Group Day 7 1.8% H2O2 3.3% H2O2 5.3% H2O2 Day 14 1.8% H2O2 3.3% H2O2 5.3% H2O2 Day 28 1.8% H2O2 3.3% H2O2 5.3% H2O2 Mean Change From Baseline (SE) 1.01 (0.204) 1.66 (0.204) 2.30 (0.214) 1.83 (0.182) 2.39 (0.223) 2.84 (0.211) 2.00 (0.289) 3.23 (0.272) 3.26 (0.246) Two-Sided p-Value 3.3% H2O2 0.031 5.3% H2O2 <0.001 0.041

0.061

0.001 0.158

0.005

0.003 0.944

48

Figure 1

49

Figure 2

50

Figure 3

51

REFERENCES
1. Watts A, Addy M. Tooth discolouration and staining: a review of the literature. Br Dent J 2001;190:309-16. 2. Odioso LL, Gibb RD, Gerlach RW. Impact of demographic, behavioral and utilization parameters on tooth color and personal satisfaction. Compend Contin Educ Dent 2000;21:S3541. 3. Niederman R, Tantraphol MC, Slinin P, Hayes C, Conway S. Effectiveness of dentistprescribed, home-applied tooth whitening. A meta analysis. J Contemp Dent Pract 2000;15:2036. 4. Haywood VB. Current status of nightguard vital bleaching. Compend Contin Educ Dent 2000;28:S10-7. 5. Gerlach RW, Zhou X. Vital bleaching with whitening strips: Summary of clinical research on effectiveness and tolerability. J Contemp Dent Pract 2001;2:1-16. 6. Kugel G, Aboushala A, Zhou X, Gerlach RW. Daily use of whitening strips on tetracyclinestained teeth: comparative results after 2 months. Compend Contin Educ Dent 2002;23:29-34. 7. Matis BA, Wang Y, Jiang T, Eckert GJ. Extended at-home bleaching of tetracycline-stained teeth with different concentrations of carbamide peroxide. Quintessence Int 2002;33:645-55. 8. Ritter AV, Leonard RH Jr, St Georges AJ, Caplan DJ, Haywood VB. Safety and stability of nightguard vital bleaching: 9 to 12 years post-treatment. J Esthet Restor Dent 2002;14:275-85. 9. Leonard RH Jr, Van Haywood B, Caplan DJ, Tart ND. Nightguard vital bleaching of tetracycline-stained teeth: 90 months post treatment. J Esthet Restor Dent. 2003;15:142-52. 10. Matis BA. Tray whitening: what the evidence shows. Compend Contin Educ Dent 2003;24:354-62. 11. Gallagher A, Maggio B, Bowman J, Borden L, Mason S, Felix H. Clinical study to compare two in-office (chairside) whitening systems. J Clin Dent 2002;13:219-24. 12. Papathanasiou A, Kastali S, Perry RD, Kugel G. Clinical evaluation of a 35% hydrogen peroxide in-office whitening system. Compend Contin Educ Dent 2002;23:335-44. 13. Matis BA, Yousef M, Cochran MA, Eckert GJ. Degradation of bleaching gels in vivo as a function of tray design and carbamide peroxide concentration. Oper Dent 2002;27:12-8. 14. Leonard RH, Sharma A, Haywood VB. Use of different concentrations of carbamide peroxide for bleaching teeth: an in vitro study. Quintessence Int 1998;29:503-7. 15. Gerlach RW, Gibb RD, Sagel PA: A randomized clinical trial comparing a novel 5.3% hydrogen peroxide bleaching strip to 10%, 15% and 20% carbamide peroxide tray-based bleaching systems. Compend Contin Educ Dent 2000;21:S22-28. 16. Leonard RH, Haywood VB, Phillips C. Risk factors for developing tooth sensitivity and gingival irritation associated with nightguard vital bleaching. Quintessence Int 1997;28:527-34. 17. Commission Internationale de L’Eclairage: Recommendations on uniform color spaces. Color difference equations. Psychometric color terms. Suppl 2 to CIE pub 15 (E-13.1)1971/(TC1.3), Paris, France: Bureau Central de la CIE, 1978. 18. Gerlach RW, Barker ML, Sagel PA. Objective and subjective whitening response of two self-directed bleaching systems. Am J Dent 2002;15:7-12A. 19. Karpinia KA, Magnusson I, Sagel PA, Zhou X, Gerlach RW. Vital bleaching with two athome professional systems. Am J Dent 2002;15:13-18A.

52

Chapter 4 Light activated Tooth Whitening

Clinical Evaluation of a 35% Hydrogen Peroxide In-Office Whitening System

ABSTRACT
This study evaluated the effectiveness of light-curing (heat conversion) vs no light-curing (no heat conversion) of a 35% hydrogen peroxide in-office tooth whitening system. Twenty patients with sound medical history (without tooth sensitivity) participated in this randomized, parallel clinical evaluation. Only six maxillary anterior teeth with discoloration and a tooth shade of A3 or darker were selected. Patients received a complete prophylaxis and were evaluated for initial (baseline) shade by three independent evaluators, precalibrated at 85% rater reliability in determining shades before the experiment began. Participants received a 20-minute chairside whitening treatment with a 35% hydrogen peroxide agent using a reflective resin barrier for gingival isolation. During the whitening treatment, the 35% hydrogen peroxide agent was light activated with a halogen curing light on teeth Nos. 6 through 8 (Group I), but was not lightactivated on teeth Nos. 9 through 11 (Group II). All patients returned 24 hours after the whitening application for shade evaluation. Although there were isolated instances (7 out of 20 patients) of greater degrees of lightening in the light-curing group, there was no statistically significant difference using the Mann-Whitney U test (P > .05). This study indicates that lightcuring is optional with this 35% tooth whitening system.

53

Learning Objectives
After reading this article, the reader should be able to: describe an in-office whitening technique using 35% hydrogen peroxide. discuss tooth color modifications produced using a 35% hydrogen peroxide. recognize the effectiveness of tooth color modifications produced with 35% hydrogen peroxide in-office technique.

Tooth whitening has become one of the most popular esthetic dental procedures. The management of the discolored dentition is not new to the dental profession—it was first reported 1 in 1877. Whitening offers a conservative, simplified, and economical approach to changing the color of one’s teeth. Candidates for whitening include patients whose teeth have been stained over time by aging, chromogenic foods, endodontic treatment, tetracycline use, and smoking or the use of other tobacco products. 2

Acceptable whitening techniques include the in-office procedure, the dentist-prescribed homeapplied technique, or a combination of the two. Recently, whitening strips have been introduced 3 as an alternative whitening method. In the 1970s, vital tooth whitening was being performed with in-office treatments using different concentrations of liquid hydrogen peroxide solutions and 4 (sometimes) a heat lamp. In 1989, the first article on nightguard vital bleaching using carbamide peroxide was published by Haywood and Heymann after evaluation at the University 5 of North Carolina. Currently, the in-office whitening technique uses a 15% to 35% hydrogen peroxide whitening agent (heated or nonheated); the dentist-prescribed home-applied technique most commonly uses a 10% to 15% carbamide peroxide gel. The advantage of the in-office procedure is that it does not require patient compliance and results may be seen immediately. The disadvantage is the chair time, cost to the patient, and the possibility of multiple visits. A light-activated chairside whitening system has the potential advantages of taking less time and providing quicker results. 54

The purpose of this study was to evaluate:

1.

The effectiveness of a 35% hydrogen peroxide in-office system ® ®,a ®,a (Opalescence Xtra and OpalDam ) in tooth color modifications.

2.

The effect of light when compared to no-light activation (light-to-heat activator and light-to-nonheated activator).

3.

The incidence of soft tissue irritation related to the active whitening chemical, hydrogen peroxide.

4.

Patient responses to the whitening treatment.

METHODS AND MATERIALS
Before participating in this blinded, parallel tooth whitening study, all patients were asked to sign an informed consent form. Both the form and the research protocol were reviewed and approved by the Human Investigational Review Committee at Tufts University. A total of 20 patients (with no medically compromised history or tooth sensitivity) were recruited from the Tufts University dental clinic to participate in this randomized, parallel clinical evaluation. The criteria used to recruit participants for this investigation included: No active caries. 18 years of age or older. Maxillary and mandibular teeth with the same color. The exclusion criteria were: Intrinsic dental staining (ie, tetracycline or fluorosis). Nonvital teeth.

Patients that had previous tooth whitening procedures. Extended composite restorations at the teeth that would be included in this study.

55

Only 6 maxillary anterior teeth with minor uniform staining or discoloration with a shade no lighter than A3 were selected. The six mandibular anterior and contralateral maxillary, non–lightcured teeth were used as the control group. At the initial appointment, all necessary consent forms were signed before any treatment was rendered. Then, a thorough clinical and medical evaluation was taken for each patient. All patients received a complete oral prophylaxis (cleaning and polishing) 2 weeks before beginning the whitening process. At the next appointment, all of the subjects underwent a baseline periodontal evaluation, which included color, size, shape, and consistency of the involved gingival tissue. Each patient was evaluated for initial (baseline) shade by three independent evaluators. The evaluators consisted of the subject, the dentist treating the subject, and a second dentist. All evaluators were calibrated at 85% rater reliability in determining shades before the onset of this project. A consensus method (two of the three evaluators) was used

to record the shades of the 6 test anterior maxillary teeth and 6 lower anterior teeth as the control group. Shades were assessed using the Standard VitaShade Guideb. All
shade measurements were recorded at baseline and an initial photograph was taken of the maxillary and mandibular teeth. At this appointment, the 20 participants received a 20-minute chairside whitening treatment with a 35% hydrogen peroxide whitening agent (Opalescence Xtra), using OpalDam for gingival isolation. Before the hydrogen peroxide application, all teeth were cleaned using pumice and a slow-speed rotary brush/prophy cup. Teeth Nos. 6 through 11 were whitened using the 35% hydrogen peroxide whitening agent, but only teeth Nos. 6 through 8 were light activated with a curing light. A questionnaire was provided to the patients for recording any comments. All participants were able to contact any of the principle investigators if any side effects such

as tooth sensitivity, gum tissue irritation, or bad taste were experienced. All patients were required to return 24 hours after the day of the second appointment for a recall appointment. A final periodontal evaluation was taken for all patients, which
consisted of visual gingival recordings using standardized Löe and Silness Gingival Index: 56

0 = No inflammation 1 = Slight inflammation 2 = Moderate inflammation 3 = Severe inflammation In addition, recordings of loss of sensation, change in gingival texture, spontaneous bleeding, and the sloughing of gingival tissue were noted. A final shade was then selected and a final intraoral photograph was taken at the 24-hour recall appointment. Data (degree of color change from baseline) were analyzed using statistical tests to determine the significance of the light activation when using the 35% hydrogen peroxide tooth whitening agent.

RESULTS
The 35% hydrogen peroxide in-office tooth whitening system was effective in lightening teeth. However, the purpose of this study was to evaluate the effectiveness of light-curing vs no lightcuring of this whitening system. Although there were isolated instances (7 out of 20 patients) of greater degrees of lightening in the light-curing group (median for Group I was 7.21 and Group II was 6.78) (Table 1), there was no statistical significant difference using the Mann-Whitney U test (P > .05). Both whitening protocols were effective in the lightening of teeth with no adverse effects. All shade evaluations using the VitaShade Guide were recorded with the guide arranged in value order, where they are assigned a number from 1 through 16. This order is shown at the bottom of Table 1. Patients were given questionnaires to record tooth sensitivity, gingival irritation, bad taste, and noticeable shade change. One patient experienced slight tooth sensitivity (only at one tooth) at the end of the whitening procedure, which subsided before the 24-hour recall visit. No bad taste and no gingival irritation were reported and OpalDam  appeared to be effective in isolating the

tissues against any caustic behavior. All participants in the study expressed satisfaction with the whitening process and the results (Table 2). 57

DISCUSSION
Traditionally, in-office whitening products have been used to give a patient a head start in the whitening process, to touch-up postwhitening cases if they should regress in shade, and to   6 function solely as a whitening product. Opalescence Xtra is a commonly used 35% hydrogen peroxide tooth whitening agent for in-office treatment. After gingival isolation with  OpalDam , the whitening material was applied to each facial enamel surface on the six maxillary anterior teeth, but was light-cured only on teeth Nos. 6 through 8. This light-activated material is contained in a carotene base to absorb light, providing an increased whitening 7 effect. The results of this study revealed that the use of the halogen light improved the effectiveness of the whitening material in some cases. However, in those cases, the difference between light-cured vs non–light-cured teeth was 1 to 3 shades, which was not noticeable to the ® patients. Shade evaluation determined Vita shade B1 for teeth Nos. 6 through 8 (light-cured) and A1 for teeth Nos. 9 through 11 (non–light-cured). As stated earlier, the purpose of this study was to determine if the use of a light in the in-office whitening process would increase the effect of whitening on the teeth. Of the 20 patients in this study, 7 patients experienced an increase in lightening of the split arch protocol. The increase was an average lightened increase of 1.714 shades as compared to the non–light-cured side. This was not a significant clinical change. Any shade difference as noted by the light-activated side was most likely a result of dehydration resulting from heat generated by the halogen curing light. Statistically, there was no significant difference between the light-activated side when compared to non–light-activated side. The results contradict other studies, which have indicated that light activation causes an increased whitening effect as used with hydrogen peroxide whitening agents. 8,9 Based on the

Clinical Research Associates’ report, the use of a curing light in addition to the manufacturerrecommended exposure times, does not produce sufficient heat generation was to significantly 58

increase the breakdown of H2O2.

10

It is this activation of H2O2 that results in the increased

whitening effect. A transient whitening effect may be the result of dehydration. To potentiate the effect of H2O2, high temperatures must be reached, which could potentially cause damage to the tooth. This report also states that OpalescenceXtra experiences a relatively low rate increase in H2O2 even when temperatures are raised as high as 100° C. 10 This would also

support our findings that the addition of light does not increase the effect of the whitening process.

CONCLUSION
This study evaluated the effectiveness of light-curing vs no light-curing of a 35% hydrogen peroxide in-office tooth whitening system. Tweny patients with sound medical history (without tooth sensitivity) participated in this randomized, parallel clinical evaluation. The outcome of this study leads to the conclusion that the use of a halogen curing light to increase the activation of 35% hydrogen peroxide is of no benefit to the dentist or the patient.

59

Table 1 Tooth Color Modifications as Ascertained by The Consensus Method
Subject Light Cured) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Initial A3 A3 A3.5 A3 A3 D3 A3 D3 C3 A3 A3 A3 A3 D3 A3 A3 D3 A3 A3 A3 Final (Light Cured) B1 A1 A2 A1 A1 B1 A1 A1 C1 A2 A1 A2 D2 A1 D2 A1 A1 B1 D2 B1 (8) (7) (7) (7) (7) (9) (7) (8) (8) (4) (7) (4) (5) (8) (5) (7) (8) (8) (5) (8) Final (No A1 A2 A2 A1 D2 A1 A1 A1 C1 A2 A1 A2 D2 A2 D2 A1 A1 A1 A2 B1 (7) (4) (7) (7) (5) (8) (7) (8) (8) (4) (7) (4) (5) (5) (5) (7) (8) (7) (4) (8)

Totals: Group I:137, Group II:125. Median Group I: 7.21 Median Group II: 6.78
The numbers in parentheses show how many shade changes were accomplished with the use ® ® of Opalescence Xtra during the study, from the initial to the final appointment. ® Vita Shade Guide arranged in value order:

B1 1

A1 2

B2 3

D2 4

A2 5

C1 6

C2 7

D4 8

A3 9

D3 10

B3 11

A3.5 12

B4 13

C3 14

A4 15

C4 16

Table 2—Tooth Sensitivity, Gingival Irritation, Bad Taste, and Noticeable Shade Change Evaluation by Each Subject in the Exit Questionnaire

60

Subject Shade Change 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Tooth Sensitivity

Gingival Irritation

Bad Taste

Noticeable

No No No No No No No No No No Yes No No No No No No No No No

No No No No No No No No No No No No No No No No No No No No

No No No No No No No No No No No No No No No No No No No No

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

61

PRODUCT REFERENCES
a Ultradent Products, Inc., South Jordan, UT 84095; (800) 552-5512 b Vita Zahnfabrik, Germany, distributed in US by Vident, Brea, CA 92621; (800) 828-3839).

REFERENCES
1. Fasanaro TS: Bleaching teeth: history, chemicals and methods used for common tooth discoloration. J Esthet Dent 4: 71-78, 1992. 2. Kugel G: Nontray whitening. Compend Contin Educ Dent 21(6):524-528, 2000. 3. Kugel G, Kastali S: Tooth whitening eficacy and safety: randomized and control clinical trial. Compend Contin Educ Dent 21(Suppl 28): 2000. 4. Nathanson D: Vital bleaching sensitivity and pulpal considerations. J Am Dent Assoc 128(Suppl):41S-44S, 1997. 5. Haywood VB, Heymann HO: Nightguard vital bleaching. Quintessence Int 20(3):173-176, 1989. 6. Kugel G, Perry RD, Hoang E, et al: Effective tooth bleaching in 5 days: using a combined inoffice and at-home bleaching system. Compend Contin Educ Dent 18(4):378-383, 1997. 7. Gultz J, Kaim J, Scherer W, et al: Two in-office bleaching systems: a scanning electron microscope study. Compend Contin Educ Dent 20(10):965-970, 1999. 8. Li Y, Cartwright S, Lezama M, et al: Effect of light application on an in-office bleaching gel [abstract]. J Dent Research 80(147), 2001. Abstract 895. 9. Tavares M, Goodson JM, Stutz J, et al: A randomized single blind clinical trial of tooth whitening with peroxide and light [abstract]. J Dent Research 80(182):2001. Abstract 1171. 10. CRA Newsletter August, 2000.

62

CHAPTER 5 CHEMICAL VS LIGHT ACTIVATED TOOTH WHITENING
Clinical Evaluation of Chemical and Light-Activated Tooth Whitening Systems

ABSTRACT

BACKGROUND Tooth whitening has become one of the most popular of dental treatments. There are many options available. The paper attempts to compare the efficacy of two in-office whitening systems.

METHODS In this split-arch, randomized, parallel, blinded clinical evaluation six maxillary anterior teeth (N=60) A-2 or darker were selected using the value order Vita Shade Guide. Patients received one-hour light-activated chairside treatment using 15% H2O2 teeth 6-8 (Group I), teeth 9-11 received a 38% H2O2 system for 1 hr without a light (Group II). Before and after treatment images were taken. L*, a* and b* and Vita shades were measured. Patients returned after 2 weeks for final shade evaluation.

RESULTS Both in-office tooth whitening systems were effective. Group I averaged 5.9 ± 2.5 and Group II 3.97 ± 2.33 shade changes immediately after treatment. At the 2-week recall, Group I scored an average of 4.6 ± 2.14 and Group II 4.6 7± 2.3 shade changes, compared to the pre-bleaching shades. A paired sample t-test revealed statistically significant difference (p<0.0001) between Groups I and II immediately after bleaching, with Group I performing better. At the 2-week recall, however, only Group I showed a significant rebound (p=0.0002). At the completion of the study, there was no significant difference between Groups I and II (p=0.7826). 63

CONCLUSION This study indicated that both chairside tooth whitening systems are effective and that no statistically significant differences were observed over the 2-week period of observation.

CLINICAL IMPLICATIONS Both systems were effective in whitening teeth. The use of light did not demonstrate an increase in the effectiveness of Britesmile after a two-week recall.

INTRODUCTION
Technological advances in dentistry make it possible for the practitioner to deliver the highest level of care in an efficient and often economical way. With the introduction of light activated devices such as Plasma arc, Light Emitting Diodes (LED), Argon lasers, metal halide and xenon-halogen lights, being promoted as ―the future of dentistry,‖ dental manufacturers have helped create a public awareness and demand for the so-called: ― Light enhanced tooth whitening systems‖. In 2002 one article and more recently two papers were published evaluating the efficacy of light activated bleaching agents. One study reported positive results1, whereas the other articles concluded the opposite 2,3. Reviews of these articles were either in support 4 or discredited the findings5. It is apparent that the dental profession needs more evidence in order to provide for better and more efficient treatment. The lack of knowledge is to the detriment of the dentist and patient alike. The need for more knowledge becomes even more important as manufacturers inundate the dental profession with advertisements emphasizing that light activated tooth whitening is ―the state of the art‖ and should be part of the armamentarium of the ―up to date‖ dental office. Bleaching is the most conservative treatment for discolored teeth when compared to resin bonded composites, porcelain veneers or crowns. It offers a simple and economical approach to changing the color of teeth. Success of the treatment depends on a careful diagnosis by the 64

practitioner. Candidates for whitening procedures include patients whose teeth are stained by aging, chromogenic foods, endodontic treatment, tetracycline use and smoking or use of other tobacco products. Acceptable tooth whitening techniques include the in-office technique, dentist-prescribed homeapplied technique, or a combination of the two. The use of hydrogen peroxide (H202) for bleaching teeth dates back to 1995 6. To reduce treatment time, clinicians attempted to accelerate the degradation of H202 by heat or light. In 1970, Cohen and Parkins introduced a technique for bleaching discolored teeth, such as tetracycline stained-teeth, using hydrogen peroxide and a hand-held heating source 7. Most clinicians know that hydrogen peroxide is a bleaching agent that can attain a desired whitening effect. Bleaching can also be accomplished with Carbamide Peroxide, a lower concentration of hydrogen peroxide and urea, which breaks down to 3.6% hydrogen peroxide
8,9

.The degree of whitening correlates directly with the amount of contact time and concentration

of the active ingredient, the pH and viscosity 9. The side effects are usually diminished when lower concentrations are used. The in-office bleaching treatment using hydrogen peroxide and an accelerating source (heat or light) were predominant until 1989 when Haywood published the first article on nightguard vital bleaching using carbamide peroxide 10. Currently, the in-office bleaching technique employs a 15 - 40% hydrogen peroxide bleaching agent (heat activated or not), while the dentist prescribed home-applied technique most commonly uses a 10 - 15% carbamide peroxide gel. The advantages of an in-office procedure are twofold. It does not require patient compliance and immediate results can be accomplished. The disadvantages are the chair side time

involved and the cost to the patient, as the procedure usually requires multiple visits. Lightactivated chair side bleaching systems potentially offer the benefit of being less time-consuming while producing faster results. The introduction of very high intensity Plasma Arc lights and Argon Lasers meets the need of an ever increasing demand for whiter teeth. Research in vitro has demonstrated that the use of 65

laser-activated hydrogen peroxide did not produce any perceivable color change 11. Another recent in vitro study, and one which should be of concern to the practitioner, has shown that the use of these intense lights does elevate temperature of the bleaching material and as a result caused an increase in intrapulpal temperature. This may have an impact on post bleaching tooth sensitivity and pulpal health 12. The efficacy of a bleaching treatment can be determined through first or second evaluators or various technical methods. The use of a shade guide, colorimeter, or computer digitization to measure color change over time has been currently included in clinical trials to assure efficacy assessment 13, 14, 15. The purpose of this study was to compare the efficacy of color changes of two in-office tooth whitening systems, Brite Smile, a 15% Hydrogen peroxide system
a

and Opalescence Xtra

Boost, a 38% Hydrogen Peroxide system b. In addition, feed back from the participants allowed for an evaluation of their satisfaction with the results of the treatment and the occurrence of sensitivity during and after the bleaching treatment.

MATERIALS AND METHODS
Ten patients with no medical contraindications to treatment and an absence of tooth sensitivity were asked to participate in this split-arch, randomized, parallel, blinded clinical evaluation. Only six to eight upper anterior teeth with minor uniform intrinsic staining or discoloration with a shade no lighter than A-3 were selected. The six lower anterior teeth and contra lateral upper incisors were used as control groups. All patients had received a prophylaxis (cleaning and polishing) less than 3 months before starting the experiment. Each patient was evaluated for initial (baseline) shade by two evaluators. The evaluators consisted of the dentist treating the subject and a second dentist. Both evaluators were calibrated at 85% rater reliability in determining shades before the onset of this project. Calibration was conducted pre and post study to ensure inter and intra rater reliability. 66

At the initial appointment shades were assessed using a Standard Vita Shade Guide c. All shade measurements were recorded at baseline and an initial photograph was taken of the upper and lower teeth. At the same appointment the patient received a one-hour chair side bleaching treatment for teeth 5-8 using Brite Smile according to manufacturer’s recommendations; 3 applications of 20 minutes each in one visit. Opal Dam b was used for gingival isolation. Teeth 9-12 were isolated from the Brite Smile material and light source during treatment by means of a custom made poly vinylsiloxane (PVS) block. Teeth were also kept moist using wet gauze under the PVS block. Upon completion, teeth 5-8 were isolated as descrived above and teeth # 9-12 were treated with Opalescence Xtra Boost without the use of a curing light (3 applications of 20 minutes each in one visit), following the manufacturer’s recommendations. Three measurements were recorded from each side before and immediately after treatment. In addition 35mm transparencies, as well as digital photos were taken before and after treatment. All patients were scheduled to return 2 weeks after the day of the tooth whitening treatment for a recall appointment. Once more post bleaching records by means of transparencies and digital photography were taken. In addition a determination of the final shade was made. As a service to the patient the mandibular teeth were whitened after final recording at the end of the study using Opalescence 10% carbamide peroxide take-home system. b

A. Efficacy Assessment The efficacy of the whitening system was evaluated with the use of a Digital Imaging Camera d, a 35 mm camera e and Standard Vita Shade Guidec15,16. The Olympus C2500L high resolution digital camera is utilized for sampling. To ensure proper color analysis an extended procedure of sampling nine locations on the central incisor, lateral incisors of the maxillary and mandibular arches was completed. This data is then averaged to find a mean color and standard deviation of color on each tooth. A Gaussian blur filter was

67

applied during post processing which does an averaging of color over the digitally sampled photo. All digital images were then analyzed to yield L*, a* and b* data 15. All individuals are located in the same position in a single operatory with the camera positioned 9 inches and perpendicular from the tooth surface of the left central incisor. Patients are presented edge to edge with retractors and asked to touch the tip of their tongue to their soft palate. This allows light to readily pass through the tooth surface and reduce reflectance from their tongue. A polarized filter is used on the camera to reduce the gloss that occurs from the flash further ensuring the reduction of hot spots and increase consistent color accuracy. The camera flash is used to ensure the consistency of light source due to its great influence on value data. The camera is plugged in to a 120-volt source to ensure no fluctuation of flash intensity between subjects and maintain stability of the light source. A Standard Vita Shade Guide, arranged in order of value, was used for subjective evaluation of the shades. Furthermore, 35mm transparencies were taken as part of the shade evaluation protocol. Each participant was asked to brush with water and an extra-soft toothbrush, according to Brite Smile recommendations, to remove any debris that could interfere with shade evaluation and photography. To standardize the photography, cheek retractors were used to retract the cheeks and lips and the patient was instructed to line-up the lower incisal edges with the upper front teeth. Additional photos were taken positioning the baseline shade tab next to the teeth to be evaluated. All digital photos and analysis were performed by a blinded evaluator.

B. Safety Assessment This clinical study assessed the efficacy and patient tolerance of two different in-office tooth whitening systems after a single visit one-hour application. Clinical safety data information indicated that the use of these systems, when used according to the protocol specified in this clinical trial, did not present any undue risks to the participants.

68

This was a randomized, blinded, parallel group study with 10 healthy participants, which approved by the Institutional Review Board of the University where the study was conducted. Subjects that met inclusion criteria were asked to report whether they had any teeth that were sensitive. During the initial visit an informed consent form and an explanation of the eligibility criteria were presented. The health of the oral soft tissues was examined and recorded and a shade determination made. Photography as described previously was also done at this visit. Both whitening systems were used for each patient. The Brite Smile System for teeth #5-8 and Opalescence Xtra Boost for teeth # 9-12. The application lasted for 60 minutes, according to the protocol and instructions provided by the manufacturers. An evaluation of the oral soft tissues, tooth sensitivity and change in shade was completed after the tooth whitening treatment and two weeks after application. The mandibular teeth were whitened after the end of the study using Opalescence, a 10% carbamide peroxide tray-delivered home bleaching system. Safety and comfort was determined by an absence of irreversible effects associated with the use of the systems and included assessment of oral soft tissues and the degree of tooth hypersensitivity. Oral soft tissue examination was conducted visually utilizing a standard dental light, dental mirror and gauze. Abnormal soft tissue findings were noted after the tooth whitening treatment had been completed. The Brite Smile System consists of a 15% hydrogen peroxide gel, Opalescence Xtra Boost of 38% hydrogen peroxide gel and Opalescence is 10% carbamide peroxide. All three whitening systems have undergone previous clinical safety testing
17,18

. Two types of adverse reactions

have been reported, i.e. oral soft tissue irritation and tooth sensitivity 17,18. The occurrence of these reactions were carefully evaluated and recorded following completion of the bleaching treatment.

RESULTS
During the in-office treatment, soft tissue irritation was usually avoided with the appropriate placement of a gingival isolation gel recommended and included in each in-office tooth 69

whitening system. Soft tissue irritation was typically of mild severity and was usually observed at the gingival margin. The irritation resolved while the subject were still undergoing tooth whitening treatment or within 1-3 days after discontinuation of use. Baseline values were

confirmed using the lower teeth as a control group. Tooth sensitivity was experienced and recorded and was of mild severity, which resolved usually within 1-2 days after discontinuation of the product.

A. Shade Guide Evaluation
Both in-office whitening systems were effective in making teeth lighter. The Vita Shade Guide scores from the lightest to the darkest shade in numeric code order (Table I). The recorded shades utilizing the Vita Shade Guide showed that Brite Smile averaged 5.9  2.5 and Opalescence Xtra Boost averaged 3.97  2.33 shade changes immediately after the whitening procedure. At the 2 week recall, Brite Smile’s effect was reduced to an average of 4.6  2.14 while Opalescence Xtra Boost increased to 4.67  2.3 shade changes (Table II and Table III). Patients were given a questionnaire to record tooth sensitivity, gingival irritation, bad taste and noticeable shade changes. Six patients experienced tooth sensitivity in which four patients reported sensitivity in both sides; one patient reported sensitivity on the Britesmile side and the other patient reported sensitivity on the Opalescence Xtra Boost side. One patient reported gingival irritation at the end of the whitening procedure, observed in both sides, which subsided in less than 24 hour. No bad taste was reported and all participants in the study expressed satisfaction with the whitening process and the results.

B. Digital Photography Evaluation

The digital photography revealed the following results (Table IV): Whitening benefit is defined as tooth color change from baseline assessed by the digital imaging measurements b* (yellow – blue), L* (light – dark), and a* (red – green). For a given
70

post-baseline visit: b* = b*visit - b*baseline, L* = L*visit - L* baseline, a* = a* visit - a* baseline. Preoperative vs. Immediate Post Bleaching
There was a significant difference in b (p=0.01) for the BriteSmile compared to Opalescence Xtra Boost immediately post bleaching, while Opalescence Xtra Boost had a significant decrease in the a score (p=0.01) post bleaching compared to BriteSmile. The other values showed no significant differences between the two products. The data indicates that BriteSmile had a greater whitening effect when evaluated immediately post bleaching based on L* and b* which are directly linked to bleached dentition (citation). Both products show statistical difference (P=.01) before and after treatment for L* and b*.

Immediate Postoperative vs. 2 Weeks Post Bleaching
BriteSmile demonstrated a significant rebound by a positive b value (p<0.001). This signifies that the BriteSmile subjects had an increase in yellow coloration. This may be attributed to dehydration of the tooth from the application of the light or it may be a normal response of rebound. The Opalescence Xtra Boost may not have displayed this rebound due to the

prolonged activity of the bleaching material after the sample readings were taken immediately post bleaching. The a* values showed no statistical change in either group. The L* displayed no significant change for the Britesmile yet the Ultra Boost showed the mean L* increase in value by 1.7 units.

Preoperative vs. 2 Weeks Post Bleaching (Overall)
The data indicates that both BriteSmile and Opalescence Xtra Boost whitened teeth to statistically significant level (P=.01) for L* 3.6 (BriteSmile), 3.8 (Xtra Boost) and b* -6.0 (BriteSmile), -5.0 (Xtra Boost) equivalent to between 3 and 6 shades as determined on a Vita shade guide (cite). The two whitening systems were not statistically significantly different from pre-bleaching to two weeks post bleaching. All patients reported to be satisfied with the results 71

at the end of the treatment. Sensitivity appeared not to be an issue and none of the patients expressed concern or complained about this side effect.

DISCUSSION
The question as to whether to use light activation during chair side bleaching or not and the purported benefits are still an issue of debate. The use of two blinded and calibrated evaluators in this study set it apart it from other publications evaluating this technology 1. In this study, the direct in-office whitening system using a gas plasma light for three twenty minute applications in conjunction with 15%hydrogen peroxide gel, was compared to a chemically activated system using 38% hydrogen peroxide. Either heat or a chemical reaction can cause the peroxide to break down into oxygen radicals and water more quickly. The more oxygen is liberated, the more oxydation can take place. In the absence of heat, lowering the pH is one such mechanism, by which, when Opal Xtra Boost is chemically activated, oxygen and water are liberated. The clinical observation using a value ordered Vita Shade Guide was confirmed using digital analysis of L*, a*, b* color values
15

. In addition the digital camera was calibrated for each

image. Unlike other studies, the teeth of the one side were kept moist during bleaching, thus minimizing the effect of dehydration that can occur while the other lateral side was being bleached. This might explain why our data does not show the dramatic results reported in another paper 1. The use of light activation using the Britesmile in-office bleaching system resulted in increased whitening compared to Opalescence Xtra Boost, which does not require light activation. This is believed to be the result of dehydration of the tooth caused by the generation of heat from the curing light 2. This increase, however, was of temporary nature, as after 2 weeks no differences were recorded between the two systems. The initial improvement in tooth whitening observed with the Britesmile system is therefore most probably the result of dehydration. The Britesmile system incorporates the use of ―hydrogel‖ and it has been suggested that this hydrogel (the company does not volunteer the composition), prevents the teeth from dehydrating. Prevention 72

of dehydration of any light activated in office bleaching procedure is virtually impossible, however. Opalescence Xtra Boost did not demonstrate significant rebound and actually showed a slight improvement after 2 weeks. This is possibly due to the fact that there was less dehydration since no light and /or heat are required to activate the system. Furthermore, it is also possible that a prolonged exposure and activity after the gel took place after it was rinsed off. It is believed that continued oxydation can take place over time with the chemically activated system, as activated hydrogen peroxide in water is able to penetrate deeper and/or reside in the tooth longer, since it is not driven out by evaporation due the application of heat. It is reasonable to conclude that with the increase in temperature, dehydration did occur, which was subsequently followed by rehydration. Therefore in spite of the initial perception that an increase in whitening took place, the 2-week post-operative evaluation did not demonstrate a difference, which was confirmed by an absence of a statically significant difference between the two materials. We realize that this study represents a small sample size. This was due in part to the difficulty in obtaining a Bristesmile unit. More independent research evaluating a larger sample size is recommended. Factors such as cost of the light, operatory space, and maintenance should be entered in the equation when purchasing a light. Advantages and disadvantages of light activated whitening systems should be carefully considered.

CONCLUSIONS 1. BriteSmile and Opalescence Xtra Boost whitened teeth between 3 and 6 shades and
were not statistically significantly different from pre-bleaching to two weeks post bleaching,

2. BriteSmile had a greater whitening effect when evaluated immediately post bleaching,
but demonstrated a significant rebound of the b score (p<0.001). This may be attributed 73

to dehydration of the tooth from the application of the light (heat) or it may be a normal response of rebound,

3. Opalescence Xtra Boost did not display this rebound effect, probably due to a more
prolonged activity of the bleaching material after the sample readings were taken immediately post bleaching,

4. All patients reported to be satisfied with the results at the end of the treatment; 5. Sensitivity appeared not to be an issue and none of the patients expressed concern or
complained about this side effect.
a b c d e

BriteSmileTM,Inc., Walnut Creek, CA 94598;(925) 941-6260 Ultradent Products Inc., South Jordan, UT USA VITA Zahnfabrik, Bad Säckingen, Germany Olympus Camedia C2500L-SLR, Olympus America Inc., Melville, NY USA Dental Eye III, Yashica-kyocera, Somerset, New Jersey USA

Tables: Table I: Table II: Table III: Table IV: Vita Shade Guide c scores from the lightest to the darkest shade in numeric code order. Mean Shade Change from Baseline Mean Shade Change from Baseline Results showed from digital photography analysis

TABLE I Lightest Darkest

B1 1

A1 2

B2 3

D2 4

A2 5

C1 6

C2 7

D4 8

A3 9

D3 10

B3 11

A3.5 12

B4 13

C3 14

A4 15

C4 16

Corresponding Numeric Code

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TABLE II
Initial Shade (# 6-11) C1 A2 B3 B4 B4 A4 A3 A3.5 A3.5 A2 A2 A3.5 A2 A2 A3 D3 A3.5 A4 A2 A2 B3 A2 A2 A3 D3 A3 A3.5 A2 A2 A3.5 Brite Smile (# 6-8) Postoper. A1 (4) B1 (4) A1 (9) A2 (8) A1 (11) A3 (6) B1 (8) B1 (11) A2 (7) A1 (3) A1 (3) A2 (7) B1 (4) A1 (3) A1 (7) A1 (8) A1 (10) A3 (6) A1 (3) A1 (3) A2 (6) A1 (3) A1 (3) B2 (6) A1 (8) D2 (5) A2 (7) A1 (3) B1 (4) A2 (7) Opal. Xtra Boost (#9-11) Postoper. A1 (4) A1 (3) A3 (2) A2 (8) D2 (9) A3 (6) B2 (6) A2 (7) A3 (3) A1 (3) A1 (3) A2 (7) B1 (4) A1 (3) D2 (5) B2 (7) A2 (7) A3.5 (3) B2 (2) A1 (3) A3 (2) A2 (0) A2 (0) A3 (0) A2 (5) A2 (4) A3 (3) A1 (3) B1 (4) A3 (3) Brite Smile (# 6-8) 2 w. recall A1 (4) A1 (3) A2 (6) C2 (6) C1 (7) A3 (6) A1 (7) A2 (7) A2 (7) A1 (3) A1 (3) A2 (7) D2 (1) D2 (1) D2 (5) A1 (8) A2 (7) A3 (6) A1 (3) A1 (3) A2 (6) A1 (3) A1 (3) A3 (0) A2 (5) A2 (4) A3 (3) A1 (3) B1 (4) A2 (7) Opal. Xt. Boost (#9-11) 2 w. rec. A1 (4) A1 (3) A2 (6) C2 (6) C1 (7) A3 (6) A1 (7) A2 (7) A2 (7) A1 (3) A1 (3) A2 (7) D2 (1) D2 (1) D2 (5) A1 (8) A2 (7) A2 (10) B2 (2) A1 (3) A3 (2) B2 (2) A1 (3) A2 (4) A2 (5) A2 (4) A3 (3) A1 (3) B1 (4) A2 (7)

Patient 1

Teeth central lateral canine central lateral canine central lateral canine

2

3

4

central lateral canine

5

6

central lateral canine central lateral

7

8

9

10

canine central lateral canine central lateral canine central lateral canine central lateral canine

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TABLE III Mean Shade Change from Baseline

12 10 8 6 4 2 0 -2 Brite Smile - Brite Smile - 2 Opal Boost - Opal Boost - 2 After bleaching week recall After bleaching week recall

n

Mean

SD

SE

95% CI of Mean Median 4.958 to 6.842 3.800 to 5.400 3.098 to 4.835 3.810 to 5.523 6.000 4.500 3.000 4.000

IQR

95% CI of Median

Brite Smile After bleaching 30 5.900 Brite Smile 2 week recall 30 4.600

2.524 0.461 2.143 0.391 2.327 0.425 2.294 0.419

4.000 4.000 to 7.000 3.250 3.000 to 6.000 2.250 3.000 to 5.000 4.000 3.000 to 6.000

Opal Boost After bleaching 30 3.967 Opal Boost 2 week recall 30 4.667

TABLE IV
Post 2 Week Brite Smile Ultradent Boost Brite Smile Ultradent Boost L* a* b* L* a* b* L* a* b* L* a* b* L* a* b* Mean 70.4 -2.8 7.3 73.6 -2.6 0.2 72.5 -1.9 3.2 74.0 -2.4 1.6 74.2 -1.9 2.0 St.Dev. 7.4 1.9 4.4 6.0 0.7 2.3 6.1 1.2 3.0 5.4 0.9 1.8 5.3 1.3 2.4 Pre

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REFERENCES
1. Tavares M. Stultz J. Newman M. Smith V. Kent R. Carpino E. Goodson JM. Light augments tooth whitening with peroxide.[comment]. Journal of the American Dental Association. 134(2):167-75, 2003 Feb 2. Hein DK. Ploeger BJ. Hartup JK. Wagstaff RS. Palmer TM. Hansen LD. In-office vital tooth bleaching--what do lights add?. Compendium of Continuing Education in Dentistry. 24(4A):34052, 2003 Apr. 3. Papathanasiou A, Kastali S, Perry RD, Kugel G. Clinical evaluation of a 35% hydrogen peroxide in-office whitening system. Compend Contin Educ Dent. 2002 Apr; 23(4): 335-8, 340, 343-4 passim; quiz 348 4. Jones AH, Diaz-Arnold AM, Vargas MA, Cobb DS.Colorimetric assessment of laser and home bleaching techniques. J Esthet Dent. 1999; 11(2): 87-94 5. Anonymous. Laser-assisted bleaching: an update. ADA Council on Scientific Affairs.[comment]. Journal of the American Dental Association. 129(10):1484-7, 1998 Oct
6. Goldstein RE. Esthetics in Dentistry-Principles, Comunications, Treatment Methods. 2nd ed;vol 1. Hamilton-London: B.C BeckerYear Book; 1998:245.

7. Cohen S, Parkins FM. Bleaching tetracycline-stained vital teeth. Oral Surg 1970 Mar; 29:46571 8. Goldstein RE, Garber DA. Complete dental bleaching. Chicago: Quintessence, 1995 9. Clinical Research Associates. Tooth Bleaching, state-of-art ’97. CRA Newsletter. April, 1997

10. Haywood VB, Heymann HO. Nightguard vital bleaching. Quintessence Int 1989;20: 173-6.
11. Jones AH. Diaz-Arnold AM. Vargas MA. Cobb DS. Colorimetric assessment of laser and home bleaching techniques. Journal of Esthetic Dentistry. 11(2):87-94, 1999 12. Baik JW, Rueggeberg FA, LiewehrFR. Effect of light-enhanced bleaching on in vitro surface and intrapulpal temperature rise. J Esthet Restor Dent. 2001; 13(6): 370-8

13. Haywood VB. Historical development of whiteners: clinical safety and efficacy. Dent Update. 1997;24:98-104. 14. Gegauff AG, Rosenstiel SF, Langhout KJ, Johnston WM.Evaluating tooth color change from carbamide peroxide gel. J Am Dent Assoc. 1993;124:65-72 15. Kugel G, Aboushala A, Sharma S, Ferreira S, Anderson C. Maintenance of Whitening with Sonicare Advance Toothbrush after bleaching treatment. Compend
Contin Educ Dent. 2004 Feb; 25(2): 17-24; quiz 25

16. Anderson C, Kugel G. Rebound evaluation of tetracycline stained subjects treated with a 6.5% hydrogen peroxide gel; quantitative assessment by standard digital photography[abstract]. J Dent Res. 2002;81(special issue):A-429.Abstract 3488. 17. Deliperi S, Bardwell D, Papathanasiou A, Kim M-J. Effectiveness of a Combined In-office and Take-home Bleaching System. AADR Abstract. March 2003 18. Papathanasiou A, Deliperi S, Bardwell D, Wegley C. In vitro Evaluation of a Combined In-office and Take-home Bleaching System. AADR Abstract. March 2003.

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Chapter 6 Tooth whitening and its Effect on Dentin
Daily Use of Whitening Strips on Tetracycline Stained Teeth: Comparative Results After Two Months

ABSTRACT
This clinical article reviews the efficacy of a new 6.5% hydrogen peroxide tooth-whitening gel strip for bleaching teeth that have been intrinsically stained from tetracycline. Given the severity of the staining in the cases presented during a recently conducted clinical trial, the resulting efficacy is dramatic. Additionally, the continuous use of these strips for 30 minutes per day, twice daily for 4 months with no adverse effects—unlike many previously prescribed whitening alternatives—is also noteworthy.

INTRODUCTION
In cases requiring esthetic enhancement of discolored dentition, those involving tetracycline stains are among the most challenging. These intrinsic stains, which cannot be removed with polishing or abrasive mechanisms, may result from the administration of tetracycline during childhood for the treatment of disease. The color and severity of stains vary and are influenced by the duration of tetracycline use, and the stage of tooth development at the time the medication was prescribed. While some patients may select veneers or full-coverage crown restorations as the method with which to brighten their smile, still others may desire a more conservative approach. To that end, tooth whitening offers a conservative, simplified, and economical alternative for changing tooth color.

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When clinicians are faced with the prospect of whitening a patient’s intrinsically stained teeth, considerations for treatment include shade and location of discoloration,1 as well as which formulation of whitening solutions to use. Whether whitening should take place in the office or at home under the dentist’s supervision, along with the longevity of the whitening protocol, must also be decided. It has been suggested that when discoloration appears at the neck of the tooth, the whitening results may be poorest; when the stain is dark gray or blue, the prognosis is similarly unimpressive. When whitening tetracycline-stained teeth, patients may need to commit to a course of treatment lasting several weeks or months.2-4

Treatment commonly involves the use of at-home vital bleaching kits, which were first introduced in 1989.5 According to some reports, tetracycline-stained teeth have been shown to demonstrate a favorable prognosis dependent upon the treatment considerations, even though they are the most resistant to bleaching.6 Specifically, one report showed that 97% of patients with tetracycline stains experienced successful tooth lightening when a carbamide peroxide whitening solution was used in a nightguard.1

A recently introduced 6.5% hydrogen peroxide whitening delivery system (Crest® Professional Whitestrips)a shows promise for use in whitening tetracycline-stained dentition when used at home for two months and under a dentist’s supervision. The hydrogen peroxide-impregnated polyethylene strips represent a treatment alternative for patients who cannot afford the cost of other whitening treatments and/or do not have time for multiple dental visits.7 This article presents the recent research findings of a clinical trial designed to evaluate the efficacy of two at-home vital bleaching systems on tetracycline-stained teeth.

METHODS
A randomized clinical trial compared the efficacy of two at-home vital bleaching systems on tetracycline-stained teeth. Daily bleaching was conducted over two months. Eligibility was 79

limited to healthy adult volunteers who had 16 or more natural teeth, including at least 3 gradable maxillary incisors with significant tetracycline staining. Individuals demonstrating tooth sensitivity or an immediate need for dental treatment were excluded from participation in this trial.

The study protocol, informed consent, and advertising were reviewed and approved by the Institutional Review Board. Written and verbal informed consent was received prior to study initiation. After informed consent and baseline measurements, subjects were randomized 3:1 to a strip-based, hydrogen peroxide tooth-whitening system (Crest® Professional Whitestrips) or a marketed tray-based, carbamide peroxide whitening system control (Opalescence® 10%)b.

Subjects in both groups were supplied with a standard dentifrice (Crest® Cavity Protection Regular Paste)a, and soft toothbrush (Crest® Complete)a, for use throughout the study. All test products were overpackaged in 1-month product kits, and all labeling was identical except for a unique subject identification number.

The 40 randomized subjects included 30 assigned to the strip group and 10 assigned to the tray group. The study population ranged from 22 to 70 years of age. Approximately half of the sample presented with moderate to severe tetracycline staining (levels II through IV), one third of who had the more severe banding that is occasionally reported following childhood antibiotic use. While tobacco use was uncommon (15% of the sample), 95% of the study participants consumed coffee, tea, or cola beverages daily. Treatment groups were generally well balanced with respect to demographic and behavioral parameters and tetracycline stain levels.

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The first product application was supervised for instructional purposes, but all other treatment was unsupervised. Only the maxillary arch was treated. Participants in the strip group were instructed to wear a whitening strip for 30 minutes twice daily. Individuals in the tray group had a custom soft, full-arch bleaching tray fabricated with gingival scalloping and gel reservoirs using materials supplied by the manufacturer. Subjects in that group were instructed to place one half to three quarters of the contents of a bleaching syringe into the custom tray and wear the device for two hours daily.

Clinical response was evaluated at entry and again each month after treatment. First, the level of tetracycline staining on the maxillary anterior teeth was assessed using a modified standard 3-point index.8 This modification recognized the possibility of successfully bleaching teeth with relatively severe tetracycline stain (Table 1). These baseline values, along with age, were used for balance and assignment during treatment randomization. Efficacy was assessed using a standard 16-step value-oriented tooth shade guidec used in dentistry to match artificial crowns to the natural dentition. Shade assessments were performed in a neutral-colored dental operatory under color-balanced lighting conditions by a trained and calibrated examiner. Tolerability was assessed by intraoral examination and subject report at each study visit (Table 1).

Individual shade scores were determined by ordering the 16 shades arranged from dark to light according to the rank ordering suggested by the manufacturer. To account for unusually dark colors (often seen with tetracycline stain) or white colors (often seen postbleaching), this 16step guide was supplemented by 2 additional values (C4+ and B1-) representing shades darker than C4 or lighter than B1. Effectiveness was determined by calculating the change in shade scores from baseline at each posttreatment visit. Using this method, a decrease in numeric shade score represented an increase in tooth whiteness. Treatment groups were compared

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using analysis of covariance with the baseline shade as the covariant. Comparisons to baseline were 1-sided, while between-group comparisons were 2-sided using a 5% significance level.

RESULTS
Both treatments were effective overall in improving the shade of tetracycline-stained teeth (Table 2). Relative to baseline, the 2 groups averaged approximately 4 to 6.5 units of shade improvement after 2 months of treatment. Observed changes were greater on average after 2 months as compared to 1 month. Response was faster in the strip group. During the first month’s treatment, individuals in the strip group averaged greater than a 4-unit reduction in tooth shade, which represented a highly statistically significant (P < .0001) improvement vs baseline. In contrast, subjects in the tray group averaged less than a 1-shade reduction during the first month, not differing statistically from baseline (P > .10). Adjusting for baseline, the strip group averaged 2.6 to 3.2 units more shade reduction compared with the tray group control. With respect to between-group comparisons, the strip group experienced statistically significantly superior reductions (P < .01) in shade compared with the tray group at both the 1and 2-month time points (Table 3).

Both treatments were generally well tolerated. Mild and transient tooth sensitivity and oral irritation were the most common adverse events associated with daily bleaching (Table 4). All such events were typically reported early in the treatment regimen, and there were no clinical manifestations present at the Month 1 or Month 2 clinical examinations. Six subjects discontinued treatment during the first 2 months (3 in each treatment group). Of these, 2 individuals in the tray group reported the regimen was inconvenient and withdrew after the Month 1 visit. No one withdrew early or reported modifying their treatment regimen because of an adverse event.

82

DISCUSSION
This study was designed to evaluate clinical response following longer-term, daily use of 6.5% hydrogen peroxide whitening strips. The researchers elected to test extended treatment in individuals with tetracycline staining, because this clinical condition is reported to require extended treatment of several weeks or months in order to achieve meaningful whitening.9 A marketed 10% carbamide peroxide, tray-based system was selected as the control group, because this agent has been previously used and reported to be effective in longer-term studies of tetracycline staining.10,11

Both the strip and tray-bleaching systems were effective, with both groups differing significantly from baseline at the end of the 2-month monitoring period. Color response in the strip group was superior to the tray group, as evidenced by the significant (P < .01) between-group treatment differences at both Months 1 and 2, favoring the ―trayless‖ whitening strip system. Onset of these clinical benefits was more rapid in the strip group. After 1 month of treatment, the strip group averaged more than a 4-shade improvement compared to less than 1 shade in the tray group, with only the strip group experiencing statistically significant improvements in tooth color after 1 month. After 2 months, the strip group averaged a 67% greater shade improvement overall compared to the tray control group. While overnight tray use may improve clinical response in that group, such daily treatment conducted during the long term could also affect subject compliance.

Treatment response in some individuals was impressive (Figures 1 and 2). However, this study confirms early observations of the need for extended contact time in many tetracycline-stained patients. After 2 months of daily treatment, involving approximately 60 hours of strip use or 120 hours of tray use, no subjects had yet reached the predetermined bleaching cutoff (B1-). In these subjects, additional time may be necessary to affect maximum color change. Previous reports suggest a minimum of 2 months of treatment, hence the time point elected in this 83

study.12 The researchers expect to continue treatment and observation of this study population for up to 6 months to further assess the effectiveness and tolerability of these agents with even longer-term exposure.

Twice-daily use of the 6.5% hydrogen peroxide whitening strips was well tolerated over the 2month treatment period. The side effects in this study—transient tooth sensitivity and gingival irritation—were generally similar in nature and severity to the primary events reported in other longitudinal trials using the at-home tray-bleaching systems.9 In the current study, where the whitening strips were used for a total of 60 contact hours over a 2-month period, no subject in the strip group discontinued treatment due to an adverse event. This extended exposure associated with long-term, daily treatment of tetracycline stain corroborates and extends the safety of strip-based tooth whitening as reported in earlier, shorter-duration clinical trials.13-20

CONCLUSION
The use of whitening strips has been proposed as a viable option for longer-term whitening because of favorable compliance, lower systemic exposure, and other factors associated with this easy-to-use bleaching system.14 New clinical research involving extended treatment of tetracycline stain over 2 months confirms this proposition. In the current study, daily treatment for 1 month with a 6.5% hydrogen peroxide whitening strip provided similar efficacy as 2 months of treatment with a 10% carbamide peroxide tray system.

84

Tables
Table 1—Tetracycline Stain Classification Table 2—Baseline Demographic and Behavioral Information Table 3—Tooth Shade by Treatment and Time Table 4—Tooth Sensitivity and Oral Irritation

Table 1—Tetracycline Stain Classification*
Score 0 I the crown II III IV Deep yellow, brown, or grey stain, without banding Dark grey or blue stain with marked banding More severe or extreme staining Clinical Presentation No tetracycline staining evident Uniform light yellow, brown, or grey stain confined to incisal three-quarters of

*Modified from Boksman and Jordan, 1983.

85

Table 2—Baseline Demographic, Behavioral and Tooth Shade Information Demographic Strip Tray (n =30) Overall (n =10) Two-Sided (n =40)

Characteristic/Statistic P-value Age (Years) Mean (SD) Minimum - Maximum Sex Female Male Race Asian (Oriental) Caucasian Tobacco Use No Yes 25 (83.3%) 5 (16.7%) 6 (20%) 24 (80%) 19 (63.3%) 11 (36.7%) 37.7 (9.46) 22 - 58

38.9 (14.72) 25 - 70

38 (10.81) 22 - 70

.7591

3 (30%) 7 (70%)

22 (55%) 18 (45%)

.1401

4 (40%) 6 (60%)

10 (25%) 30 (75%)

.2323

9 (90%) 1 (10%)

34 (85%) 6 (15%)

1.0000

Daily Coffee/Tea/Cola Consumption No Yes 2 (6.7%) 28 (93.3%) 0 (0.0%) 10 (100%) 2 (5%) 38 (95%) 1.0000

Tetracycline Stain Levels I II III IV Tooth Shade Mean Minimum-Maximum 11.1 6-17 13.5 7-17 11.7 6-17 .0823 15 (50%) 7 (23.3%) 8 (26.7%) 0 (0.0%) 4 (40%) 1 (10%) 4 (40%) 1 (10%) 19 (47.5%) 8 (20%) 12 (30%) 1 (2.5%) .3176

86

Table 3—Tooth Shade by Treatmemt and Time Comparison to Baseline Comparisons N Mean Change (S.E.) P-Value Mean P-Value Between-Group

Treatment Difference (S.E.)

Month 1 Strip Tray Month 2 Strip Tray 26 7 -6.6 (0.418) -3.96 (0.835) <. 0001 <. 0001 -2.63 (0.993) .0097 26 9 -4.05 (0.397) -0.9 (0.696) <. 0001 0.1014 -3.15 (0.852) .0005

Table 4—Tooth Sensitivity and Oral Irritation Strip Tray Overall (n=30)(n=10)(n=40) No. Subj. Reported Gingival Irritation Tooth Sensitivity Observed Gingival Irritation 0 0 0 0 0 0 10 13 33.3 43.3 1 4 10 40 11 17 27.5 42.5 % Subj. No. Subj. % Subj. No. Subj. % Subj.

87

PRODUCT REFERENCES
a

The Procter & Gamble Co, Cinncinati, OH 45202; 800-492-7378 Ultradent Products, Inc, South Jordan, UT 84095; 800-552-5512 Vita Zahnfabrik, Germany; distributed in the US by Vident™, Brea, CA 92621; 800-828-3839

b

c

REFERENCES
1. Haywood VB, Leonard RH, Nelson CF, et al: Effectiveness, side effects and long-term status of nightguard vital bleaching. J Am Dent Assoc 125(9):1219-1226, 1994. 2. Haywood VB, Leonard RH, Dickinson GL: Efficacy of six months of nightguard vital bleaching of tetracycline-stained teeth. J Esthet Dent 9(1):13-19, 1997. 3. Haywood VB: Extended bleaching of tetracycline-stained teeth. Contemporary Esthetics and Restorative Practice 1(1):14-21, 1997. 4. Haywood VB: Bleaching tetracycline-stained teeth. Esthet Dent Update 7(1):25-26, 1996. 5. Haywood VB, Heymann HO: Nightguard vital bleaching. Quintessence Int 20(3):173-176, 1989. 6. Haywood VB, Leonard RH, Nelson CF: Efficacy of 6-months nightguard vital bleaching of tetracycline-stained teeth. J Dent Res 73 1994. 7. Kugel G: Nontray whitening. Compend Contin Educ Dent 21(6):524-528, 2000. 8. Boksman L, Jordan RE: Conservative treatment of the stained dentition: vital bleaching. Aust Dent J 28(2):67-72, 1983. 9. Leonard RH: Nightguard vital bleaching: Dark stains and long-term results. Compend Contin Educ Dent 21(suppl 28):S18-S27, 2000. 10. Leonard RH, Haywood VB, Eagle JC, et al: Nightguard vital bleaching of tetracyclinestained teeth: 54 months post treatment. J Esthet Dent 11(5):265-77, 1999. 11. Matis BA, Wang Y, Jiang T, et al: Six-month evaluation of bleaching agents in patients with tetracycline staining (abs). J Dent Res 80:182, 2001. 12. Haywood VB: Current status of nightguard vital bleaching. Compend Contin Educ Dent 21(suppl 28):S10-S17, 2000. 13. Gerlach RW: Shifting paradigms in whitening: introduction of a novel system for vital tooth bleaching. Compend Contin Educ Dent 21(suppl 29):S4-S9, 2000. 14. Kugel G, Kastali S: Tooth whitening efficacy and safety: a randomized and controlled clinical trial. Compend Contin Educ Dent 21(suppl 29):S16-S21, 2000. 15. Gerlach RW, Jeffers MJ, Pernik PS, et al: Impact of prior tooth brushing on whitening strip clinical response (abs). J Dent Res 80:151, 2001. 16. Gerlach RW, Campolongo KL, Hoke PD, et al: Use of peroxide-containing polyethylene strips: effect of dosing duration on initial and sustained shade change (abs). J Dent Res 80:150, 2001. 17. Gerlach RW, Gibb RD, Sagel PA: A randomized clinical trial comparing a novel 5.3% hydrogen peroxide whitening strip to 10%, 15% and 20% carbamide peroxide tray-based bleaching systems. Compend Contin Educ Dent 21(suppl 29):S22-S28, 2000. 18. McMillan DA, Gibb RD, Gerlach RW: Impact of increasing hydrogen peroxide concentration on bleaching strip efficacy and tolerability (abs). J Dent Res 80:173, 2001. 19. Swift EJ, Heymann HO, Ritter AV, et al: Clinical evaluation of a novel ―trayless‖ tooth whitening system. J Dent Res 80:151, 2001

88

Chapter 7 Long Term Hydrogen Peroxide Exposure and its Effect on Dentin
Comparative Study of 6.5% Hydrogen Peroxide Bleaching Strips On Tetracycline Stain: Clinical Response After Six Months Daily Use

ABSTRACT
BACKGROUND A variety of indications exist for bleaching single or multiple teeth, including tetracycline staining. The primary objective of this study was to evaluate clinical response following extended daily use of a trayless 6.5% hydrogen peroxide tooth bleaching gel (Crest® Professional Whitestrips, The Proctor & Gamble, Cincinnati, OH USA) on tetracycline stain. In this research, 10% carbamide peroxide in an at-home daytime tray delivery system (Opalescence® 10%, Ultradent Products, Inc., South Jordan, UT, USA) was used for comparison purposesas an experimental control. MATERIALS AND METHODS In this single-blind clinical trial, subjects were randomly

assigned to a Strip group (30 subjects) or a Tray group (10 subjects) following screening for tetracycline staining. Subjects used their respective products for approximately 6 months, with clinical safety and efficacy measurements taken at the end of each month. The strip product was used for 30 minutes, twice daily (maxillary arch only). The tray product was used for 2 hours daily (maxillary arch only). Treatment efficacy was determined by the tooth color change from baseline using an expanded Vita Shade guide. RESULTS The Strip group averaged greater shade reduction compared to the day wear Tray group at the Months 1, 2, and 3 visits, respectively. After Month 3, there were no significant between-group differences in shade. Of the subjects in the Strip group, 65 % reached B1 tooth color by Month 6, while 43% of subjects in Tray group obtained this result after 6 months. Both treatments were generally well tolerated. Mild and transient tooth sensitivity (40-47%) and oral irritation (30-47%) were the most common adverse events associated with daily bleaching, yet 89

neither affected study participation. Conclusions: Both the 6.5% H2O2 experimental bleaching strip (Crest Professional Whitestrips) and daywear marketed tray-based carbamide peroxide system (Opalescence 10%) provided significant tooth whitening in subjects with tetracycline stain. The Strip group obtained the results in a shorter pproximately half the time compared to the day wear Tray group.

CLINICAL SIGNIFICANCE
When used daily for 6 months, a 6.5% H2O2 bleaching strip and the 10% carbamide peroxide tray system can be effective in whitening tetracycline stain. Both the professional strip and tray systems were well tolerated throughout the 6-month usage period. This extended use provides additional evidence of clinical safety associated with use of these products for vital bleaching.

INTRODCUTION
Aging, chromatogenic food and drinks, excessive fluoride intake, medication (tetracycline) and others can be the cause of intrinsic stains. Tetracycline stains, though, are considered to be the most difficult types of intrinsic stains to manage clinically. The devastating effect on tooth formation of as little as one gram of tetracycline was recognized in the late 1950s1 and confirmed by a study of cystic fibrosis patients by Swachman et al 2. In 1970, Cohen and Parkins published a method for bleaching the discolored dentin of young adults with cystic fibrosis who had undergone tetracycline treatment 3. Different variations of tetracycline and derivates produce different colors in the tooth. When the teeth are exposed to the sunlight, they become darker, with a distinct gray/blue tinge. It is suggested that the reason that the front incisor teeth darken while the molars remain yellow longer is the different exposure to light 3. The discoloration of the permanent dentition depends on the amount and duration of tetracycline use4. The portion of the tooth, color and severity of the stains can be determined by the stage of the tooth development at the time of the drug administration. Tetracycline is incorporated into dentin during tooth calcification intra and post 90

partum, probably through chelation with calcium forming tetracycline orthophosphate 5. It can be deposited in fetal tooth buds when administered in the third trimester of pregnancy or by a child during the development of the tooth (between ages 3 to 4 months and 7 to 8 years) 6, 7. Colors may vary intensity of gray, blue, brown and yellow. The different banding can also be attributed to the variations of the tetracycline derivates. Clinicians are aware of the results from the use of tetracycline in pregnancy and young children. Even though physicians and dentists should seek other sources of treatment, tetracycline is still the drug of choice for treatment of Rocky Mountain spotted fever and it is also the most prescribed medication for acne. Tetracycline stained teeth may respond to bleaching treatments but in a different rate from the other types of stains 8,9. Treatment is usually achieved by at-home vital bleaching kits, which were first introduced in 1989 10. The most common regimen in the literature involves overnight application of the bleaching tray for periods of several months8. treatment, clinical outcomes may be mixed. Even with this extended

Recently, a strip-based system was developed to deliver peroxide topically without fabrication of a custom tray
11,12

. This trayless approach may be particularly relevant

where professionally-directed long term use is indicated, and where compliance with trays may be problematic12. This new research was conducted to extend strip treatment over a much longer duration than heretofore in order to evaluate clinical safety and effectiveness of vital bleaching in patient’s longer treatment.

MATERIALS AND METHODS
Clinical research was conducted to evaluate clinical safety and effectiveness of a hydrogen peroxide-based tooth whitening system under conditions of extended (long term) daily use. The research was a randomized, examiner-blind, parallel group clinical trial comparing two peroxide systems that differed with respect to delivery, and peroxide source. The experimental group 91

was 6.5% hydrogen peroxide whitening strips (Crest® Professional Whitestrips, The Procter & Gamble Co., Cincinnati, OH USA). The comparison group positive control was a 10%

carbamide peroxide gel (Opalescence® 10%, Ultradent Products, Inc., South Jordan, UT, USA) delivered in a custom bleaching tray. This system, which carries the American Dental

Association ―Seal of Acceptance‖13 for tooth whitening products, has been shown to be safe and effective in numerous clinical trials14,15,16,17.

Bleaching was conducted each day over a 6 month period.

The target population was

individuals with tetracycline staining, because these case types are widely recognized to require several months of treatment
18

. Eligibility was limited to healthy adult volunteers who had a

minimum of 16 natural teeth, including all 4 maxillary central and lateral incisors, and at least 3 gradable maxillary incisors having clinical evidence of tetracycline-related staining. Individuals with untreated periodontal disease or dental caries, or dentinal hypersensitivity were excluded from participation.

The study protocol, informed consent, and advertising were reviewed and approved by Tufts University Institutional Review Board. Written and verbal informed consent was received prior to initiating the study. Because the tray system had been used for an extended period, and shown to be safe, this research was specifically designed to thoroughly evaluate the clinical safety and effectiveness of the strip system under extended usage conditions. Because of the difficulty in identifying patients who would participate in long term research, and to assure an adequate sample size in the strip group, subjects were randomized 3:1 to the whitening strips or tray control group.

A dental impression was taken of the maxillary arch of those subjects assigned to the tray group to make custom bleaching trays. Subjects in that group received a custom, soft, fullarch bleaching tray fabricated with gingival scalloping and gel reservoirs using materials 92

supplied by the manufacturer (Ultradent Products, Inc. South Jordan, UT USA). Each strip kit contained one carton of 56 upper strips in pouches. Each tray kit contained 24 unit-dose syringes and 1 pocket tray case for the custom maxillary bleaching tray. In addition to the test products (and custom tray where appropriate), all subjects were supplied with an anticavity dentifrice (Crest® Cavity Protection, The Procter & Gamble Co., Cincinnati, OH USA), and 2 soft toothbrushes (Crest® Complete, The Procter & Gamble Co., Cincinnati, OH USA). All study-related products and materials were dispensed every four weeks in nonidentifiable kits with. For blinding purposes, kit labeling was identical, except for a unique subject identification numbers.

Only the maxillary arch was treated. Strip use was 30 minutes twice daily. Subjects in the tray group were instructed to place half to three quarters of the contents of a bleaching syringe into the custom tray and wear the device for 2 hours daily. Because both groups were assigned to a peroxide-containing product, and because only the maxillary arch was treated, all subjects were offered a marketed, peroxide-based tooth whitening system for ―compassionate use‖ on the mandibular arch after study completion.

Clinical response was evaluated at baseline and again every 4 weeks after treatment. The level of tetracycline stain on the maxillary anterior teeth was assessed using a modified standard index (Jordan and Boksman Tetracycline Stain Classification) that recognized the possibility of successfully bleaching teeth with relatively severe tetracycline stain
19,9

.

Tetracycline stain (I or II versus III or IV) and age were used for balancing during treatment randomization.

Efficacy was assessed using a standard 16-steptab value-oriented tooth shade guide (Vita Lumin, Vita Zahhnfabrik, Bad Sackingen, Germany). Shade examinations were performed 93

under color-balanced lighting conditions by a trained and calibrated examiner. Safety was assessed at baseline and each subsequent visit. Subjects were interviewed at each visit to ascertain the occurrence of any tooth hypersensitivity and/or oral irritation anytime during treatment. All adverse events were collected irrespective of causality. For subjects with findings, severity and duration were assessed, along with any interventions (rescue medications, treatment alteration, and the like) in accordance with pharmaceutical research standards.

Where banding was present, shade measurements were based on the predominant shade scored ofn the tooth outside of the banded zone. All shades were collected by an examiner who was blind to treatment assignment. Individual shade scores were determined by ranking the 16 shade tabs, arranged from light to dark, according to the rank order suggested by the manufacturer. This value-ordered ranking assigned ―B1‖ as the first (lowest) step, and ―C4‖ as the last (highest) step of the 16 possible outcomes. To account for exceedingly light or dark tooth colors, shade scores were expanded to include two additional categories representing colors lighter or darker than those available using this value-oriented system: shade ―B1–― (whiter than ―B1‖) with a numerical code ―0‖, and shade ―C4+‖ (darker than ―C4‖) with numerical code ―17‖.

Effectiveness was determined by calculating the change in shade scores from baseline at each post-treatment visit. Using the expanded 18-tabstep rank order, a decrease in numeric shade score represented an increase in tooth whiteness. Anticipating the effectiveness of long term peroxide treatment, any subject who reached the lowest numerical shade (B1 or lower) before end-of-treatment was withdrawn from active treatment by the investigator. For those subjects who were withdrawn from treatment (< or = B1 before Month 6), the ―last observation carried forward‖ method was used to compute shade improvement at 94

subsequent visits. Tobit censored regression models were used to adjust for possible bias attributable to effectiveness-related early withdrawals20,21. Treatment groups were

compared using analysis of covariance with the baseline shade as the covariant. Comparisons to baseline were 1-sided, while between-group comparisons were 2-sided using a 5% significance level.

RESULTS
Age at baseline ranged from 22 years to 70 years, with mean (SD) age of 38 (10.8) years (Table 1). Females accounted for 55% of the population. 25% of subjects reported Southeast Asian origin. There was considerable variation in tetracycline staining, with 52% of subjects

presenting with moderate-to-severe tetracycline staining (levels II-IV). Only one subject in the tray group exhibited the most severe staining/banding (level IV) at baseline. Shade scores ranged from 6 (corresponding to the ―C1‖ tab) to 17 (―C4+‖). While tobacco use was uncommon (15% of the sample), 95% of study participants consumed coffee, tea, or cola beverages daily. Treatment groups were balanced (p > 0.14) with respect to demographics, behavioral parameters and tetracycline stain levels.

Both treatments were effective overall in improving the shade of tetracycline-stained teeth, as evidenced by the significant (p < 0.05) improvement in shade after 1-2 months depending on treatment. After 1-month treatment, the strip group averaged more than a 4-shade

improvement compared to a less than 1 shade in the tray group. The strip group exhibited a statistically significant (p<0.0001) improvement in tooth shade after 1 month (Table 2). Both groups experienced incremental shade improvement with continued use after Month 1. This incremental benefit was more apparent in the tray group, such that, by Month 4, there were no significant (p > 0.48) differences between groups with respect to mean shade improvement from baseline. After 6-months daily use, the groups averaged a 10-11 shade improvement from baseline. 95

During the first 2 months of continuous daily treatment, no subjects in either treatment group reached or exceeded the minimum shade level. By Month 3, only 2 subjects (both in the strip group reached) reached ―B1‖ or lighter and were withdrawn from treatment. After 6 months daily treatment, 40% of study subjects still had not reached or exceeded this minimal shade cutoff. Use of Tobit (censored regression) models, which adjusted for the biases in the treatment difference at Month 3, 4, 5 and 6 visits, yielded treatment differences ranging from 1.3 to 0.6 shades favoring of the strip group (Table 3). Groups differed significantly (p = 0.04) with respect to this ―carry-forward‖ response only at the Month 3 time point.

Mild and transient tooth sensitivity and oral irritation were the most common adverse events associated with treatment (Table 4). Findings were symptomatic in nature, as there were no product-related clinical manifestations present at any of the monthly clinical examinations. Occurrence of tooth sensitivity and oral irritation, which ranged from 30-47%, was somewhat higher in the strip group compared to the tray group. Onset was generally during the first month of treatment, and transitory, resolving fully concurrent with treatment.

Six subjects discontinued treatment during the first 2 months (3 in each treatment group). Two individuals (both in the tray group) found the daily treatment regimen to be inconvenient and withdrew after the Month 1 visit. The other 4 were ―lost-to-follow-up‖. There were no systemic or non-oral adverse events (nausea or others) relating to product usage anytime during the 6month treatment period. No subjects reported using any ―rescue medication‖ such as

analgesics because of treatment-related sensitivity. There were no reports of early withdrawal due to a product-related adverse event, and none of the study subjects reported modifying usage because of treatment-related irritation or sensitivity.

96

DISCUSSION
This study evaluated clinical response following longer-term, daily use of hydrogen peroxidecontaining whitening strips relative to thea carbamide peroxide day wear tray-based group.control. The target population consisted of individuals with tetracycline staining, because clinical research repeatedly has demonstrated the need for extended treatment over several months to achieve meaningful whitening with these cases
220

. A marketed 10% carbamide

peroxide, tray-based system was selected for as the comparisoncontrol group, because this agent has been previously reported to be safe and effective on tetracycline stain when used overnight over a 6 month period.(1144) .. Subjects used their assigned treatment regimen throughout the 6-month test period unless they reached an average Vita Shade score of ―B1‖ or lighter prior to last evaluation. Those attaining this degree of whiteness were withdrawn from additional bleaching but were followed through the remainder of the trial for efficacy and safety outcomes.

In this research, both the strip and tray bleaching systems were effective, yielding a highly significant (p < 0.001) and similar 10-11 mean shade improvement from baseline after 6 months use. That both systems were comparable with respect to end-of-treatment efficacy may be expected given certain overt similarities between treatments. The 6.5% hydrogen peroxide strip system was used twice daily for 30 minutes, a 1-hour total daily contact time. The 10%

carbamide peroxide tray system (equivalent to ~3.5% hydrogen peroxide) was used once daily for 2-hours.

In this study, onset of shade improvement was earlier, and the magnitude of the change was greater with strips compared to trays. Through Month 3, the strip group exhibited a statistically significant (p < 0.05) 1.3 to 3.2 shade improvement relative to the tray control. What

accounteds for the significant between-group differences in shade improvement seen early in treatment? One likely explanation is that tTwice a day use of a strip for 30 minutes applied a 97

higher concentration of peroxide more frequently , which allows for episodic treatment, could represent an easier regimen for some individuals when compared to 2-hours of continuous tray use of the lower concentration carbamide peroxide gel. Other factors could have contributed to these findings, including the small sample size in the tray group, differences in the tetracycline staining at baseline, and/or compliance (strips versus the day wear regimen used for the trays). The portability and flexibility of strips may aid in treatment compliance, especially early in the treatment regimen. However, shade guides represent an imperfect measure of efficacy, especially for complex clinical presentations like those seen with tetracycline staining. As such, the comparative effectiveness of outcomes must be evaluated with caution because causality cannot be assessed from multi-factorial research like this clinical trial.

This study provides new evidence of an expanded safety in-use with strip-based tooth whitening. Both bleaching systems in this trial were well tolerated with daily use over a 6-month treatment period. No subjects in either group discontinued treatment early due to productrelated adverse events. For the tray system, these findings corroborate other reports of safe continuous daytime use of 10% carbamide peroxide on tetracycline stain
231,242

. The research

provides additional assurance of the clinical safety of this 10% carbamide peroxide tray system with conventional use over a few weeks, and longer term use for treatment of tetracycline staining. For the strip system, the findings provide first evidence of in-use clinical safety with extended treatment. The research, which expands on an earlier report establishing clinical safety at concentrations up to 6.5% hydrogen peroxide on strips for periods of up to 2 months daily use, extends treatment duration through 6-months 9. Twice-daily use of the 6.5% hydrogen peroxide whitening strips was well tolerated over that period, with the principal side effects being —ttransient tooth sensitivity and gingival irritation. These events were observed to occur more frequently in the strip group. Differences in occurrence rates between groups could be

attributable to the higher peroxide concentration in the strip versus the day wear tray group, or other factors, including random chance. —being similar in nature and severity to the carbamide 98

peroxide, tray-based control group. Compared to the earlier 2-month findings, extended use resulted in only a few additional reports of sensitivity/irritation, with no increasing severity or persistence. Longer-term use through Month 6 showed no evidence of any cumulative toxicity.

While the sample size is small, (n=7) this research also suggests that a 10% carbamide peroxide tray based system can result a meaningful reduction in tetracycline stain with day-time use. Previous research showed the effectiveness of 10% carbamide peroxide used overnight in a tray based system 8. This new research suggests day-time use may be a viable option where indicated due to compliance, patient preference or other factors.

Long term clinical trials of this duration may be particularly relevant in establishing clinical safety associated with routine treatment, as a research model that evaluates extreme (intentional or unintentional) use. Such research may only be appropriate with populations such as this one, where long-term treatment is common and/or necessary to achieve a desired endpoint, where ethical and experimental controls are adequate to interpret outcomes, and where rigorous and sufficient exit criteria are established to assure in-use safety. Under these conditions, longer duration trials represent a ―torture test‖ of sorts, offering additional insight on short-term clinical safety. This extended duration research, wherein whitening strips were professionally-

dispensed following clinical examination, and used for 180 contact hours over a 6-month period to treat tetracycline stain, corroborates and extends the safety of strip-based tooth whitening as reported in earlier, shorter duration clinical trials 9,253-27,24.

Tetracycline staining is complex, and may necessitate extensive esthetic intervention. Vital bleaching with professional tray or strip systems can yield an evident improvement in appearance within a few weeks. While this non-invasive, treatment may need to continue over an extended period. Some individuals will show favorable response after 3-4 months, after

which treatment may be discontinued. Duration may be difficult to predict, given the variable 99

clinical manifestations of tetracycline staining. Practitioners and patients should be advised that optimal bleaching of tetracycline staining may necessitate extended daily at-home treatment over a period of 3-6 months. The costs, risks, and benefits of the various treatment options must be considered as part of overall patient management.

CONCLUSION
Both the 6.5% hydrogen peroxide bleaching strip (Crest Professional Whitestrips) and the daytime tray-based carbamide peroxide tray systems (Opalescence 10%) provided significant tooth whitening of tetracycline stain. While shade improvement generally occurred earlier with the strips compared to the trays, by Month 4, groups did not differ significantly in this whitening end point. Both groups demonstrated similar results after 6 months. Daily use of strips or daytime tray bleaching for an extended 6-month period (approximately 180 contact hours) was generally well-tolerated, with no subjects discontinuing treatment early due to an adverse event, and with the principal adverse events—mild tooth sensitivity or and oral irritation—being similar to that seen with the at-home carbamide peroxide tray system.

100

Tables and Figures Table 1. Table 2. Figure 1. Figure 2. Table 3. BASELINE DEMOGRAPHIC CHARACTERISTICS
AND

TETRACYCLINE

STAINING

Treatment Comparisons, Mean Shade Change at Months 1-3 Mean Shade Change by Group Percent of Subjects Who Reached Minimum (―B1‖) Shade by Group Treatment Comparisons, Percent of Subjects Who Reached Minimum Shade at Months 3-6

Table 4.

Occurrence of Oral Irritation and Tooth Sensitivity

TABLE 1 BASELINE DEMOGRAPHIC CHARACTERISTICS AND TETRACYCLINE STAINING CHARACTERISTIC STATISTIC AGE (YEARS) Mean (SD) Minimum Maximum 37.7 (9.46) 22 - 58 38.9 (14.72) 25 - 70 38.0 (10.81) 22 - 70 0.7591 STRIP GROUP (n =30) TRAY GROUP (n =10) OVERALL (n =40) TWO-SIDED p-VALUE

Sex
Female Male TETRACYLINE STAIN LEVEL I II III IV 19 (63.3%) 11 (36.7%) 15 (50%) 7 (23.3%) 8 (26.7%) 0 (0.0%) 3 (30%) 7 (70%) 4 (40%) 1 (10%) 4 (40%) 1 (10%) 22 (55%) 18 (45%) 19 (47.5%) 8 (20%) 12 (30%) 1 (2.5%) 0.1401 e

0.3176 e

101

Table 2
Treatment Comparisons Shade Change from Baseline at Months 1-3
CHANGE FROM BASELINE N ADJ. (S.E.) MEAN ADJUSTED MEAN CHANGE (P-VALUE ) 95% C. I. ADJUSTED MEAN TREATMENT DIFFERENCE (S.E.)
PVALUE

Month 1
Strip Group Tray Group 26 9 8.13(0.397) -4.05 (<0.001) (-4.83,3.27) (-2.27,0.46) -3.15 (0.852) <0.001

11.28(0.696) -0.9 (0.101)

Month 2
Strip Group Tray Group 26 7 5.49(0.417) 8.13(0.833) -6.61 (<0.001) -3.98 (<0.001) (-7.43,5.79) (-5.61,2.34) -2.64 (0.991) 0.010

Month 3
Strip Group Tray Group 26 7 3.52 (0.267) 4.77 (0.533) -8.59 (<0.001) -7.33 (<0.001) (-9.11,8.07) (-8.38,6.29) -1.26 (0.634) 0.048

Month 4
Strip Group Tray Group 24 7 2.37 (0.309) 2.78 (0.592) -9.84 (<.0001) -9.43 (<.0001) (-10.45,9.24) (-10.59,8.27) -0.41 (0.713) 0.5484

Month 5
Strip Group Tray Group 23 7 2.04 (0.262) 2.35 (0.49) -10.35 (<.0001) -10.04 (<.0001) (-10.86,9.83) (-11,-9.08) -0.31 (0.593) 0.5876

Month 6
Strip Group Tray Group 23 7 1.71 (0.285) 1.89 (0.532) -10.67 (<.0001) -10.5 (<.0001) (-11.23,10.12) (-11.54,9.45)
102

-0.18 (0.645)

0.7764

Table 3
Treatment Comparisons Percent of Subjects Who Reached Minimum Shade at Months 3-6

Subjects who Reached B1/B1-

Treatment Difference

N

# (%) SUBJECTS

P-VALUE

ADJUSTED MEAN TREATMENT DIFFERENCE (S.E.) -1.26 (0.61)

P-VALUE

Month 3
Strip Group Tray Group 26 7 2 (7.7%) 0 (0%) 1.00 0.039

Month 4
Strip Group Tray Group 24 7 11 (45.8%) 1 (14.3%) 0.202 -0.63 (0.96) 0.511

Month 5
Strip Group Tray Group 23 7 12 (52.2%) 1 (14.3%) 0.103 -0.60 (0.85) 0.481

Month 6
Strip Group Tray Group 23 7 15 (65.2%) 3 (42.9) 0.394 -0.55 (1.25) 0.657

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Table 4 OCCURRENCE OF ORAL IRRITATION AND TOOTH SENSITIVITY STRIP (n =30)a AE SOURCE/AE CLASSIFICATION No. Subj. 13 14 0 GROUP TRAY (n =10)a % Subj. 43.3 46.7 0 No. Subj. 3 4 0 GROUP OVERALL (n =40)a % Subj. 30 40 0 No. Subj. 16 18 0 % Subj. 40.0 45.0 0

Reported
Oral Discomfort Tooth Sensitivity

Observed
Oral Irritation

Figure 1

104

Figure 2

105

REFERENCES
1. Arens D. The role of bleaching in esthetics. Dent Clin North Am 1989; 33:319-36 2. Swachman H, Fekete E, Kulezychi L, Foley T. The effect of long-term antibiotic therapy in patients with cystic fibrosis of the pancreas. Antibiot Annu 1958; 9:622-9 3. Cohen S, Parkins FM. Bleaching tetracycline-stained vital teeth. Oral Surg 1970; 29:465 4. Christensen GJ: Bleaching vital tetracycline stained teeth. Quintessence Int.1978 Jun: 9(6): 13-9 5. Mello HS. The mechanism of tetracycline staining in primary and permanent teeth. J Dent Child 1967; 34(6): 478 6. Moffitt JM, Cooley RO, Olsen NH, et al. Prediction of tetracycline-induced tooth discoloration. J Am Dent Assoc 1974; 88:547-552 7. Mull MM. The tetracycline and the teeth. Dent Abstr 1967; 12:346-350 8. Haywood VB, Leonard RH. Six-and 12-month color stability after 6 months bleaching tetracycline teeth [abstract 2891]. J Dent Res 1996; 75(special issue): 379 9. Kugel G, Aboushala A, Zhou X, Gerlach RW. Daily use of strips on tetracycline-stained teeth: comparative results after 2 months. Comp of Cont Edu in Dent. Jan 2002; 23 (1A): 2934 10. Haywood VB, Heymann HO:Nightguard vital bleaching . Quintessence Int 20(3):173176,1989.

Kugel G. Nontray whitening. Compend Contin Educ Dent 2000;6:524-528. 11. Gerlach RW. Whitening paradigms 1 year later: Introduction of a novel professional tooth-bleaching system. Compend Contin Educ Dent 2002;23:4-8. 12. Siew C. American Dental Association. ADA Guidelines for the acceptance of tooth-whitening products. Compend Contin Educ Dent. Supplem (28): S44-7, 2000 Jun.
13. Haywood VB, Leonard RH, Dickinson GL. Efficacy of six months of nightguard vital bleaching of tetracycline-stained teeth. J Esthet Dent. 1997;9:13-9. 14. Matis BA, Cochran MA, Eckert G, Carlson TJ. The efficacy and safety of a 10% carbamide peroxide bleaching gel. Quintessence Int. 1998;29:555-63. 15. Gerlach RW, Gibb RD, Sagel PA. A randomized clinical trial comparing a novel 5.3% hydrogen peroxide bleaching strip to 10%, 15% and 20% carbamide peroxide tray-based bleaching systems. Compend Contin Educ Dent 2000;21:S22-S28. 16. Matis BA. Tray whitening: What the evidence shows. Compend Contin Educ Dent 2003;24:354-362. 17. Haywood VB. Frequently asked questions about bleaching. Compend Contin Educ Dent 2003;24:324-338. 18. Boksman L, Jordan RE. Conservative treatment of the stained dentition: vital bleaching. Aust Dent J 1983;28:67-72. 19. Tobin, J. Estimation of Relationships for Limited Dependent Variables. Econometrica, 1958;26, 24 -36. 20. Green, W.H. Econometric Analysis, 2nd Edition, New York: Cambridge University Press, 1993. 21. Leonard RH. Long-term treatment results with nightguard vital bleaching. Compend Contin Educ Dent. 2003;24:364-74. 22. Leonard RH Jr, Haywood VB, Caplan DJ, Tart ND. Nightguard vital bleaching of tetracycline-stained teeth: 90 months post treatment. J Esthet Restor Dent. 2003;15:142-52 23. Matis BA, Wang Y, Jiang T, Eckert GJ. Extended at-home bleaching of tetracyclinestained teeth with different concentrations of carbamide peroxide. Quintessence Int. 2002;33:645-55. 24. Gerlach RW. Zhou X. Comparative clinical efficacy of two professional bleaching systems. Compend Contin Educ Dent 2002;23:35-41.

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25. Karpinia KA, Magnusson I, Sagel PA, Zhou X, Gerlach RW. Vital bleaching with two athome professional systems. Am J Dent 2002;15:13-18A. 1. Li Y, Lee SS, Cartwright SL, Wilson AC. Comparison of clinical efficacy and safety of three professional at-home tooth whitening systems. Compend Contin Educ Dent 2003;24(5):357-64.

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Chapter 8 Paint on delivery systems
A Clinical Comparison of Two Paint on Whitening Systems

INTRODUCTION
The use of peroxide to whiten teeth dates back over 100 years. The advent of patient-applied kits, bleaching has become both common and popular, and use of peroxide is now generally recognized as a safe and effective method for tooth whitening1-3. There are a variety of indications for bleaching single or multiple teeth, including staining from chromagenic foods or other sources, dental fluorosis, tetracycline staining and devital discolored teeth4-7. Delivery is via in-office, at-home regimens, such as polyethylene strips and paint-on, or combination regimens with or without professional supervision8-9.

Easy availability of over the counter whitening products has made whitening of teeth more popular amongst people of all ages. There are different types of over the counter products like whitening dentifrices, tray based, whitening strips and the recently introduced brush applications.

Over the counter bleaching kit requires the consumer to use either a prefabricated tray or fabricate their own semi-molded tray then fill it with supplied bleaching agents. These types are less than ideal because the trays are not custom fitted and the formulation is not sophisticated as those dispensed by the dentist.10

Whitening toothpastes contain mild abrasives to remove surface stains. The peroxide content in the toothpastes are very low ( 1% or less ), also the exposures of the toothpastes on the tooth is minimal hence any whitening minimal.11 108

Whitening Strips is an alternative to rigid tray system for vital tooth whitening. The strip technology uses same peroxide chemistry used in tray systems. The main drawback is that they are limited to the anterior teeth and cannot be easily adapted to the malposed teeth.

The latest inclusion to OTC products is a Brush technique. This technique is non-tray based paint on application. These products include a 19% sodium percarbonate film (5.3% hydrogen peroxide) along with an 18% carbamide peroxide paint-on gel. The advantages to the paint- on products is ease of use as well as the elimination of the need for a tray. These systems also limit gingival exposure. There is little data on efficacy of these products.

Study Objectives
The objective of this trial was to compare the safety and whitening efficacy of an experimental liquid strip (four weeks of use) to Colgate Simply White (three weeks of use).

Study Design
This was a randomized, controlled, double-blind, parallel, single-center study. Fifty (50) generally healthy subjects who desired to have their teeth whitened were enrolled in the study. Subjects who qualified for the study based on the results of their Baseline visit were randomly assigned to one of two treatment groups. The first product use was supervised at the Product Distribution visit. All product use followed the labeled use instructions. Digital imaging and oral tissue examinations were conducted at Baseline, Week 2, Week 3, and Week 4. Subjects assigned to Simply White discontinued product use after the Week 3 visit and returned one week later for digital imaging and oral tissue examinations. Subjects assigned to the experimental product continued product use for all four weeks of the study. During the entire

109

study period (treatment and post-treatment), subjects brushed with Crest Cavity Protection dentifrice and an extra-soft toothbrush. .

Selection of Study Population
Fifty (50) generally healthy adults with a Vita Shade score of B2 or darker who met all study entrance criteria were enrolled. Subjects who withdrew from the study were not replaced.

INCLUSION CRITERIA To be included in this study, each subject must have:

presented with a Vita Shade score of B2 or darker on Teeth 8 and 9;

provided written informed consent prior to their participation and be given a copy of the signed consent form;

been at least 18 years of age at the time of enrollment;

agreed not to participate in any other oral/dental product clinical studies during the course of this study;

agreed to return for the scheduled visits and follow the study procedures; and

agreed to refrain from the use of any non-study dentifrices and tooth whitening products for the study duration.

EXCLUSION CRITERIA The subjects were excluded from this study if they: 110

a. had dental crowns or clinically meaningful malocclusion involving the maxillary or mandibular anterior dentition (also confirmed by Investigator at Baseline visit);

b. reported having teeth previously bleached by a professional treatment, over-the-counter bleaching kit, or clinical trial test product;

c. presented with any pre-existing oral or medical condition that the examiner or Investigator determined may have placed the subject at increased health risk from study participation;

d. had any dental care planned during the duration of the study that may have: impacted the general health of the subject, impacted the ability of the subject to bleach teeth according to the protocol, required a dental prophylaxis, or involved the anterior dentition;

were undergoing current treatment for gingivitis, periodontitis, or caries;

were currently using a chlorhexidine mouth rinse or Listerine mouth rinse;

had teeth with clinically meaningful intrinsic staining due to tetracycline, fluorosis or hypocalcification;

had self-reported dentinal sensitivity, or

had teeth that could not be imaged. 111

CONTINUANCE CRITERIA Subjects may have been discontinued from the study or been excluded from the efficacy analysis if they:

a. used a chlorhexidine mouth rinse and/or Listerine mouth rinse;

b. received a dental prophylaxis; or

c. used any tooth whitening products other than assigned study products.

Removal of Subjects from the Study

Subjects were encouraged to complete the full course of the study; however subjects may have withdrawn from the study at any time or for any reason. The reason for withdrawal was documented on the appropriate case report form (CRF). The Investigator may have removed subjects from the study for medical reasons and where, in his judgment, there was significant lack of compliance at any time.

Study Procedures

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There were 5 study visits. A table detailing the procedures performed at each visit is provided in Table 1.

SCHEDULE OF EVENTS

Study No. 2002147

Table 1 Schedule of Events PreTreatment Visit 2 Visit 1 Procedures Informed Consent Inclusion/Exclusion Criteria Demographics Balance & Assignment Supervised Product Application Product Distribution Product Return Oral Status Interview Oral Hard & Soft Tissue Examination Continuance Criteria X X X X X X X X X X X X X X Baseline X X X X X Product Distribution Visit 3 Week 2 Visit 4 Week 3 Visit 5 Week 4 Treatment

113

Study No. 2002147

Table 1 Schedule of Events PreTreatment Visit 2 Visit 1 Procedures Digital Imaging Adverse Events Subject Accountability Baseline X Product Distribution Visit 3 Week 2 X X Visit 4 Week 3 X X Visit 5 Week 4 X X X Treatment

BASELINE VISIT
Written informed consent was obtained from each subject following review of the study design and test regimen. Demographic information and inclusion/exclusion criteria were obtained and documented on the appropriate CRF. Each subject was given an oral status interview prior to receiving an oral soft tissue (OST) examination that included a self-reported tooth sensitivity assessment. Digital images of the facial anterior dentition were collected.

PRODUCT DISTRIBUTION/BALANCE & ASSIGNMENT VISIT
The b* and L* digital imaging scores obtained at the Baseline visit, along with age, were arrayed to balance and assign subjects to treatment groups. Test product (kit boxes plus Crest) was distributed and written instructions were reviewed. Subjects completed their first product use under supervision.

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WEEK 2 VISIT Approximately 2 weeks after beginning test product use, subjects returned to the clinical site. Continuance criteria were assessed. An oral status interview and an oral exam were conducted. Self-reported, clinical OST and tooth sensitivity abnormal findings not present at Baseline were documented on the AE CRF. Digital images of the facial anterior dentition were collected.

WEEK 3 VISIT Approximately 3 weeks after beginning test product use, subjects returned to the clinical site. Continuance criteria were assessed. An oral status interview and an oral tissue exam were conducted. Self-reported, clinical OST and tooth sensitivity abnormal findings not present at Baseline were documented on the AE CRF. Digital images of the facial anterior dentition were collected. Subjects assigned to Simply White discontinued product use at this time (per labeling), but continued to brush with the provided toothbrush and dentifrice.

WEEK 4 VISIT Continuance criteria were assessed. An oral status interview and an OST exam were conducted. Self-reported, clinical OST, and tooth sensitivity abnormal findings not present at Baseline were documented on the AE CRF. Digital images of the facial anterior dentition were collected. All test product was returned. Subjects were exited from the study

EFFICACY ASSESSMENTS DIGITAL IMAGING CAMERA
The photographic system consisted of a HC2500 CCD high resolution digital camera manufactured by Fuji. It was equipped with a Fujinon A8x12BMD, 1:2.8/12-96mm zoom lens and a linear polarizer to permit cross-polarized light. Two 150-watt lights located on each side of a CCD camera provided the lighting. The unit was connected to a personal computer which 115

recorded and analyzed the images. Prior to daily use, the system was calibrated to assure proper operation. Additionally, a color standard was centered and imaged every hour, then was removed prior to imaging subjects. Maxillary anterior facial surfaces were measured for tooth color using the digital image technology. One color value (L* a* b*) was generated from the complete surface of the measured teeth.

For each examination period, lighting in the exam room was background or ambient. Each subject was asked to brush with water and an extra-soft toothbrush to dislodge any debris that may have interfered with photography. The subject sat on a stool in front of a chin rest used to hold the head still. The subject placed his/her chin on the chin rest, then positioned two plastic retractors into the mouth to retract his/her lips and cheeks.

It was also acceptable for the subject to position the retractors, then place their chin on the chin rest. The subject was instructed to use the retractors to retract his/her lips and cheeks (toward their ears) as far as possible. The incisal edges of the front teeth were placed together and centered in the camera. The chin rest may have been adjusted to bring the teeth into the plane of focus and ensured the image was centered. Prior to exposure, the subject was instructed to draw air through their teeth and to position their tongue away from the teeth so that the tongue was not visible. By proper positioning of the camera, frontal images of each subject were taken at each visit.

SAFETY ASSESSMENTS
In this study, an AE was defined as any negative oral cavity health effect, either reported by the subject or noted by the Investigator. Serious adverse events (SAEs), which occurred during the course of the study and were reported to or observed by the study Investigator/examiner, were documented on the appropriate CRF. All SAEs were to be followed until resolution or until

116

discharge from follow-up was warranted based on consultation between the Sponsor and the Investigator.

Serious AEs were defined as one or more of the following: a) death, b) life-threatening, c) required in-patient hospitalization, and d) resulted in persistent or significant disability. When the Investigator was notified of an SAE, the Investigator must have promptly (within 24 hours) notified Procter & Gamble (P&G, the CRA or the Medical Monitor) of the SAE, regardless of causality. Within 5 working days, a written report describing the circumstances of the event must have been submitted to P&G.

ORAL SOFT TISSUE (OST) EXAMINATION
Assessment of the OST was conducted via a visual examination of the oral cavity and perioral area utilizing a standard dental light, dental mirror, and gauze. The structures examined included the gingiva (free and attached), hard and soft palate, oropharynx/uvula, buccal mucosa, tongue, floor of the mouth, labial mucosa, mucobuccal/mucolabial folds, lips, and perioral area. All abnormal OST findings noted after test product assignment which were not documented at Baseline, or were present at Baseline but had worsened during test product usage, were recorded as AEs on the AE CRF.

TREATMENTS Method of Assigning Subjects to Treatment Groups
After the Baseline visit, digital images were processed and subjects were randomly assigned in approximately equal numbers to one of the two treatment groups. The randomization balanced for Baseline b* and L* scores, as well as age. Subjects who resided in the same household were assigned to identical marketed products. A statistician that was not a member of the project team carried out the assignment procedure.

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TREATMENTS ADMINISTERED Experimental Whitening Product

Subjects were instructed to follow their customary brushing regimen for the study duration using the Crest Cavity Protection dentifrice and toothbrush provided. Prior to using the test product, subjects were instructed to brush and dry their teeth. Subjects applied the liquid strip to the facial surfaces of the maxillary anterior teeth once daily just prior to bedtime. Subjects were instructed not to eat, drink, or smoke for 90 minutes following treatment application. The test product was removed each morning by thoroughly brushing the teeth. Subjects were supplied with written instructions and shown pictures on how to apply the product. The first product use was completed under supervision at the Product Distribution visit. All other uses were unsupervised at-home.

Colgate Simply White
Subjects followed the manufacturer directions for product use, and followed their customary brushing regimen for the study duration using Crest Cavity Protection dentifrice and the toothbrush provided. Prior to using the test product, subjects were instructed to brush and dry their teeth. Subjects applied the whitening product to the facial surfaces of the maxillary anterior teeth twice per day. Subjects were instructed not to eat or drink for 30 minutes following treatment application. Subjects were supplied with the marketed instructions for use and shown pictures on how to apply the product. The first product use is completed under supervision at the Product Distribution visit. All other uses are unsupervised at-home.

IDENTITY OF INVESTIGATIONAL PRODUCTS
 Experimental tooth whitener (19.0% sodium percarbonate, equivalent to 5.3% hydrogen peroxide), manufactured by The Procter & Gamble Company. Packaged in individual sachets / stick packs. 118



Colgate Simply White (commercial product)

Experimental Whitening Product
Each kit contained a four-week supply of single unit doses (sachets), 20 micro brushes for product application, one tube of toothpaste (Cavity Protection Crest, The Procter & Gamble Co., Cincinnati, OH, USA) one extra-soft toothbrush (Crest Complete, The Procter & Gamble Co., Cincinnati, OH, USA), and one instruction sheet. The sachets were labeled with study number, product number, applicable caution and warning statements, usage directions and other information as dictated by internal regulatory requirements and clinical standard operating procedures (SOPs).

Colgate Simply White
Product was supplied in subject kit boxes. Each kit contained one 0.34 oz polypropylene bottle with applicator, one tube of toothpaste (Cavity Protection Crest, The Procter & Gamble Co., Cincinnati, OH, USA) one extra-soft toothbrush (Crest Complete, The Procter & Gamble Co., Cincinnati, OH, USA), and one instruction sheet. The kits were labeled with study number, product number, applicable caution and warning statements, labeled usage directions and other information as required by internal regulatory and clinical SOPs.

Supplemental product was provided to the Investigator if additional product was needed, and was dispensed only after consulting with the Sponsor for correct treatment group identification. The shipping containers were labeled with the "ship to" clinical site address and a "content statement" listing study number and subject numbers contained within.

119

BLINDING
This was a double-blind study. Product use was conducted in an area where the examiner was not present. Subjects were instructed not to discuss product appearance or physical qualities with the examiner.

TREATMENT COMPLIANCE
Subjects received verbal and written instructions on dentifrice usage. Subjects used their product for the first time on site under supervision as part of the instructions. Subjects were queried regarding compliance at each visit.

STATISTICAL ANALYSIS PLANS
The primary assessment compared the treatment groups for yellowness reduction (b*) at the end-of-treatment visit. The secondary assessment compared the treatment groups for yellowness reduction (b*) at the Week 2 visit. The tertiary assessment compared the treatment groups for yellowness reduction (b*) at the end-of-study visit. The mean whitening benefit for each treatment group was assessed at the post-baseline visits. The safety profile of each treatment group was characterized.

Operational Trial Hypotheses
Tooth color was assessed by the digital imaging measurements b* (yellow – blue), L* (lightness), and a* (red – green). For a given post-baseline visit: b* = b*visit - b*baseline, L* = L*visit - L*baseline, a* = a*visit - a*baseline, and E* = (L*2 + a*2 + b*2) ½. In the case of tooth color, whitening benefit resulted primarily from negative b* (yellowness reduction). Additionally, positive L* (increasing lightness) and negative a* (redness reduction) may have been observed. Changes in b*, L*, and a* resulted in increased E* (overall color change).

120

An additional color quantity was computed from the L*a*b* color values for each subject and visit: W* = (b*visit2 + a*visit2 + (L*visit - 100)2) ½ which represented the distance to pure white for a given visit. One may have defined W* = (b*visit2 + a*visit2 + (L*visit - 100)2) ½ – (b*baseline2 + a*baseline2 + (L*baseline - 100)2) ½ as the distance to pure white at a given visit minus the distance to pure white at Baseline. In the equations above, pure whiteness was achieved when b* = 0, a* = 0, and L* = 100.

Primary Hypotheses
The following hypothesis was tested at the end-of-treatment visit.

Null:

The mean level of b* in the experimental group is equal to the mean level of b* in the Simply White group.

Alternative: The mean level of b* in the experimental is not equal to the mean level of b* in the Simply White group.

Secondary Hypotheses
The following hypothesis was tested at the Week 2 visit.

Null:

The mean level of b* in the experimental group is equal to the mean level of b* in the Simply White group.

Alternative: The mean level of b* in the experimental is not equal to the mean level of b* in the Simply White group.

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Tertiary Hypotheses
The following hypothesis was tested at the end-of-study visit.

Null:

The mean level of b* in the experimental group is equal to the mean level of b* in the Simply White group.

Alternative: The mean level of b* in the experimental is not equal to the mean level of b* in the Simply White group.

The following hypothesis was tested for each treatment group and post-baseline visit. Null: The mean level of b* is equal to zero.

Alternative: The mean level of b* is not equal to zero.

The hypotheses above were investigated for other color parameters as well.

Efficacy Analysis Plans
Summary statistics (e.g., means, standard deviations, frequencies, etc.) of the demographic characteristics, b*, L*, a*, W*, and E* were calculated for each treatment group and visit. The treatment groups were compared using analysis of covariance (ANCOVA) methods. The response was color change from Baseline and the covariate was the color at Baseline. Age was used as a covariate. Treatment comparisons were tested at the 0.05 level of significance. Whitening benefit at each post-baseline visit was investigated using the mean color change from Baseline within each treatment group and then performing one-sample t-tests. Comparisons to Baseline were tested using a two-sided 0.05 level of significance.

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Safety Analysis Plans
The safety data were summarized with respect to tooth sensitivity and oral irritation. Following the end-of-study visit, all AEs, including OST-related AEs and dentinal hypersensitivity AEs were summarized overall and by treatment group. The safety data were also summarized through the Week 2 visit.

POWER AND SAMPLE SIZE CONSIDERATIONS
At least 23 subjects per treatment group completing the study ensured at least 80% power to detect a difference of 0.7 b* units between the treatment groups with a common standard deviation of 0.7, in two-sided testing at a 0.05 significance level. A target of up to 25 subjects was recruited per group (total of up to 50).

CHANGES TO THE ANALYSIS PLANS
All planned analyses were performed. In addition, efficacy comparisons were made between Week 2 for the Experimental Film group and Week 3 for the Colgate Simply White group. Also, the treatment groups were compared at the Week 3 visit as well. Safety data was also summarized through the Week 2 visit of the study.

RESULTS DISPOSITION OF SUBJECTS

Fifty-one subjects were screened, however, Subject 3021 was dropped from the study at Baseline due to investigator recommendation. Fifty subjects were randomized to treatment, and 47 subjects received product. Three subjects failed to present for product distribution visit: Subject 3007 voluntarily withdrew from the study, Subjects 3013 and 3041 were lost to follow-

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up. Thirty-nine subjects completed the study. Eight subjects 3024, 3025, 3027, 3032, 3033, 3045, 3057, 3016 were lost to follow-up (Table 3).

DATA SETS ANALYZED
Demographic, digital imaging and adverse event data were all analyzed for this study. Three subjects failed to present for the product distribution visit: Subject 3007 voluntarily withdrew from the study, Subjects 3013 and 3041 were lost to follow-up. In the Colgate Simply White group, one subject (3045) was lost follow-up starting at the Week 2 visit and six subjects (3024, 3025, 3027, 3032, 3033, and 3057) were lost to follow-up at the Week 4 visit, two subjects (3002 and 3015) each missed one visit. In the Experimental Film group, one subject (3016) was lost follow-up starting at the Week 2 visit, two subjects (3008 and 3022) each missed one visit (Table 3).

DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Subjects ranged in age from 21 to 70 years with an average of 35 years. Sixty-four percent of the subjects were female. Twenty-eight subjects (59.6%) were Caucasian, 12 subjects (25.5%) were Black, 3 subjects (6.4%) were Asian, 2 subjects (4.3%) were Asian and 2 subjects (4.3%) were Multi-racial. Cigarette and cigar smokers accounted for 10.6% of the subjects. Coffee, tea, and dark cola drinkers accounted for 89.4% of the subjects with a median of 2 drinks per day. Treatment groups were relatively balanced in demographic characteristics and behavioral parameters (Table 4-5).

Efficacy Results PRIMARY EFFICACY
The end-of-treatment comparison compared the Experimental Film group at Week 4 relative to the Colgate Simply White group at Week 3. At the end-of-treatment visit, the Experimental Film group provided more than 7.9 times greater reduction in yellowness (b*) when compared to the 124

Colgate Simply White group with estimated means and standard errors of –0.782 ± 0.137 and – 0.098 ± 0.131, respectively. The treatment comparison for b* was statistically significant (pvalue = 0.0009 from Table 16).

SECONDARY EFFICACY
At Week 2 visit, the Experimental Film group provided more than 3.0 times greater reduction in yellowness (b*) when compared to the Colgate Simply White group with estimated means and standard errors of –0.691 ± 0.124 and –0.230 ± 0.116, respectively. The treatment comparison for b* was statistically significant (p-value = 0.0109 from Table 11).

TERTIARY EFFICACY
At the end-of-study visit (Week 4), the Experimental Film group provided more than 4.4 times greater reduction in yellowness (b*) when compared to the Colgate Simply White group with estimated means and standard errors of –0.788 ± 0.140 and –0.177 ± 0.152, respectively. The treatment comparison for b* was statistically significant (p-value = 0.006 from Table 11).

For the whitening benefit measured by mean change in b* (yellowness) from Baseline, the Experimental Film group was effective at each post-baseline visit (p-values  0.0003 from Table 6), while the Colgate Simply White group was only statistically significant at the Week 2 visit (pvalue = 0.0305 from Table 6).

ADDITIONAL EFFICACY
Summary statistics were calculated for b*, L*, a*, W* and E* (Tables 6-10). The treatment groups were well balanced on b* (yellowness), L* (lightness), and a* (redness) at Baseline. Figure 1 displays the adjusted means of b* for each treatment group at each visit. Figure 2 displays the adjusted means of L* for each treatment group at each visit. 125

END-OF-TREATMENT (Experimental Film at Week 4 versus Colgate Simply White at Week 3)
At the end-of-treatment visit, the Experimental Film group provided more than 7.3 times greater improvement in lightness (L*) when compared to the Colgate Simply White group with estimated means and standard errors of 1.061± 0.124 and 0.145 ± 0.118, respectively. The treatment comparison for L* was statistically significant (p-value < 0.0001 from Table 16). The Experimental Film group provided more than 39 times greater improvement in redness (a*) when compared to the Colgate Simply White group with estimated means and standard errors of –0.394 ± 0.073 and –0.010 ± 0.070, respectively. The treatment comparison for a* was statistically significant (p-value = 0.0005 from Table 16). The Experimental Film group provided more than 8 times greater improvement in composite whiteness (W*) when compared to the Colgate Simply White group with estimated means and standard errors of –1.377 ± 0.149 and –0.172 ± 0.142, respectively. The treatment comparison for W* was statistically significant (pvalue < 0.0001 from Table 16). The Experimental Film group provided more than 2.3 times greater overall color change (E*) when compared to the Colgate Simply White group with estimated means and standard errors of 1.526 ± 0.137 and 0.670 ± 0.131, respectively. The treatment comparison for E* was statistically significant (p-value < 0.0001 from Table 16).

ADDITIONAL TREATMENT COMPARISONS (Experimental Film at Week 2 versus Colgate Simply White at Week 3)
The Experimental Film group at Week 2 provided more than 6.3 times greater reduction in yellowness (b*) when compared to the Colgate Simply White group at Week 3 with estimated means and standard errors of –0.691 ± 0.122 and –0.108 ± 0.114, respectively. The treatment comparison for b* was statistically significant (p-value = 0.0014 from Table 17). The Experimental Film group at Week 2 provided more than 4.5 times greater improvement in 126

lightness (L*) when compared to the Colgate Simply White group at Week 3 with estimated means and standard errors of 0.690 ± 0.114 and 0.152 ± 0.106, respectively. The treatment comparison for L* was statistically significant (p-value = 0.0015 from Table 17). The Experimental Film group at Week 2 provided more than 29.9 times greater improvement in redness (a*) when compared to the Colgate Simply White group at Week 3 with estimated means and standard errors of –0.419 ± 0.067 and –0.014 ± 0.062, respectively. The treatment comparison for a* was statistically significant (p-value < 0.0001 from Table 17). The Experimental Film group provided more than 5.5 times greater improvement in composite whiteness (W*) when compared to the Colgate Simply White group with estimated means and standard errors of –1.028 ± 0.138 and –0.185 ± 0.129, respectively. The treatment comparison for W* was statistically significant (p-value < 0.0001 from Table 17). The Experimental Film group provided more than 1.7 times greater overall color change (E*) when compared to the Colgate Simply White group with estimated means and standard errors of 1.183 ± 0.114 and 0.683 ± 0.106, respectively. The treatment comparison for E* was statistically significant (pvalue = 0.0032 from Table 17).

Week 2 Comparisons At the Week 2 visit, only Experimental Film group was effective in whitening teeth as measured by mean change in L* (lightness) from Baseline (p-value < 0.0001 from Table 7). The Experimental Film group provided more than 13 times greater improvement in lightness (L*) when compared to the Colgate Simply White group with estimated means and standard errors of 0.693 ± 0.132 and 0.053 ± 0.123, respectively. The treatment comparison for L* was statistically significant (p-value = 0.0012 from Table 12). Both treatments were effective in whitening teeth as measured by mean change in a* (redness) from Baseline: the Experimental Film group had a p-value < 0.0001 and the Colgate Simply White group had a p-value equal to 0.0163 (Table 8). The Experimental Film group provided more than 3.4 times greater improvement in redness (a*) when compared to the Colgate Simply White group with 127

estimated means and standard errors of –0.430 ± 0.062 and –0.124 ± 0.058, respectively. The treatment comparison for a* was statistically significant (p-value = 0.0010 from Table 13). Only the Experimental Film group was effective in whitening teeth as measured by mean change in W* (composite whiteness) from Baseline with p-value < 0.0001 (Table 9). The Experimental Film provided more than 5.3 times greater improvement in composite whiteness (W*) when compared to the Colgate Simply White group with estimated means and standard errors of –1.034 ± 0.148 and –0.193 ± 0.138, respectively. The treatment comparison for W* was statistically significant (p-value = 0.0002 from Table 14). Both treatments were effective at increasing overall color change (E*) with p-values < 0.0001 (Table 10). The Experimental Film group provided more than 1.5 times greater overall color change (E*) when compared to the Colgate Simply White group with estimated means and standard errors of 1.199 ± 0.120 and 0.773 ± 0.112, respectively. The treatment comparison for E* was statistically significant (pvalue = 0.0154 from Table 15).

Week 3 Comparisons At the Week 3 visit, the Experimental Film group provided more than 6.3 times greater reduction in yellowness (b*) when compared to the Colgate Simply White group with estimated means and standard errors of –0.705 ± 0.129 and –0.111 ± 0.123, respectively. The treatment comparison for b* was statistically significant (p-value = 0.0021 from Table 11). Only the Experimental Film group was effective in whitening teeth as measured by mean change in L* (lightness) from Baseline (p-value < 0.0001 from Table 7). The Experimental Film group provided more than 7 times greater improvement in lightness (L*) when compared to the Colgate Simply White group with estimated means and standard errors of 1.071± 0.137 and 0.149 ± 0.131, respectively. The treatment comparison for L* was statistically significant (pvalue < 0.0001 from Table 12). Only the Experimental Film group effective in whitening teeth as measured by mean change in a* (redness) from Baseline (p-value = 0.0025 from Table 8). The Experimental Film provided more than 15.7 times greater improvement in redness (a*) 128

when compared to the Colgate Simply White group with estimated means and standard errors of –0.268 ± 0.069 and –0.017 ± 0.066, respectively. The treatment comparison for a* was statistically significant (p-value = 0.0126 from Table 13). Only the Experimental Film group was effective in whitening teeth as measured by mean change in W* (composite whiteness) from Baseline with p-value < 0.0001 (Table 9). The Experimental Film group provided more than 6.9 times greater improvement in composite whiteness (W*) when compared to the Colgate Simply White group with estimated means and standard errors of –1.313 ± 0.159 and –0.188 ± 0.152, respectively. The treatment comparison for W* was statistically significant (p-value < 0.0001 from Table 14). Both treatments were effective at increasing overall color change (E*) with p-values < 0.0001 (Table 10). The Experimental Film provided more than 1.9 times greater overall color change (E*) when compared to the Colgate Simply White group with estimated means and standard errors of 1.464 ± 0.136 and 0.692 ± 0.129, respectively. The treatment comparison for E* was statistically significant (p-value = 0.0002 from Table 15).

End-of-Study (Week 4) Comparisons At the Week 4 visit, only the Experimental Film group was effective in whitening teeth as measured by mean change in L* (lightness) from Baseline (p-value < 0.0001 from Table 7). The Experimental Film group provided more than 4 times greater improvement in lightness (L*) when compared to the Colgate Simply White group with estimated means and standard errors of 1.065± 0.135 and 0.263 ± 0.146, respectively. The treatment comparison for L* was statistically significant (p-value = 0.0003 from Table 12). Only the Experimental Film group effective in whitening teeth as measured by mean change in a* (redness) from Baseline (pvalue = 0.0003 from Table 8). The Experimental Film group provided more than 3.8 times greater improvement in redness (a*) when compared to the Colgate Simply White group with estimated means and standard errors of –0.397 ± 0.072 and –0.104 ± 0.078, respectively. The treatment comparison for a* was statistically significant (p-value = 0.0099 from Table 13). Both treatments were effective in whitening teeth as measured by mean change in W* 129

(composite whiteness) from Baseline with p-values ≤ 0.0029 (Table 9). The Experimental Film group provided more than 4.2 times greater improvement in composite whiteness (W*) when compared to the Colgate Simply White group with estimated means and standard errors of –1.385 ± 0.146 and –0.325 ± 0.158, respectively. The treatment comparison for W* was statistically significant (p-value < 0.0001 from Table 14). Both treatments were effective at increasing overall color change (E*) with p-values < 0.0001 (Table 10). The Experimental Film group provided more than 1.9 times greater overall color change (E*) when compared to the Colgate Simply White group with estimated means and standard errors of 1.534 ± 0.147 and 0.788 ± 0.160, respectively. The treatment comparison for E* was statistically significant (pvalue = 0.0020 from Table 15).

SAFETY RESULTS
For Adverse Events Through Week 4 (End-of-Study) Only the Experimental Film group had reported or observed tooth sensitivity and oral irritation. Eight subjects (36.4%) reported oral irritation and four subjects (18.2%) reported tooth sensitivity. Two subjects (9.1%) had both tooth sensitivity and oral irritation (Table 18.1).

Overall, there were a total of 14 adverse events involving 11 different study subjects: Ten subjects in the Experimental Film group and one subject in the Colgate Simply White group (Table 19.1). By type, the most frequently reported AEs were gingivitis and hyperesthesia which accounted for 50% and 36%, respectively, of all events (Table 18).

One hundred percent of all events were ―mild‖ in severity. No subjects discontinued treatment early ―for cause‖ – that is – due to a treatment-related adverse events (Table 3).

130

For Adverse Events Beginning On or Before Week 2 Only the Experimental Film group had reported or observed tooth sensitivity and oral irritation. Two subjects (9.1%) reported oral irritation and two subjects reported tooth sensitivity. No subjects reported both tooth sensitivity and oral irritation (Table 18.2). Overall, there were a total of 5 adverse events involving 5 different study subjects who were all in the Experimental Film group. One hundred percent of all events were ―mild‖ in severity (Table 19.2).

CONCLUSIONS



The Experimental Film provided significant whitening improvement from Baseline as measured by all color parameters at all post-baseline visits.



In general, the Colgate Simply White did not differ statistically from Baseline with the exception of b* at the Week 2 visit.



The Experimental Film provided significant whitening improvement relative to Colgate Simply White for all comparisons of interest and all color parameters. Whitening benefit for the Experimental Film group improved slightly after 2 weeks of treatment, in contrast, whitening benefit for the Colgate Simply White relapsed by Week 3 and rebounded for subjects completing the study at 1 week post-treatment (Week 4).



Both products were generally well tolerated overall.

131

Tables and Figures

TABLE 1 SUBJECT DISPOSITION NUMBER OF SUBJECTS ENROLLED AT EACH VISITa,b VISIT Baseline
Week 2 Week 3 Week 4
a b c

COLGATE SIMPLY WHITE 25 25 25 25

EXPERIMENTAL FILM 25 22 22 22

OVERALL 50 47 47 47

See Appendices 2.1 for data listing and evaluability memo for details. Randomization to treatment occurred after the Baseline visit and prior to product distribution. Fifty-one subjects were screened, however, Subject 3021 was dropped from the study at Baseline due to investigator recommendation. Fifty subjects were enrolled and randomized to treatment, and 47 subjects received product.

132

TABLE 2 SUMMARY OF EVALUABLE SUBJECT POPULATIONa EVALUABLE VISIT/ TREATMENT GROUP
BASELINE

NON-EVALUABLE
b

NO. SUBJ.

NO. SUBJ.

% SUBJ.

NO. SUBJ.

% SUBJ.b 0.0 0.0 0.0 8.0 9.1 8.5 8.0 4.5 6.4 28.0 4.5 17.0

Colgate Simply White Experimental Film Overall
WEEK 2

25 22 47 25 22 47 25 22 47 25 22 47

25 22 47 23 20 43 23 21 44 18 21 39

100.0 100.0 100.0 92.0 90.9 91.5 92.0 95.5 93.6 72.0 95.5 83.0

0 0 0 2 2 4 2 1 3 7 1 8

Colgate Simply White Experimental Film Overall
WEEK 3

Colgate Simply White Experimental Film Overall
WEEK 4

Colgate Simply White Experimental Film Overall
a b

See Appendices 3.1 and 4.1 for the statistical analysis program and output, respectively. Percent of subjects evaluable or non-evaluable out of the number of subjects treated.

133

TABLE 3 LISTING OF SUBJECTS EXCLUDED FROM EVALUABLE POPULATIONa,b TREATMENT/ SUBJECT NO. COLGATE SIMPLY WHITE 3002 3015 3024 3025 3027 3032 3033 3045 3057 EXPERIMENTAL FILM 3008 3016 3022
a b c

NON-EVALUABLE VISIT(S)c Week 3 Week 2 Week 4 Week 4 Week 4 Week 4 Week 4 Week 2+ Week 4 Week 3 Week 2+ Week 2

REASON(S)

Missed Visit Missed Visit Lost to Follow-up Lost to Follow-up Lost to Follow-up Lost to Follow-up Lost to Follow-up Lost to Follow-up Lost to Follow-up Missed Visit Lost to Follow-up Missed Visit

See Appendix 2.1 for the data listing and evaluability memo for details. Three subjects failed to present for product distribution visit: Subject 3007 voluntarily withdrew from the study, Subjects 3013 and 3041 were lost to follow-up. ―+‖ indicates that the subject was excluded from the evaluable population at the indicated visit and all subsequent visits.

134

TABLE 4 BASELINE DEMOGRAPHIC CHARACTERISTICSa,b ALL SUBJECTS TREATED BASELINE CHARACTERISTIC/ STATISTIC AGE (YEARS) Mean (SD) Minimum-Maximum
SEX

COLGATE SIMPLY WHITE (n = 25)c

EXPERIMENTAL FILM (n = 22)c

OVERALL (n = 47)c

TWOSIDED p-VALUE 0.2446 f

36.9 (13.02) 21 - 65 15 (60.0%) 10 (40.0%) 1 (4.0%) 7 (28.0%) 15 (60.0%) 1 (4.0%) 1 (4.0%) 22 (88.0%) 3 (12.0%)

32.6 (11.72) 22 - 70 15 (68.2%) 7 (31.8%) 2 (9.1%) 5 (22.7%) 13 (59.1%) 1 (4.5%) 1 (4.5%) 20 (90.9%) 2 (9.1%)

34.9 (12.48) 21 - 70 30 (63.8%) 17 (36.2%) 3 (6.4%) 12 (25.5%) 28 (59.6%) 2 (4.3%) 2 (4.3%) 42 (89.4%) 5 (10.6%)

Female d Male d
RACE

0.7617 g

Asian d Black d Caucasian d Hispanic d Multi - racial d
SMOKER

0.9463 g

No d Yes d COFFEE/TEA/COLA DRINKERe No d Yes d NUMBER OF DRINKS PER DAY Median Minimum-Maximum
a b c d e f g h

1.0000 g

2 (8.0%) 23 (92.0%)

3 (13.6%) 19 (86.4%)

5 (10.6%) 42 (89.4%)

0.6536 g

2.0 0-8

2.0 0 - 14

2.0 0 - 14

0.7502 h

See Appendices 2.1, 3.2, and 4.2 for the data listing, statistical analysis program, and output, respectively. Demographics were collected at the baseline visit. n = number of treated subjects in each treatment group and overall. Number and percent of subjects in each category. A drink consists of a cup for coffee or tea or a 12 ounce can of dark cola. Two-sided p-value for the treatment comparison from a two-sample t-test. Two-sided p-value for the treatment comparison from Fisher's Exact test. Two-sided p-value for the treatment comparison from an exact Wilcoxon rank-sum test.

135

TABLE 5 DESCRIPTIVE SUMMARYa BASELINE COLOR VALUES ALL SUBJECTS TREATED COLOR VALUE / TREATMENT b*
Colgate Simply White

N

MINIMUM

MEDIAN

MAXIMUM

MEAN (SD)

P-VALUEb

25 22

13.79 15.27

17.57 17.63

21.58 20.64

Experimental Film L*
Colgate Simply White

17.89 (2.059) 17.67 (1.598) 73.14 (2.932) 73.67 (2.382)

0.6825

25 22

66.94 68.10

73.68 73.91

77.43 78.73

0.5026

Experimental Film a* Colgate Simply White Experimental Film W* Colgate Simply White Experimental Film
a b

25 22

5.30 4.88

6.70 6.61

9.57 7.79

6.78 (0.919) 6.52 (0.814) 33.01 (3.417) 32.42 (2.406)

0.3052

25 22

27.58 26.95

32.18 32.67

40.25 37.60

0.5017

See Appendices 2.1, 3.3, and 4.3 for the data listing, statistical analysis program, and output, respectively. Two-sided p-value for the treatment comparison from a two-sample t-test.

136

TABLE 6 DESCRIPTIVE SUMMARYa b* EVALUABLE SUBJECTS CHANGE FROM BASELINE COLOR VALUE / TREATMENT
WEEK 2 Colgate Simply White

N

MEAN (SD) 17.69 (2.097) 17.14 (1.484)

MINI MUM 1.21 4 1.93 5 1.15 3 2.17 4 1.30 3 2.07 4

MEDIA
N

MAXI
MUM

MEAN (SD) -0.257 (0.532) -0.660 (0.592)

PVALU E
b

23

-0.370

0.67 2 0.11 7

0.030 5 < 0.000 1 0.221 1 0.000 2

Experimental Film
WEEK 3 Colgate Simply White

20

-0.529

23

17.84 (2.094) 16.95 (1.466)

-0.270

0.86 0 0.77 5

-0.135 (0.516) -0.677 (0.682)

Experimental Film
WEEK 4 Colgate Simply White

21

-0.636

18

17.93 (2.006) 17.03 (1.422)

-0.260

0.68 5 0.72 7

-0.232 (0.587) -0.741 (0.765)

0.111 5 0.000 3

Experimental Film
a b

21

-0.771

See Appendices 2.1, 3.4, and 4.4 for the data listing, statistical analysis program, and output, respectively. Two-sided p-value for the mean color change from screening using the one-sample t-test.

137

TABLE 7 DESCRIPTIVE SUMMARYa L* EVALUABLE SUBJECTS CHANGE FROM BASELINE COLOR VALUE / TREATMENT
WEEK 2 Colgate Simply White
N

MEAN (SD) 73.14 (3.142) 74.19 (2.124) 73.15 (3.145) 74.65 (2.430) 73.74 (3.286) 74.49 (2.111)

MINIMU
M

MAXIMU MEDIAN 0.058 0.869
M

MEAN (SD) 0.046 (0.600) 0.702 (0.534) 0.141 (0.452) 1.079 (0.745) 0.264 (0.550) 1.064 (0.638)

PVALUE
b

23 20

-1.242 -0.126

0.864 1.554

0.7189 < 0.0001 0.1477 < 0.0001 0.0575 < 0.0001

Experimental Film WEEK 3
Colgate Simply White

23 21

-0.886 -0.172

0.137 1.149

1.071 3.019

Experimental Film WEEK 4
Colgate Simply White

18 21

-1.291 0.160

0.420 0.903

1.081 2.463

Experimental Film
a b

See Appendices 2.1, 3.4, and 4.4 for the data listing, statistical analysis program, and output, respectively. Two-sided p-value for the mean color change from screening using the one-sample t-test.

138

TABLE 8 DESCRIPTIVE SUMMARYa a* EVALUABLE SUBJECTS CHANGE FROM BASELINE COLOR VALUE / TREATMENT
WEEK 2 Colgate White Simply

MINIMU
N

MAXIMU MEDIAN -0.084 -0.472
M

P-

MEAN (SD) 6.71 (0.846) 6.15 (0.786) 6.82 (0.913) 6.25 (0.790) 6.80 (0.926) 6.18 (0.790)

M

MEAN (SD) -0.151 (0.279) -0.398 (0.310) -0.031 (0.293) -0.252 (0.333) -0.136 (0.314) -0.370 (0.382)

VALUE

b

23 20

-0.943 -0.871

0.356 0.125

0.0163 < 0.0001 0.6119 0.0025

Experimental Film WEEK 3
Colgate White Simply

23 21

-0.715 -0.666

-0.062 -0.315

0.558 0.533

Experimental Film WEEK 4
Colgate White Simply

18 21

-1.026 -1.132

-0.094 -0.428

0.287 0.290

0.0836 0.0003

Experimental Film
a b

See Appendices 2.1, 3.4, and 4.4 for the data listing, statistical analysis program, and output, respectively. Two-sided p-value for the mean color change from screening using the one-sample t-test.

139

TABLE 9 DESCRIPTIVE SUMMARYa W* EVALUABLE SUBJECTS CHANGE FROM BASELINE COLOR VALUE / TREATMENT
WEEK 2 Colgate White Simply

MINIMU
N

MAXIMU MEDIAN -0.270 -0.833
M

P-

MEAN (SD) 32.88 (3.638) 31.64 (2.060) 32.98 (3.637) 31.18 (2.447) 32.54 (3.737) 31.33 (2.077)

M

MEAN (SD) -0.212 (0.591) -1.012 (0.694) -0.199 (0.505) -1.302 (0.879) -0.367 (0.449) -1.348 (0.825)

VALUE

b

23 20

-1.234 -2.280

0.927 -0.128

0.0992 < 0.0001 0.0724 < 0.0001 0.0029 < 0.0001

Experimental Film WEEK 3
Colgate White Simply

23 21

-1.145 -3.530

-0.227 -1.232

0.744 -0.026

Experimental Film WEEK 4
Colgate White Simply

18 21

-1.471 -2.704

-0.384 -1.221

0.351 -0.090

Experimental Film
a b

See Appendices 2.1, 3.4, and 4.4 for the data listing, statistical analysis program, and output, respectively. Two-sided p-value for the mean color change from screening using the one-sample t-test.

140

TABLE 10 DESCRIPTIVE SUMMARYa E* EVALUABLE SUBJECTS CHANGE FROM BASELINE COLOR VALUE / TREATMENT
WEEK 2 Colgate Simply White
N

MINIMUM 0.107 0.238

MEDIAN 0.759 1.099

MAXIMUM 1.706 2.371

MEAN (SD) 0.796 (0.392) 1.172 (0.656) 0.693 (0.309) 1.463 (0.809) 0.827 (0.415) 1.501 (0.825)

P-VALUE

b

23 20

< 0.0001 < 0.0001

Experimental Film WEEK 3
Colgate Simply White

23 21

0.168 0.342

0.672 1.353

1.247 3.534

< 0.0001 < 0.0001

Experimental Film WEEK 4
Colgate Simply White

18 21

0.358 0.271

0.688 1.272

2.102 2.815

< 0.0001 < 0.0001

Experimental Film
a b

See Appendices 2.1, 3.4, and 4.4 for the data listing, statistical analysis program, and output, respectively. Two-sided p-value for the mean color change from screening using the one-sample t-test.

141

TABLE 11 TREATMENT COMPARISONS ANALYSIS OF COVARIANCEa MEAN b* ADJUSTED FOR BASELINE AND AGE EVALUABLE SUBJECTS TREATMENT COMPARISON VISIT/ TREATMENT GROUP
WEEK 2 Colgate Simply White

N 23 20

BASELINE MEAN (SE) 17.948 (0.446) 17.805 (0.356)

ADJUSTED MEAN CHANGE FROM BASELINE (SE)b -0.230 (0.116) -0.691 (0.124)

TREATMENT DIFFERENCE (SE) 0.462 (0.173)

p-VALUEc 0.0109

Experimental Film
WEEK 3 Colgate Simply White

23 21

17.974 (0.443) 17.629 (0.355)

-0.111 (0.123) -0.705 (0.129)

0.594 (0.180)

0.0021

Experimental Film
WEEK 4 Colgate Simply White

18 21

18.161 (0.489) 17.775 (0.340)

-0.177 (0.152) -0.788 (0.140)

0.610 (0.209)

0.0060

Experimental Film
a b c

See Appendices 2.1, 3.5, and 4.5 for the data listing, statistical analysis program, and output, respectively. Means adjusted for baseline b* value and age. Two-sided p-value for the treatment comparison of the difference in mean change of

b*.

142

TABLE 12 TREATMENT COMPARISONS ANALYSIS OF COVARIANCEa MEAN L* ADJUSTED FOR BASELINE AND AGE EVALUABLE SUBJECTS TREATMENT COMPARISON VISIT/ TREATMENT GROUP
WEEK 2 Colgate Simply White

N 23 20

BASELINE MEAN (SE) 73.092 (0.638) 73.490 (0.489)

ADJUSTED MEAN CHANGE FROM BASELINE (SE)b 0.053 (0.123) 0.693 (0.132)

TREATMENT DIFFERENCE (SE) -0.640 (0.183)

p-VALUEc 0.0012

Experimental Film
WEEK 3 Colgate Simply White

23 21

73.004 (0.627) 73.566 (0.522)

0.149 (0.131) 1.071 (0.137)

-0.922 (0.192)

< 0.0001

Experimental Film
WEEK 4 Colgate Simply White

18 21

73.473 (0.711) 73.428 (0.469)

0.263 (0.146) 1.065 (0.135)

-0.802 (0.201)

0.0003

Experimental Film
a b c

See Appendices 2.1, 3.5, and 4.5 for the data listing, statistical analysis program, and output, respectively. Means adjusted for baseline L* value and age. Two-sided p-value for the treatment comparison of the difference in mean change of

L*.

143

TABLE 13 TREATMENT COMPARISONS ANALYSIS OF COVARIANCEa MEAN a* ADJUSTED FOR BASELINE AND AGE EVALUABLE SUBJECTS TREATMENT COMPARISON VISIT/ TREATMENT GROUP
WEEK 2 Colgate Simply White

N 23 20

BASELINE MEAN (SE) 6.865 (0.189) 6.552 (0.188)

ADJUSTED MEAN CHANGE FROM BASELINE (SE)b -0.124 (0.058) -0.430 (0.062)

TREATMENT DIFFERENCE (SE) 0.307 (0.086)

p-VALUEc 0.0010

Experimental Film
WEEK 3 Colgate Simply White

23 21

6.847 (0.192) 6.506 (0.181)

-0.017 (0.066) -0.268 (0.069)

0.251 (0.096)

0.0126

Experimental Film
WEEK 4 Colgate Simply White

18 21

6.940 (0.223) 6.553 (0.179)

-0.104 (0.078) -0.397 (0.072)

0.293 (0.108)

0.0099

Experimental Film
a b c

See Appendices 2.1, 3.5, and 4.5 for the data listing, statistical analysis program, and output, respectively. Means adjusted for baseline a* value and age. Two-sided p-value for the treatment comparison of the difference in mean change of

a*.

144

TABLE 14 TREATMENT COMPARISONS ANALYSIS OF COVARIANCEa MEAN W* ADJUSTED FOR BASELINE AND AGE EVALUABLE SUBJECTS TREATMENT COMPARISON VISIT/ TREATMENT GROUP
WEEK 2 Colgate Simply White

N 23 20

BASELINE MEAN (SE) 33.096 (0.741) 32.647 (0.486)

ADJUSTED MEAN CHANGE FROM BASELINE (SE)b -0.193 (0.138) -1.034 (0.148)

TREATMENT DIFFERENCE (SE) 0.841 (0.205)

p-VALUEc 0.0002

Experimental Film
WEEK 3 Colgate Simply White

23 21

33.178 (0.730) 32.477 (0.535)

-0.188 (0.152) -1.313 (0.159)

1.125 (0.222)

< 0.0001

Experimental Film
WEEK 4 Colgate Simply White

18 21

32.910 (0.842) 32.681 (0.463)

-0.325 (0.158) -1.385 (0.146)

1.060 (0.217)

< 0.0001

Experimental Film
a b c

See Appendices 2.1, 3.5, and 4.5 for the data listing, statistical analysis program, and output, respectively. Means adjusted for baseline W* value and age. Two-sided p-value for the treatment comparison of the difference in mean change of

W *.

145

TABLE 15 TREATMENT COMPARISONS ANALYSIS OF COVARIANCEa MEAN E* ADJUSTED FOR BASELINE AND AGE EVALUABLE SUBJECTS
TREATMENT COMPARISON

VISIT/ TREATMENT GROUP
WEEK 2 Colgate Simply White

MEAN CHANGE FROM BASELINE N 23 20 (SE) 0.773 (0.112) 1.199 (0.120)

TREATMENT DIFFERENCE (SE) -0.426 (0.168)

p-VALUEb 0.0154

Experimental Film
WEEK 3 Colgate Simply White

23 21

0.692 (0.129) 1.464 (0.136)

-0.772 (0.190)

0.0002

Experimental Film
WEEK 4 Colgate Simply White

18 21

0.788 (0.160) 1.534 (0.147)

-0.746 (0.222)

0.0020

Experimental Film
a b

See Appendices 2.1, 3.5, and 4.5 for the data listing, statistical analysis program, and output, respectively. Means adjusted for baseline b*, L*, and a* values as well as age. Two-sided p-value for the treatment comparison of the difference in mean change of

c

E*.

146

TABLE 16 END-OF-TREATMENT COMPARISONS – ANALYSIS OF COVARIANCE a EXPERIMENTAL FILM AT WEEK 4 VS COLGATE SIMPLY WHITE AT WEEK 3 ADJUSTED FOR BASELINE AND AGE EVALUABLE SUBJECTS TREATMENT COMPARISON ADJUSTED MEAN TREATMENT CHANGE FROM DIFFERENCE VISIT/ BASELINE BASELINE (SE)b p-VALUEc TREATMENT GROUP N MEAN (SE) (SE)
b* Colgate Simply White

23 21

17.974 (0.443) 17.775 (0.340)

-0.098 (0.131) -0.782 (0.137)

0.684 (0.191)

0.0009

Experimental Film
L* Colgate Simply White

23 21

73.004 (0.627) 73.428 (0.469)

0.145 (0.118) 1.061 (0.124)

-0.916 (0.173)

< 0.0001

Experimental Film
a* Colgate Simply White

23 21

6.847 (0.192) 6.553 (0.179)

-0.010 (0.070) -0.394 (0.073)

0.384 (0.102)

0.0005

Experimental Film W*
Colgate Simply White

23 21

33.178 (0.730) 32.681 (0.463)

-0.172 (0.142) -1.377 (0.149)

1.205 (0.208)

< 0.0001

Experimental Film E*
Colgate Simply White

23 21

0.670 (0.131) 1.526 (0.137)

-0.855 (0.193)

< 0.0001

Experimental Film
a b c

See Appendices 2.1, 3.6, and 4.6 for the data listing, statistical analysis program, and output, respectively. Means adjusted for baseline color and age. Two-sided p-value for the treatment comparison of the difference in mean color change from baseline.

147

TABLE 17 ADDITIONAL TREATMENT COMPARISONS – ANALYSIS OF COVARIANCE a EXPERIMENTAL FILM AT WEEK 2 VS COLGATE SIMPLY WHITE AT WEEK 3 ADJUSTED FOR BASELINE AND AGE EVALUABLE SUBJECTS TREATMENT COMPARISON ADJUSTED MEAN TREATMENT CHANGE FROM DIFFERENCE VISIT/ BASELINE BASELINE (SE)b p-VALUEc TREATMENT GROUP N MEAN (SE) (SE)
b* Colgate Simply White

23 20

17.974 (0.443) 17.805 (0.356)

-0.108 (0.114) -0.691 (0.122)

0.583 (0.170)

0.0014

Experimental Film
L* Colgate Simply White

23 20

73.004 (0.627) 73.490 (0.489)

0.152 (0.106) 0.690 (0.114)

-0.538 (0.157)

0.0015

Experimental Film
a* Colgate Simply White

23 20

6.847 (0.192) 6.552 (0.188)

-0.014 (0.062) -0.419 (0.067)

0.405 (0.093)

< 0.0001

Experimental Film W*
Colgate Simply White

23 20

33.178 (0.730) 32.647 (0.486)

-0.185 (0.129) -1.028 (0.138)

0.843 (0.192)

< 0.0001

Experimental Film E*
Colgate Simply White

23 20

0.683 (0.106) 1.183 (0.114)

-0.501 (0.159)

0.0032

Experimental Film
a b c

See Appendices 2.1, 3.7, and 4.7 for the data listing, statistical analysis program, and output, respectively. Means adjusted for baseline color and age. Two-sided p-value for the treatment comparison of the difference in mean color change from baseline.

148

TABLE 18.1 POSSIBLE OR PROBABLE TREATMENT RELATED (BY WEEK 4) ORAL IRRITATION OR TOOTH SENSITIVITYa ALL SUBJECTS TREATED COLGATE SIMPLY EXPERIMENTAL WHITE FILM b (n = 25) (n = 22)b
AE SOURCE/AE CLASSIFICATION SELF REPORTED

OVERALL (n = 47)b NO. SUBJ. (% c SUBJ.)

NO. SUBJ. (% c SUBJ.)

NO. SUBJ. (% c SUBJ.)

Oral Irritation Tooth Sensitivity Oral Irritation and Tooth Sensitivity Oral Irritation or Tooth Sensitivity
OBSERVED

0 (0) 0 (0) 0 (0) 0 (0)

8 (36.4) 4 (18.2) 2 (9.1) 10 (45.5)

8 (17.0) 4 (8.5) 2 (4.3) 10 (21.3)

Oral Irritation
EITHER OBSERVED SELF REPORTED
OR

0 (0)

1 (4.5)

1 (2.1)

Oral irritation Tooth Sensitivity Oral irritation and Tooth Sensitivity Oral irritation or Tooth Sensitivity
a b c

0 (0) 0 (0) 0 (0) 0 (0)

8 (36.4) 4 (18.2) 2 (9.1) 10 (45.5)

8 (17.0) 4 (8.5) 2 (4.3) 10 (21.3)

See Appendices 2.1, 3.8, and 4.8 for the data listing, statistical analysis program, and output, respectively. Number of subjects randomized in each group and overall. Number (Percent) of randomized subjects with the indicated AE (out of the number reported in each group).

149

TABLE 18.2 POSSIBLE OR PROBABLE TREATMENT RELATED (BY WEEK 2) ORAL IRRITATION OR TOOTH SENSITIVITYa ALL SUBJECTS TREATED COLGATE SIMPLY WHITE (n = 25)b
AE SOURCE/AE CLASSIFICATION SELF REPORTED

EXPERIMENTAL FILM (n = 22)b NO. SUBJ. (% c SUBJ.) 2 (9.1) 2 (9.1) 0 (0) 4 (18.2)

OVERALL (n = 47)b NO. SUBJ. (% c SUBJ.) 2 (4.3) 2 (4.3) 0 (0) 4 (8.5)

NO. SUBJ. (% SUBJ.)c

Oral Irritation Tooth Sensitivity Oral Irritation and Tooth Sensitivity Oral Irritation or Tooth Sensitivity
OBSERVED

0 (0) 0 (0) 0 (0) 0 (0)

Oral Irritation
EITHER OBSERVED REPORTED
OR

0 (0)
SELF

1 (4.5)

1 (2.1)

Oral irritation Tooth Sensitivity Oral irritation and Tooth Sensitivity Oral irritation or Tooth Sensitivity
a b c

0 (0) 0 (0) 0 (0) 0 (0)

2 (9.1) 2 (9.1) 0 (0) 4 (18.2)

2 (4.3) 2 (4.3) 0 (0) 4 (8.5)

See Appendices 2.1, 3.9, and 4.9 for the data listing, statistical analysis program, and output, respectively. Number of subjects randomized in each group and overall. Number (Percent) of randomized subjects with the indicated AE (out of the number reported in each group).

150

TABLE 19.1 SUMMARY OF ADVERSE EVENTSa (BY WEEK 4) ALL SUBJECTS TREATED COLGATE SIMPLY WHITE (n = 25)b NO. SUBJ. (% c SUBJ.) Serious AEs Mild AEs Moderate AEs Severe AEs Not Related Doubtful Related Possibly Related Probably Related
Total

EXPERIMENTAL FILM (n = 22)b NO. SUBJ. (% c SUBJ.) 0(0) 10(45) 0(0) 0(0) 0(0) 1(5) 7(32) 4(18) 10(45) NO. AES (% AES)d 0(0) 13(100) 0(0) 0(0) 0(0) 1(8) 8(62) 4(31) 13(100)

OVERALL (n = 47)b NO. SUBJ. (% SUBJ.)c 0(0) 11(23) 0(0) 0(0) 0(0) 2(4) 7(15) 4(9) 11(23) 0.3 1.27 NO. AES d (% AES)

NO. AES (% AES)d 0(0) 1(100) 0(0) 0(0) 0(0) 1(100) 0(0) 0(0) 1(100)

0(0) 1(4) 0(0) 0(0) 0(0) 1(4) 0(0) 0(0) 1(4) 0.04 1

0(0) 14(100) 0(0) 0(0) 0(0) 2(14) 8(57) 4(29) 14(100)

Mean number of AEs per subject (all subjects) Mean number of AEs per subject (only subjects with AEs)
a b c d

0.59 1.3

See Appendices 2.1, 3.10, and 4.10 for the data listing, statistical analysis program, and output, respectively. n = number of subjects within the specified treatment group or overall. Number (Percent) of subjects with the indicated AE category (out of the number of subjects in each group). Number (Percent) of AEs reported within the category (out of the total number of AEs reported in each group).

151

TABLE 19.2 SUMMARY OF ADVERSE EVENTSa (BY WEEK 2) ALL SUBJECTS TREATED COLGATE SIMPLY WHITE (n = 25)b NO. SUBJ. (% SUBJ.)c Serious AEs Mild AEs Moderate AEs Severe AEs Not Related Doubtful Related Possibly Related Probably Related
Total

EXPERIMENTAL FILM (n = 22)b NO. SUBJ. (% c SUBJ.) 0(0) 5(23) 0(0) 0(0) 0(0) 1(5) 0(0) 4(18) 5(23) 0.23 1 NO. AES (% AES)d 0(0) 5(100) 0(0) 0(0) 0(0) 1(20) 0(0) 4(80) 5(100)

OVERALL (n = 47)b NO. SUBJ. (% SUBJ.)c 0(0) 5(11) 0(0) 0(0) 0(0) 1(2) 0(0) 4(9) 5(11) 0.11 1 NO. AES d (% AES)

NO. AES (% AES)d 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0 0

0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0)

0(0) 5(100) 0(0) 0(0) 0(0) 1(20) 0(0) 4(80) 5(100)

Mean number of AEs per subject (all subjects) Mean number of AEs per subject (only subjects with AEs)
a b c d

See Appendices 2.1, 3.11, and 4.11 for the data listing, statistical analysis program, and output, respectively. n = number of subjects within the specified treatment group or overall. Number (Percent) of subjects with the indicated AE category (out of the number of subjects in each group). Number (Percent) of AEs reported within the category (out of the total number of AEs reported in each group).

152

TABLE 20 ADVERSE EVENTS IN DECREASING ORDER OF INCIDENCE a BY COSTART PREFERRED TERM AND TREATMENT GROUP ALL SUBJECTS TREATED COLGATE SIMPLY WHITE (n = 25)b NO. SUBJ. (% SUBJ.)c 1(4) 0(0) 0(0) 0(0) 1(4) NO. AES (% AES)d 1(100) 0(0) 0(0) 0(0) 1(100) EXPERIMENTAL FILM (n = 22)b NO. SUBJ. NO. AES (% SUBJ.)c (% AES)d 6(27) 5(23) 1(5) 1(5) 10(45) 6(46) 5(38) 1(8) 1(8) 13(100) OVERALL (n = 47)b NO. SUBJ. (% SUBJ.)c 7(15) 5(11) 1(2) 1(2) 11(23) NO. AES (% AES)d 7(50) 5(36) 1(7) 1(7) 14(100)

COSTART PREFERRED TERM GINGIVITIS HYPERESTHESIA CHEILITIS STOMATITIS TOTAL
a b c d

See Appendices 2.1, 3.12, and 4.12 for the data listing, statistical analysis program, and output, respectively. n = number of subjects within the specified treatment group or overall. Number (Percent) of subjects with the indicated AE category (out of the number of subjects in each group). Number (Percent) of AEs reported within the category (out of the total number of AEs reported in each group).

153

TABLE 21 MILD ADVERSE EVENTS a BY COSTART PREFERRED TERM AND TREATMENT GROUP ALL SUBJECTS TREATED COLGATE SIMPLY WHITE (n = 25)b NO. SUBJ. (% SUBJ.)c 1(4) 0(0) 0(0) 0(0) 1(4) NO. AES (% AES)d 1(100) 0(0) 0(0) 0(0) 1(100) EXPERIMENTAL FILM (n = 22)b NO. SUBJ. NO. AES (% SUBJ.)c (% AES)d 6(27) 5(23) 1(5) 1(5) 10(45) 6(46) 5(38) 1(8) 1(8) 13(100) OVERALL (n = 47)b NO. SUBJ. (% c SUBJ.) 7(15) 5(11) 1(2) 1(2) 11(23) NO. AES (% AES)d 7(50) 5(36) 1(7) 1(7) 14(100)

COSTART PREFERRED TERM

GINGIVITIS HYPERESTHESIA CHEILITIS STOMATITIS TOTAL
a b c d

See Appendices 2.1, 3.12, and 4.12 for the data listing, statistical analysis program, and output, respectively. n = number of subjects within the specified treatment group or overall . Number (Percent) of subjects with the indicated AE category (out of the number of subjects in each group). Number (Percent) of AEs reported within the category (out of the total number of AEs reported in each group).

154

TABLE 22 NOT OR DOUBTFUL TREATMENT RELATED ADVERSE EVENTS a BY COSTART PREFERRED TERM AND TREATMENT GROUP ALL EVALUABLE SUBJECTS COLGATE SIMPLY WHITE (n = 25)b NO. SUBJ. (% SUBJ.)c 1(4) 0(0) 1(4) NO. AES (% AES)d 1(100) 0(0) 1(100) EXPERIMENTAL FILM (n = 22)b NO. SUBJ. NO. AES (% SUBJ.)c (% AES)d 0(0) 1(5) 1(5) 0(0) 1(8) 1(8) OVERALL (n = 47)b NO. SUBJ. (% SUBJ.)c 1(2) 1(2) 2(4) NO. AES (% AES)d 1(7) 1(7) 2(14)

COSTART PREFERRED TERM GINGIVITIS HYPERESTHESIA TOTAL
a b c d

See Appendices 2.1, 3.12, and 4.12 for the data listing, statistical analysis program, and output, respectively. n = number of subjects within the specified treatment group or overall. Number (Percent) of subjects with the indicated AE category (out of the number of subjects in each group). Number (Percent) of AEs reported within the category (out of the total number of AEs reported in each group).

155

TABLE 23 POSSIBLE OR PROBABLE TREATMENT RELATED ADVERSE EVENTS a BY COSTART PREFERRED TERM AND TREATMENT GROUP ALL SUBJECTS TREATED COLGATE SIMPLY WHITE (n = 25)b NO. SUBJ. (% SUBJ.)c 0(0) 0(0) 0(0) 0(0) 0(0) NO. AES (% AES)d 0(0) 0(0) 0(0) 0(0) 0(0) EXPERIMENTAL FILM (n = 22)b NO. SUBJ. NO. AES (% SUBJ.)c (% AES)d 6(27) 4(18) 1(5) 1(5) 10(45) 6(46) 4(31) 1(8) 1(8) 12(92) OVERALL (n = 47)b NO. SUBJ. (% SUBJ.)c 6(13) 4(9) 1(2) 1(2) 10(21) NO. AES (% AES)d 6(43) 4(29) 1(7) 1(7) 12(86)

COSTART PREFERRED TERM GINGIVITIS HYPERESTHESIA CHEILITIS STOMATITIS TOTAL
a b c d

See Appendices 2.1, 3.12, and 4.12 for the data listing, statistical analysis program, and output, respectively. n = number of subjects within the specified treatment group or overall. Number (Percent) of subjects with the indicated AE category (out of the number of subjects in each group). Number (Percent) of AEs reported within the category (out of the total number of AEs reported in each group).

156

Yellowness Improvement (–b*) Figure 1: Adjusted Mean Yellowness Improvement (–b*)
1

0 .8

0 .6

0 .4

0 .2

0 Week 2 Week 3 Week 4

C o lg a te S im p ly W h ite

E x p e r im e n ta l F ilm

Lightness Improvement (L*) Figure 2: Adjusted Mean Lightness Improvement (L*)
1 .2 1 0 .8 0 .6 0 .4 0 .2 0 Week 2 Week 3 Week 4

C o lg a te S im p ly W h ite

E x p e r im e n ta l F ilm

156

REFERENCES 1. HaywoodVB, Heymann HO. Nightguard vital bleaching. Quintessence Int.
1989; 20:173-6 2. Goldstein RE.In-office bleaching: where we came from, where we are today. Jam Dent Assoc1997;128:11S-15S 3. BurrellKH.ADA supports vital tooth bleaching –but look for the seal. J Am Dent Assoc1997 128:3S-5S. 4. CrollTP, SasaIS.Carbemide peroxide of teeth with dentiogenisis imperfecta discoloration: report of a case. Quintessence Int. 1995; 26:683-6 5. Haywood VB. Night guard bleaching to lighten a restored, nonvital discolored tooth. Compend Continuing Education Dent 1998;19:810-3 6. Frazier KB. Nightguard bleaching to lighten a restored, nonvital discolored tooth. Compend Contin Educ Dent 1998; 19:810-3 7. Small BW. The application and integration of at-home bleaching into private dental practice. Compend Contin Educ Dent 1998;19:799-806 8. HaywoodVB, Robinson FG.Vital tooth bleaching with nightgaurd vital bleaching. Curr.Opin CosmeticDent1997;4:45-52 9. KugelG,PerryRD, Hoang E,Scherer W.Effective tooth bleaching in 5days: using a combined in office and at home bleaching system . Comp contin Educ Dent 1997 ;18:378-83 10. Kugel G Over the counter tooth whitening Systems Compendium April 2003; 24;4A 376-82 11. Donly KJ, DonlyAS, BaharlooL, et al. Tooth whitening in children, Compend Contin Edu Dent. 2002; 3:22-27.

157

Chapter 9 Maintenance of Whitening
Clinical Study to Evaluate the Maintenance of Whitening after Bleaching Treatment

Abstract
A randomized, parallel, examiner-blind clinical study was conducted to examine the ability of 2 toothbrushes to maintain teeth whitening after at-home bleaching. Forty subjects used a 15% carbamide peroxide tray bleaching system at home for 2 weeks per the manufacturer’s instructions and then were randomly assigned to use either the Sonicare® Advance power toothbrush or a manual toothbrush as part of their home oral hygiene routine for 6 months. The color of the labial surfaces of the subjects’ maxillary anterior dentition was assessed before bleaching and immediately, 2 months, 3 months, and 6 months after bleaching. Color was assessed by comparison with Vita® Classical shade tabs and by digital image analysis in the CIE L*a*b* color space. Both groups demonstrated a rebound effect at the 2-month visit and beyond, with mean Vita shade scores significantly higher than immediately after bleaching. At the 6-month evaluation, there was a significant difference in the amount of rebound in each group. Specifically, the rebound of the Sonicare brush group was on average 1.12 Vita shades less than that of the manual brush group. The 6-month difference was confirmed through digital image analysis, with the Sonicare brush group 4.8 L* units lighter, corresponding to 2 Vita shades, and 2.1 b* units less yellow than the manual brush group. This clinical trial demonstrates that the Sonicare Advance toothbrush better maintains whitening after bleaching treatment than a manual toothbrush.

158

Learning Objectives
After reading this article, the reader should be able to:    Understand maintenance of whitening after bleaching using an electric toothbrush. To demonstrate that significant rebound can occur post bleaching. To demonstrate the use of digital photography in determining L* a* b* values

The use of peroxide to whiten teeth has a lengthy history dating to the early 20th century. With the advent of patient-applied kits, bleaching has become both common and popular, and use of peroxide is now generally recognized as a safe and effective method for tooth whitening.1-3 There are a variety of indications for bleaching single or multiple teeth, including staining from chromogenic foods, dental fluorosis, tetracycline staining, and devital discolored teeth.4-7 Up to 90% of U.S. dental practices offer vital tooth bleaching, and in some dental practices, up to one-fifth of patients undergo bleaching.8-9

Concentrations of up to 35% peroxide are used alone or in combination with various agents for tooth bleaching. Delivery is via in-office, at-home, or combination regimens, with or without professional supervision.10,11 Of these, bleaching is most commonly accomplished at home over a period of a few weeks.12 Treatment duration may vary based on the degree of staining because whitening is reported to be a product of peroxide concentration and contact time.13 For some difficult stains like tetracycline, daily bleaching for up to 6 months may be indicated.14

Treatment is generally effective, with 90% or more of clinical trial subjects experiencing initial whitening.15,16 The efficacy of a bleaching treatment may be established through first or second person observation or various technical methods. Clinical trials most commonly include the use of a shade guide, colorimeter, or computer digitization to measure color change over time.17,18 In these studies, efficacy is commonly monitored for 6 months.13,16 While there may be some shade deterioration over time, most patients experience a whitening effect that may persist, to at least 159

some degree, 3 years or more after initial treatment.13,15 In addition to the cosmetic benefits, bleaching is believed to contribute to various intangibles, including heightened patient involvement and increased interest in dentistry and oral health.7,8

Some patients who have undergone bleaching are concerned with the stability of their newly bleached teeth. Practitioners often have no real answer for the patient concerning the stability of bleached dentition. Rebound, the re-coloring of bleached teeth, is assumed to be a multifactor process. The factors may include the structure and composition of an individual’s dentin and enamel, the types of food and drink he or she consumes, and the oral hygiene routine. In the current study, we examined the impact of the oral hygiene routine. Specifically, we assessed the ability of the Sonicare® Advance powered toothbrusha to prevent rebound compared with a standard manual toothbrush.

The Sonicare Advance toothbrush operates with high-frequency bristle movement (260 Hz; 31,000 brush strokes per minute). In addition to cleaning by direct bristle contact, the Sonicare Advance generates significant fluid activity, which has been hypothesized as the reason for the brush’s ability to clean beyond the reach of the bristles as demonstrated in several laboratory studies.19-22 The Sonicare Advance also has been shown to remove stains in clinical and laboratory studies, removing more stain in vivo than a manual toothbrush.23, 24 A study of the brush’s ability to inhibit rebound after bleaching, a natural extension of this earlier work, was the focus of the current study.

Methods and Materials
Population Selection Potential subjects were screened and enrolled in this clinical trial at Tufts University, Boston, Massachusetts, after meeting the inclusion/exclusion criteria. At screening, written informed consent was obtained from each subject after review of the study design and test regimen. Using the Vita® Classical shade guideb, Vita shade scores were recorded for each subject on labial 160

surfaces of the maxillary anterior teeth. Subjects with individual tooth scores of A2 or darker were eligible for enrollment. Dentinal sensitivity, use of tobacco products, the presence of tetracycline stain, dental fluorosis, atypical nonuniform stain, fixed orthodontic appliances, and large intake of stain-inducing beverages were all reasons for exclusion. Subjects who qualified and agreed to participate were enrolled in the study. At the postbleaching evaluation, subjects exhibiting a decrease of at least 2 Vita shades were allowed to continue in the study; all subjects met this requirement.

STUDY DESIGN
This was an examiner blind, parallel-group, 6-month study with clinical evaluations both before (prebleaching baseline) and after (postbleaching baseline) a two-week bleaching treatment and at one, 2, 3, and 6 months after the end of bleaching. At each visit, oral soft and hard tissues were examined, subjects were questioned about presence or absence of tooth hypersensitivity to thermal, air, or other such stimuli, and a Vita shade assessment of the labial surfaces of the anterior maxillary teeth was recorded. A subset of 14 subjects, 7 per treatment group, was randomly selected for digital image analysis. For subjects in this subset, digital images of the maxillary anterior teeth also were captured at each visit. At the screening appointment, impressions of the maxillary teeth were taken and used to fabricate the bleaching trays. The trays were distributed at the first study visit, baseline prebleaching, along with a standard home bleaching system of 15% carbamide peroxide (Opalescencec). All subjects were given a standard manual toothbrush (Crest® Extra Softd) and sodium fluoride dentifrice (Crest Cavity Protectiond) for use during the bleaching period. Subjects received oral and written instructions on the bleaching system’s recommended use and the Bass brushing technique.25 Subjects were asked to use the bleaching trays twice per day for 60 minutes at each use and to brush with the manual toothbrush twice per day for 2 minutes at each brushing. At the postbleaching baseline appointment 2 weeks later, bleaching trays were collected and study 161

toothbrushes were distributed according to a stratified randomization designed to foster similar shade distributions at prebleaching baseline (low / medium / high Vita shade score means) in each brush group. Subjects exhibiting a mean Vita shade score improvement of at least 2.0 were permitted to continue in the study. Subjects in one group were asked to continue using the manual toothbrush as previously instructed. Subjects in the other group were given a Sonicare Advance toothbrush, instructed in its use according to the manufacturer’s instructions, and asked to use the toothbrush with the same study dentifrice twice daily for 2 minutes at each brushing.

EFFICACY ASSESSMENTS
Vita Shade Guide Assessment Assessments of tooth color with the Vita Classical shade guide included the maxillary incisors. The Vita shade guide is a standard scale of multiple tooth-shaped tabs, each having a different color. Commonly used in dentistry to match artificial crowns to the natural dentition, the Vita shade guide has been successfully applied in clinical studies to assess the efficacy of tooth whitening products.4,7-9 All examinations were performed under color balanced lighting conditions using diffused lighting, with color temperature approximately 5500 K. To reduce variation, all examinations were performed in the same operatory—and thus under the same lighting conditions—whenever possible. The operatory colors were neutral, and both the evaluator and subject were instructed to avoid wearing bright clothing. A blue bib was draped over all subjects, and they were instructed to remove jewelry, eyeglasses, lipstick, and anything else that could interfere with shade selection. Without drying the teeth, the evaluators judged tooth color by selecting the closest shade tab on the guide. Between individual observations, the evaluators looked at a light blue card for a few seconds. Assessment of brushing treatment efficacy was performed by a rank ordering of shade tabs arranged from dark to light according to the rank ordering suggested by the manufacturer (Table 1). To ensure maximum integrity of the data, only 2 evaluators performed Vita shade assessments in the study. Before the screening visit, the clinical evaluators examined a subset of subjects for tooth 162

color using the Vita shade guide to establish intra-evaluator repeatability. Intra-examiner kappa statistics at 3 months were 1.00 (95% confidence interval (CI): 0.73, 1.00) and 0.88 (95% CI: 0.62, 1.00) for the examiners, and the inter-examiner kappa for the 2 examiners was 0.88.

DIGITAL IMAGING
Using existing technologies of digital photography and photographic analysis software used in the printing industry, it is possible to assess the color of teeth that currently cannot be matched by existing shade guides, making it possible to assess differences as small as one-eighth of a Vita shade.26 In recent years the CIE L*a*b* color space has been accepted as the benchmark for assessing color.27 This space covers the entire range of color seen by the human eye. The L*a*b* color model consists of a luminance component, L* (black to white), and 2 chromatic components, a* (green to red) and b* (blue to yellow). Figure 1 presents the CIE L*a*b* scale as a 3-dimensional visualization. The subjects’ baseline post bleaching and 6-month rebound images were photographed using the same standard digital camera under lighting conditions identical to those used during the Vita shade assessments. Subjects were positioned with the central incisal edge 9 inches from the lens of the camera, which was mounted on an axis perpendicular to the facial surface of the central incisors. Patients were presented edge-to-edge with retractors and were asked to touch the tip of their tongue to their soft palate. This allowed light to readily pass through the tooth surface and reduce reflectance from the tongue. The camera’s flash unit was used to ensure the consistency of light source and an ultraviolet filter was used on the camera to reduce glossing, which may occur with flash usage, thereby reducing the likelihood of hot spots and increasing the consistency of color accuracy between images. The camera was plugged into a 120volt power source to ensure a constant flash intensity between images. Vita Classical and 3D Master shade guides were photographed as well, providing controls to ensure maintenance of 163

photographic settings and quality and to establish a guideline for comparison between the L*a*b* and Vita shade guide subject data collected. Adobe Photoshop softwaree was used to generate the L*a*b* scores. To ensure accuracy, 9 locations were sampled on each of the central incisors, lateral incisors and canines of the maxillary arch, and L*a*b* scores were generated at these points. These data were then averaged to find a mean color and standard deviation of color on each tooth. A Gaussian blur filter set at 13 units, which averages color over an entire photo, was then applied to the original digital image. Using this filtering technique, 4 sampling locations were identified as optimal—the incisal-middle third and the middle-middle third of the maxillary left central and lateral incisors—because they provided the same information obtained from sampling the 9 locations without a filter. This allowed for faster sampling and decreased variability in the data by moderating the color extremes. Efficacy of the brushing treatment was made by comparison of L*a*b* scores derived from images captured at the first post bleaching clinical visit (post bleaching baseline) and 3 and 6 months thereafter. L* and b* are the 2 components of L*a*b* scores most recognized as being influenced by bleaching treatment, with an increase in L* indicating lightening and a decrease in b* indicating decreasing yellow and thus decreasing stain.

STATISTICAL ANALYSIS
The primary analysis used linear mixed effect models appropriate for a repeated measures design. This type of analysis supports the use of incomplete cases and allows for the testing of overall differences between brushes, overall change over time, and differences in brushes over time. The primary Vita shade analysis focused on comparing mean Vita shade scores between treatment groups over time. Secondary Vita shade analysis included comparisons between mean Vita shade scores of individual teeth over time. The luminance component of the L*a*b* scores generated from the digital images collected on the subset of 14 subjects was analyzed with 2-sample Student t-

164

tests, comparing differences in L* and b* (post bleaching baseline to 6 months post bleaching) between groups.

RESULTS
A total of 43 subjects 18 years of age or older and in good health were enrolled in the study. At the pre-bleaching baseline examination, the groups were comparable in terms of Vita shade scores and age (Tables 2 and 3). Three subjects did not return after the bleaching treatment and were dropped from the study, making the total sample size 40. The study sample was composed of 23 women and 17 men. Thirty-one subjects, 18 from the Sonicare group and 13 from the manual toothbrush group, returned for all clinical evaluations over the course of the 6-month study. Twelve subjects, 3 from the Sonicare group and 9 from the manual toothbrush group, missed at least 1 visit over the course of the 6-month study. The mean Vita shade scores over time overall and by individual tooth are presented in FiFigure 2 and Figure 3, respectively.

After completion of the bleaching treatment, the average shade score in the manual toothbrush group was approximately 1.3 Vita shades lower than that of the Sonicare group. Clearly the 2 groups responded differently to the bleaching treatment, though both were using the same dentifrice and manual toothbrush during the bleaching process. To assess the statistical significance of the observed difference, a 2-sample Student t-test was used to test the null hypothesis of no difference in mean Vita score between groups after bleaching. Because the result was not statistically significant (P = .06), the null hypothesis of no difference in mean post bleaching shade scores between brush groups was accepted.

Results of the linear mixed effects model using the complete case data indicate a statistically significant effect per visit. With the exception of the 1-month evaluation, all visits were found to have significantly different mean Vita scores (1 month P = .14; 2 months P < .001; 3 months P = .013; 6 165

months P < .001), relative to the first post bleaching exam. That is, for both brush groups at the 2month visit and beyond, mean Vita shade scores were significantly higher (darker) than immediately after bleaching. This indicates a rebound effect after 2 months. No statistically significant effect between groups, or brush type, was found (P = .07). This is not surprising because the groups were designed to have similar shade levels and this tests the combined group averages across all visits.

To determine if rebound was affected over time by brush type, the interaction of brush type and visit was tested. A statistically significant difference was found at the 6-month evaluation (P = .04), indicating that the brush groups rebounded differently after 6 months of brushing. On average, the manual brush group rebound was 1.12 Vita shades greater than that of the Sonicare brush group.

The 2-sample Student t-test assessing the mean change in luminance L* between brush groups (post bleaching baseline to 6 months post bleaching) returned a statistically significant result (P < .001), indicating teeth darkened with the use of the manual toothbrush compared with the use of the Sonicare toothbrush. The difference was estimated at –4.8 (95% CI: –6.5, –3.1); that is, after 6 months of toothbrush use, the manual toothbrush group mean was 4.8 L* units darker than the Sonicare toothbrush group mean. This difference in luminance was equivalent to 2 Vita Classical shades. The mean change in the blue-yellow axis b* also was assessed with a 2-sample Student ttest (post bleaching baseline to 6 months post bleaching). Again, the Sonicare toothbrush group showed a statistically significant difference from the manual toothbrush group (P < .001), indicating less of the yellow component for the Sonicare toothbrush group. The difference between groups was estimated at 2.1 b* units (95% CI: 0.9 to 3.2). (Table 4)

Three subjects showed signs of gingival sensitivity associated with the bleaching treatment; all subsequently resolved with the completion of the bleaching treatment. Both brushes had excellent safety records with no adverse events or abnormal intraoral exams reported after bleaching. 166

Photographs representing the type of changes observed in each group are presented in Figure 4 and Figure 5.

DISCUSSION
The analyses of the digital images and the Vita shade data both show the Sonicare toothbrush to be superior to a manual toothbrush at maintaining whitening 6 months after bleaching. While this is the first study examining the effect of Sonicare on maintaining whitening, there are other data on the effect of a manual toothbrush. Matis and colleagues,28 for example, report an increase of 5.2 L* units and 2.9 shade guide units only 6 weeks after a 2-week bleaching regimen using 15% carbamide peroxide. Our results show a more modest but still measurable rebound effect for manual brushing.

The estimated 6-month Vita shade difference between groups was larger in the digital analysis (2 Vita shades) than in the Vita shade analysis (1.12 Vita shades). This difference in estimates may be the result of the varying precision and accuracy of the 2 efficacy measures. We additionally note that the ordering of the Vita Classical shade guide does not follow the order suggested by digital image analysis of the shade tabs. In particular, ranking the tabs by decreasing luminance L*, that is the pure value axis of the L*a*b* color sphere, suggests not only that the color tabs are incorrectly ordered but also that the color change between tabs is nonlinear (Figure 6). Similar observations have been reported by O’Brien and colleagues29 and Paravina and colleagues.30 These factors also may contribute to the difference in estimates between the 2 efficacy measures.

The choice of randomization based on pre-bleaching mean Vita scores was made after considering the alternative of basing the randomization on the post bleaching mean Vita scores. The use of the former generated treatment groups with similar color shade distribution before bleaching. It was 167

believed that the method would produce groups with similar rebound patterns because the 2 groups were comparable before bleaching. The latter method would have produced comparable groupings after bleaching, but would have ignored the initial, pre-bleaching color distributions. This could have lead to groups with different rebound responses if their initial shade colors were very different.

CONCLUSIONS

The demand for tooth bleaching products and their use by professionals and patients is increasing every day. Treatment options include in-office bleaching, take-home bleaching, or a combination of the 2, with or without professional supervision. The take-home system is the most convenient for patients and professionals alike and proves to be very effective over a period of a few weeks. Studies have shown that there is some shade rebound over time. The clinician should keep in mind that the patient’s eating and drinking habits are likely to affect rebound as extrinsic staining can be caused by the use of coffee, tea, tobacco, red wine, and red grapes. The patients’ main concern after a successful bleaching treatment remains maintaining the bleached color over a period of time. In the current study the Sonicare Advance toothbrush was proven more effective than a manual toothbrush in maintaining the color of bleached teeth for 6 months. This finding, added to the established record of safety, superior plaque removal, and gingivitis reduction31-33 and extrinsic stain removal for this device, make Sonicare an excellent choice for patients interested in overall oral health and specifically tooth whitening maintenance.

168

Table 2—Ranking and Scoring of Vita Classical Shades Shade B1– B1 A1 B2 D2 A2 C1 C2 D4 A3 D3 B3 A3.5 B4 C3 A4 C4 Score 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Darkest Lightest

169

Table 3—Number of Subjects per Group by Visit

Manual Screening Baseline prebleaching Baseline postbleaching 1 Month 2 Months 3 Months 6 Months 22 22 19 18 17 14 13

Sonicare 21 21 21 19 19 18 18

170

Table 4—Study Demographics (Age) Statistic Minimum 1st quartile Mean Median 3rd quartile Maximum N Missing Standard deviation Manual 20 26 34.0 29 44 51 22 1 10.6 21 27 36.7 32 46 66 21 0 13.3 Sonicare

Table 5—L*a*b* Mean Differences (postbleaching baseline to 6 months) Difference in Mean (SD) L* a* b* Manual Sonicare Manual Sonicare Manual Sonicare –3.3 (3.5) 1.5 (2.9) 0.9 (1.5) 0.3 (1.4) 2.3 (2.6) 0.2 (1.6) Figures

171

Figure 1—CIE L*a*b* Color Space

172

Mean Vita Scores All Teeth
Manual Sonicare

Mean (All Teeth) Vita Score

6

7

8

3

4

5

Fi

0

5

10 # Weeks Post-Bleaching

15

20

25

Figure 2—Overall mean Vita scores over time.

173

Mean Vita Scores Tooth 7
8 Mean (Tooth 7) Vita Score 7
Manual Sonicare

Mean Vita Scores Tooth 8
Mean (Tooth 8) Vita Score 8
Manual Sonicare

6

7

5

4

3

0

5

10

15

20

25

3

4

5

6

0

5

10

15

20

25

# Weeks Post-Bleaching

# Weeks Post-Bleaching

Mean Vita Scores Tooth 9
8
Manual Sonicare

Mean Vita Scores Tooth 10
Mean (Tooth 10) Vita Score 8
Manual Sonicare

Mean (Tooth 9) Vita Score

7

6

5

4

3

0

5

10

15

20

25

3

4

5

6

7

0

5

10

15

20

25

# Weeks Post-Bleaching

# Weeks Post-Bleaching

Figure 3—Mean Vita scores by tooth over time.

(a)

(b)

174

(c)

Figure 4—Images of a representative subject from the manual toothbrush group (a) at screening, (b) at post bleaching baseline, (c) at 6 months after the end of bleaching.

175

(a)

(b)

(c)

Figure 5—Images of a representative subject from the Sonicare toothbrush group (a) at screening, (b) at post bleaching baseline, (c) at 6 months after the end of bleaching.

176

80

70

Luminance L*

60

50

40

B1

A1

B2

2 A2

A3 .5 B4

4 A3 D 3 B3

3 A4

1

2

D

C

C

D

C

Vita Classical shades in manufacturer's order
Figure 6—Luminance component of CIE L*a*b* color (middle-middle third of tab) vs manufacturer’s order for Vita Classical shade tabs.

Acknowledgments This work was supported by Philips Oral Healthcare, Inc.PRODUCT REFERENCES Philips Oral Healthcare, Inc, Snoqualmie, WA 98065; (800) 676-SONIC
b

Vita Zahnfabrik, Bad Säckingen, Germany; distributed in the USA by Vident, Brea, CA 92621; (800) 828-3839
c

Ultradent Products, Inc, South Jordan, UT 84095; (800) 496-8337 The Procter & Gamble Company, Cincinnati, OH 45202; (800) 492-7378 Adobe Systems, Inc, San Jose, CA 95110; (800) 833-6687

d

e

REFERENCES
177

C

4

1. Haywood VB, Heymann HO. Nightguard vital bleaching. Quintessence Int. 1989;20:173-176. 2. Goldstein RE. In-office bleaching: where we came from, where we are today. J Am Dent Assoc. 1997;128(suppl):11S-15S. 3. Burrell KH. ADA supports vital tooth bleaching—but look for the seal. J Am Dent Assoc. 1997;128(suppl):3S-5S. 4. Croll TP, Sasa IS. Carbamide peroxide bleaching of teeth with dentinogenesis imperfecta discoloration: report of a case. Quintessence Int. 1995;26:683-686. 5. Haywood VB. Current status of nightguard vital bleaching. Compend Cont Educ Dent. 2000;21(suppl 28):S10-S17. 6. Frazier KB. Nightguard bleaching to lighten a restored, nonvital discolored tooth [published erratum appears in Compend Contin Educ Dent. 1998;19:864]. Compend Contin Educ Dent. 1998;19:810-813. 7. Small BW. The application and integration of at-home bleaching into private dental practice. Compend Contin Educ Dent. 1998;19:799-808. 8. Christensen GJ. Bleaching teeth: practitioner trends. J Am Dent Assoc. 1997;128(suppl):16S18S. 9. Christensen GJ. Bleaching teeth: report of a survey, 1997. J Esthet Dent. 199810:16-20. 10. Haywood VB, Robinson FG. Vital tooth bleaching with Nightguard vital bleaching. Curr Opin Cosmet Dent. 1997;4:45-52. 11. Kugel G, Perry RD, Hoang E, Scherer W. Effective tooth bleaching in 5 days: using a combined in-office and at-home bleaching system. Compend Contin Educ Dent. 1997;18:378-383. 12. Li Y. Toxicological considerations of tooth bleaching using peroxide-containing agents. J Am Dent Assoc. 1997;128(suppl):31S-36S. 13. Leonard RH Jr. Efficacy, longevity, side effects, and patient perceptions of nightguard vital bleaching. Compend Contin Educ Dent. 1998;19:766-774. 14. Haywood VB, Leonard RH, Dickinson GL. Efficacy of six months of nightguard vital bleaching of tetracycline-stained teeth. J Esthet Dent. 1997;9: 13-19. 15. Haywood VB, Leonard RH, Nelson CF, Brunson WD. Effectiveness, side effects and long-term status of nightguard vital bleaching. J Am Dent Assoc. 1994;125:1219-1226. 16. Matis BA, Cochran MA, Eckert G, Carlson TJ. The efficacy and safety of a 10% carbamide peroxide bleaching gel. Quintessence Int. 1998;29:555-563. 17. Haywood VB. Historical development of whiteners: clinical safety and efficacy. Dent Update. 1997;24:98-104. 18. Gegauff AG, Rosenstiel SF, Langhout KJ, Johnston WM. Evaluating tooth color change from carbamide peroxide gel. J Am Dent Assoc. 1993;124:65-72. 19. Stanford CM, Srikantha R, Wu CD. Efficacy of the Sonicare® toothbrush fluid dynamic action on removal of human supragingival plaque. J Clin Dent. 1997;8(1 Spec No):10-14. 20. Stanford CM, Srikantha R, Kirchner HL, Wu CD. Removal of supragingival plaque in an intraoral model by use of the Sonicare® toothbrush. J Int Acad Periodontol. 2000;2:115-119. 21. Wu-Yuan CD, Anderson RD, McInnes C. Ability of the Sonicare® electronic toothbrush to generate dynamic fluid activity that removes bacteria. J Clin Dent. 1994;5:89-93. 22. Hope CK, Petrie A, Wilson M. In vitro assessment of the plaque-removing ability of hydrodynamic shear forces produced beyond the bristles by two electric toothbrushes. J Periodontol. In press. 23. McInnes C, Johnson B, Emling RC, Yankell SL. Clinical and computer-assisted evaluations of the stain removal ability of the Sonicare® electronic toothbrush. J Clin Dent. 1994;5:13-18. 24. Zammitti S, Habib C, Kugel G. Use of environmental scanning electron microscopy to evaluate dental stain removal. J Clin Dent. 1997;8(1 Spec No):20-25. 25. Bass CC. An effective method of personal oral hygiene; part II. J La State Med Soc. 1954;106:100-112.

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26. Anderson C, Kugel G. Rebound evaluation of tetracycline stained subjects treated with a 6.5% hydrogen peroxide gel; quantitative assessment by standard digital photography [abstract]. J Dent Res. 2002;81(spec iss):A-429. Abstract 3488. 27. Commission Internationale de l’Eclairage. Colorimetry Official Recommendation of the International Commission on Illumination. Paris: Bureau Central de la CIE; 1971.CIE Publication 15 (E-13.1). 28. Matis BA, Mousa HN, Cochran MA, Eckert GJ. Clinical evaluation of bleaching agents of different concentrations. Quintessence Int. 2000;31:303-310. 29. O'Brien WJ, Groh CL, Boenke KM. A new, small-color-difference equation for dental shades. J Dent Res. 1990;69:1762-1764. 30. Paravina RD, Powers JM, Fay RM. Dental color standards: shade tab arrangement. J Esthet Restor Dent. 2001;13:254-263. 31. Tritten CB, Armitage GC. Comparison of a sonic and a manual toothbrush for efficacy in supragingival plaque removal and reduction of gingivitis. J Clin Periodontol. 1996;23:641-648. 32. Johnson BD, McInnes C. Clinical evaluation of the efficacy and safety of a new sonic toothbrush. J Periodontol. 1994;65:692-697. 33. O’Beirne G, Johnson RH, Persson GR, Spektor MD. Efficacy of a sonic toothbrush on inflammation and probing depth in adult periodontitis. J Periodontol. 1996;67:900-908.

Chapter 10

Intrapulpal Temperatures with Light Activated Whitening
Effects of a Light Activated Bleaching System on Pulp Chamber Temperature in Vitro

179

ABSTRACT
Several new techniques and materials for in-office bleaching have been introduced recently. The aim of this in vitro study was to measure the temperature increase in pulp chamber produced by Zoom light and to investigate the influence of this light in conjunction with the application of bleaching gel on temperature rise. Ten extracted caries-free, unrestored human maxillary anterior teeth were used for the study. Each tooth was exposed three times in both groups (n=30 per group). The root of each tooth was cut about approximately 2-3mm apically to the CEJ and the apical orifice of the root canal was enlarged. The remaining pulp tissue was removed and the empty pulp chamber was filled with a heat sink compound which replaced the pulp tissue as a heat conducting medium. A thin K-type thermocouple was inserted to the pulp chamber through the cut root area. The root surfaces of the tooth were partially submerged in a water bath during the testing procedure at 37.5oC . In the first group, whitening gel, 25% hydrogen peroxide was applied to the buccal surfaces of teeth, approximately 1-2mm thick. Then the light was positioned at ~2.50 inches. The material was applied according to manfacturers instrutions. In the second group, the same teeth were exposed with the Zoom light without application of bleaching gel. The temperature at

the pulp before treatment (baseline) and temperature increase during exposing the light were measured for both treatment modalities. There was a 5 minutes interval between the end of one measurement and begining of the next. The mean temperature rise for group I (light and bleaching gel) was 1.11oC(0.18 ). The mean temperature use for group II (light alone) was 1.01 oC (0.12 ). There was a statistically significant difference between two groups (p= 0.003). Application of Zoom light in conjuction with the application of bleaching gel produced greater temperature rise than did the light alone. The maximum temperature rise was seen in the first 5 minutes of the treatment for both groups then the temperature decreased. Although a difference was noticed between the

group receiving light and gel (group I) versus the group receiving light (group II), neither group showed significant increase in the intrapulpal temperature of teeth when used for the recommended exposure time. 180

INTRODUCTION
Tooth Whitening has become one of dentistry’s most popular esthetic procedures as it is a conservative treatment for discolored teeth 1. Power bleaching is an in-office whitening technique developed to bleach teeth in a single visit. It’s done by the combination of a whitening agent, such as, peroxide, and an auxiliary, such as light
2, 3

. Currently, the in-office whitening technique uses a

15% to 35% hydrogen peroxide whitening agent (heated or non-heated); the dentist-prescribed home-applied technique most commonly uses a 10% to 15% carbamide peroxide gel. The advantage of the in-office procedure is that it does not require patient compliance and results may be seen immediately. The disadvantage is the chair time, cost to the patient, and the possibility of multiple visits. A light-activated chairside whitening system has the potential advantages of taking less time and providing quicker results. Recently, several new techniques and materials for in-office bleaching have been introduced. The Zoom Chairside teeth whitening system is one of the power bleaching systems that consists of a mercury Halide lamp filtered to emit light in the 350-400nm range.

Tooth sensitivity is the most common side effect of whitening4 .Concerns have been raised with the use of in-office whitening system energy sources like lasers, plasma arc lights and infrared lamps. It’s believed that these systems activate peroxide formulations and may induce a temperature rise that could cause sensitivity. Additionally, it has been reported that the light by itself might have a bleaching effect 2.

Lately, one study article reported the efficacy of the light whitening system whereas another study publication accomplished the opposite1, 2. In a recent investigation done in our lab employing a mercury halide light activated bleaching system significant sensitivity was reported. In this study 30 patients received treatment with the light & 25% hydrogen peroxide gel, gel alone or light alone. 181

The gel and light group reported a 90 % severe to moderate tooth sensitivity rate. This was significantly higher than the other groups. (submitted to IADR, 2004).Therefore the aim of this in vitro study was to measure the temperature increase in pulp chamber produced by Zoom light and to investigate the influence of this light in conjunction with the application of bleaching gel on the temperature rise.

EXPERIMENTAL DESIGN
Ten extracted caries-free, unrestored human maxillary anterior teeth were used for the study. Teeth were randomized and used for three separate temperature recordings for a total of thirty readings per group. Two groups were designed Group 1 was treated with bleaching gel and ZOOM light was applied for three cycles of 20 minutes .Group 2 was treated only with ZOOM light for three cycles of 20 minutes. Every 5 minutes temperatures were measured for each group using K-type thermocouple. The mean temperature and p-value for group 1 and group 2 were calculated.

MATERIALS AND METHODS
Ten extracted caries-free, unrestored human maxillary anterior teeth were used for the study. After the teeth were polished with pure pumice to remove any surface debris or contaminants, they were stored in distilled water until used. The root of each tooth was cut about 2-3mm apically to the CEJ and the apical orifice of the root canal was enlarged. The remaining pulp tissue was removed and the empty pulp chamber was filled with heat sink compound (American Oil and Supply Co., Newark, NJ, USA) which replaced the pulp tissue as a heat conducting medium. A thin K-type thermocouple was inserted to the pulp chamber through the cut root area.

The root surfaces of the tooth were partially submerged in a water bath during the testing procedure. This method effectively stabilized the internal baseline temperature at 37.5°C This also minimized the effects of ambient temperature changes and provided a consistent initial temperature 182

for each data set. In the first group, whitening gel, 25% hydrogen peroxide was applied to the buccal surfaces of teeth, approximately 1-2mm thick. Then the light was positioned according to the manufacturer’s instructions using the integral bite appliance guide to set the distance between the teeth and the light source approximately 2.50 inches. The teeth were exposed with the Zoom light for 20 minutes. After each 20minute session the whitening gel was rinsed off, and reapplied. In the second group, the same teeth were exposed with the Zoom light without application of bleaching gel. The temperature at the pulp before treatment (baseline) and temperature increase during exposing the light were used for both treatment modalities. There was a 5 minute interval between the end of one measurement and the beginning of the next.

RESULTS
The mean temperature rise was 1.11ºC(0.18) in the first group where the light was used with bleaching gel and 1.01ºC(0.12) in the second group at 5 minutes (graph 1). According to ANOVA test, there was a statistically significant difference between two groups (p= 0.003). Application of Zoom light in conjuction with the application of bleaching gel produced greater temperature rise than did light alone at the 5 minute exposure time. The maximum temperature rise was seen in the first 5 minutes of the treatment for both groups. Temperature slowly decreased for the 10, 15 and 20 minute recordings (table1). During the 20 minute exposure time temperatures slowly decreased to 0.43ºC for the light and 0.53ºC for the gel and light system. None of the samples returned to the baseline level during the 20 minute application (table 1).

DISCUSSION
Tooth whitening lights lights may emit heat. The effects of heat on the pulp tissue has been welldocumented. Due to its low compliance nature, lights may cause a temperature increase within the pulp chamber that may harm the pulp and/or cause tooth sensitivity 5. Zach and Cohen found that a 183

temperature rise of 5,5 C in a healthy pulp resulted in necrosis in 15% of the Macaca rhesus monkey teeth 6. However in our study the maximum temperature rise was 1,01. Therefore the zoom light was found to cause only a slight increase in the temperature. However temperature was increaed when the light was used in conjunction with the 25% hydroge peroxide bleaching agent. Since these results were obtained in vitro, long-term clinical trials are needed to fully understand the reasons of hyersensitivity and performance of this new whitening sytem.

SUMMARY
This study concluded the mean temperature rise was 1.11°C for the gel & light when samples are maintained at body temperature ( table 1). Recently an article published by Hein
4

showed that in

vivo gel temperature change, Zoom! Light bleach gel reached 5°C on the tooth surface during its 20 minute exposure time. The Zoom! Light was designed specifically for tooth bleaching. The results achieved by this study indicate that although previous reports showed significant temperature rise on the tooth surface our results demonstrate that the intrapulpal temperature increases only slightly during the exposure time. Therefore the Zoom light was found to cause only a slight increase in intrapulpal temperature. The use of the light and gel demonstrated a significantly higher temperature increase than the light alone. However, this increase is still lower than the necessary to cause pulpal damage (5.5 °C). The sensitivity noted during light activated bleaching is most probably increase dehydration on the surface of the tooth. This may relate to 5°C surface temperature change previously reported on the enamel surface.

Since these results were obtained in vitro, long-term clinical trials are needed to fully understand the reasons of hypersensitivity and performance of these new whitening systems. The effects of light activated bleaching systems on temperature rise in the pulp are not clinically significant. Hanning and Bott have shown that temperatures exceeding 42.5 °C can result in irreversible damage to pulp tissue 7. The distance between the light and tooth could affect the temperature rise in the pulp chamber. It is interesting to comment that normally hot liquids are consumed with short 184

term temperatures at 60 °C to 70° C. It’s believed that the pulp only increases a few degrees due to the thermal insulting properties of the dental hard tissue, when using a regular halogen curing light
7

.Our study would indicate no long term pulpal damage from this light activated bleaching system.

Graph 1:
Zoom Light Zoom Light + Bleaching Gel

1.2

1

Mean Temperature Rise

0.8

0.6

0.4

0.2

0
0 5 10
Time of Exposure

15

20

Table 1:

Mean Temperature Rise Time in Minutes Zoom Light Baseline 5 10 0 OC(37.5ºC) 1.01OC 0.82 OC
185

Zoom Light + Bleaching Gel 0 OC(37.5ºC) 1.11 OC 0.98 OC

15 20

0.60 OC 0.43 OC

0.77 OC 0.53 OC

REFERENCES:
1. Papathanasiou A, Bardwell D, Kugel G. A clinical study evaluating a new chairside and takehome whitening system. Compendium 2001; 22: 289-297. 2. Tavares M, Stultz J, Newman M, Smith V, Kent R, Carpino E, Goodson JM. Light augments tooth whitening with peroxide. JADA 2003; 134: 167-175. 3. Nathanson D. Vital tooth bleaching: sensitivity and pulpal considerations. JADA 1997; 128: suppl: 41S-44S.

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4. Hein DK. Ploeger BJ. Hartup JK. Wagstaff RS. Palmer TM. Hansen LD. In-office vital tooth bleaching--what do lights add?. Compend of Contin Educ Dent. 2003 Apr; 24(4A):340-52. 5. Blankenau R, Goldstein R, Haywood VB. The current status of vital tooth whitening techniques. Compendium 1999; 20: 781-794. 6. Zach L, Cohen G. Pulp response to externally applied heat. Oral Surg Oral Med Oral Pathol 1965; 19: 515-530. 7. Hannig M, Bott B. In-vitro pulp chamber temperature rise during composite resin polymerization with various light-curing sources. Dent Mater. 1999 Jul;15(4):275-81

Chapter 11

Effect of Tooth Whitening on Enamel
An exploratory study using SEM to evaluate the enamel surface effects in vivo of a 6% hydrogen peroxide strip bleaching system with that of a 2.5% chlorite tray bleaching system
187

INTRODUCTION

Tooth whitening has become both common and popular, and use of peroxide is now generally recognized as a safe and effective method for tooth whitening
1-3

. There are a variety of indications

for bleaching single or multiple teeth, including staining from chromagenic foods or other sources, dental fluorosis, tetracycline staining and devital discolored teeth
4-6

. Concentrations of up to 35%

peroxide are used alone or in combination with various agents for tooth bleaching. Delivery is via in-office, at-home regimens or combination regimens with or without professional supervision
7, 8

.

Of these, bleaching is most commonly accomplished at-home over a period of a few weeks 9. Treatment duration may vary based on the degree of staining, since whitening is reported to be a product of peroxide concentration and contact time
10

. For some difficult stains like tetracycline,

daily bleaching for periods of up to 6 months may be indicated 11. Efficacy may be established through first or second person observation or various technical methods. Clinical trials most commonly include use of a shade guide, colorimeter, or computer digitization to measure color change over time. Of these, methods that assess three-direction (dimension) color space are reported to be more objective and linear, and as such, may be preferred for clinical trials research 12,13. A comprehensive literature review found tooth bleaching agents to be remarkably well-tolerated. The principal adverse events — tooth sensitivity to temperature changes and local oral mucosal irritation — were generally mild and transient. Patients with pre-existing sensitivity may be at highest risk for after-bleaching sensitivity. Several factors are reported to contribute to hard and soft tissue events, including tray design, formulation, and others 10.

Tolerability may be impacted by poor compliance, overuse, unnecessary product ingestion, and others 5,. Many of these factors may be associated with the delivery trays (either custom or stock) which are commonly used in most at-home regimens. Rapid innovation, especially with the advent of new in-office options for immediate care and the emerging popularity of the direct-to-consumer 188

systems, challenges many of the basic tray-based precepts of the previous decade. One of the most prominent of these is the whitening strip (Crest, Blend-a-Med or AZ Whitestrips), a novel system that uses a flexible polyethylene strip to deliver a hydrogen peroxide bleaching gel to the anterior dentition. These whitening strips are reported to offer specific advantages vs the more conventional custom tray-based systems, with respect to total peroxide dose, contact time, and ease of use. Evidence of safe and effective use has been established in clinical and pre-clinical studies comparing whitening strips to various negative and positive controls. The application of such bleaching agents to whiten vital-teeth is less well-characterized with little research published in the scientific literature. There have been a number of studies evaluating the effect of bleaching on the hardness and morphology of enamel. The results from these studies have varied. One study concluded that the use of bleaching agents resulted in a significant reduction in Calcium/Phosphate ratio in enamel
14

and they concluded that bleaching materials may adversely affect the dental hard tissue. Other authors state that surface hardness and tooth morphology are not deleteriously affected by bleaching 15.

This clinical trial evaluated the safety of a recently introduced 2.5% sodium chlorite tray-based whitening system, Odol-med 3 Beauty Kurr, versus a currently marketed 6% hydrogen peroxide strip system. Sodium chlorite is the only chlorite salt produced commercially in significant quantities. It is used mainly for the generation of chlorine dioxide in situ for bleaching textiles, in pulp and paper processing, and for disinfection. Scanning Electron Micrographs from replicas were used to observe surface effects/ morphological changes in teeth enamel after treatment with bleaching agents. The observations included any changes in the porosity, precipitations, erosive process, destruction and depression areas, with the formation of craters and exposure of enamel rods.

189

OBJECTIVE The aim of this exploratory study was to assess any surface morphological changes in tooth enamel after treating with a currently marketed hydrogen peroxide strip bleaching system and a currently marketed sodium chlorite tray-based system using an SEM Investigation.

MATERIAL AND METHODS This was a parallel, examiner-blind, single-center study. Approximately 10 generally healthy subjects (5 per treatment group) were randomly selected from a pool of subjects undergoing a 3 week regimen of vital tooth bleaching with either a 6% whitening strip (Group I) or 2.5% sodium chlorite tray system (Group II). The Test Products were:  AZ Whitestrips (Polyethylene strips containing 6% Hydrogen Peroxide gel). Manufactured by The Procter & Gamble Company.  Odol-med 3 Beauty Kur (Tooth Whitening System including the Activator containing 2.5% Sodium Chlorite). Manufactured by Glaxo Smithkline. Subjects assigned to Crest Whitestrips treated their anterior maxillary tooth surfaces for a period of three weeks. The product was used twice a day for 30 minutes each. Subjects assigned to Odolmed 3 also treated their maxillary surfaces for three-week duration, as per the manufacturer’s instructions. This product was used twice a day for 10 minutes. The first product use was supervised at the Product Distribution visit. All other uses were completed at home and were unsupervised.

Subjects on the Group I brushed twice daily with AZ Protezione Caries toothpaste (currently marketed cavity protection toothpaste). It contains 0.32% Sodium Fluoride (Procter & Gamble Company). Subjects on the Group II had whitening toothpaste provided to them with their test product. All subjects were assigned an Oral B40 Soft Bristle toothbrush (Braun Oral B Company).

Inclusion Criteria 190

The subjects were included if they:
1. provided written informed consent prior to their participation and be given a copy of the signed

consent form,
2. were at least 18 years of age at the time of enrolment, 3. had a minimum of 16 natural teeth, specifically all 4 maxillary anterior central and lateral

incisors.
4. agreed to return for the scheduled visits and follow the study procedures, 5. agreed not to participate in any other oral /dental product clinical studies during the course of

this study,
6. agreed to refrain from the use of any non-study dentifrices and tooth whitening products for the

study duration and
7. had teeth sufficiently free of caries

Exclusion Criteria The subjects were excluded from the 2003088 study if they:
1.

had restorations or dental crowns, generalized gingival recession or clinically meaningful malocclusion involving the maxillary or mandibular anterior dentition,

2. presented with any pre-existing oral or medical condition that the examiner or investigator

determines may place the subject at increased health risk from study participation,
3.

had any dental care planned during the duration of the study that may:     impact the general health of the subject impact the ability of the subject to bleach teeth according to the protocol require a dental prophylaxis involve the anterior dentition

4.

were undergoing current treatment for gingivitis, periodontitis, or caries,

191

5.

reported having teeth previously bleached by a professional treatment, over-the-counter bleaching kit, or clinical trial test product,

6. 7.

were currently using a chlorhexidine mouth rinse or Listerine mouth rinse, had teeth with clinically meaningful intrinsic staining due to tetracycline, fluorosis or hypocalcification,

8. 9.

had self-reported dentinal sensitivity, or had teeth that cannot be imaged.

Continuance Criteria Subjects were discontinued for the following reasons: 1. use of dentifrices or mouthrinses or tooth whitening products other than those assigned; 2. elective dentistry prior to study completion, including dental prophylaxis; 3. Inability or unwillingness to comply with study procedures including test product regimen. The same continuance criteria were governing the subject’s eligibility to continue participation in this study.

An SEM Investigation was done on Baseline, Day 14 and Day 21. Subjects discontinued product use at the Day 21 visit. During the entire study period subjects brush with their assigned toothbrush and toothpaste. An impression of the dentition and SEM investigation was conducted and used as the post treatment assessment. A rubber impression of both the maxillary and the mandibular anterior teeth was taken for each of the selected subject. These were done both at the baseline (pre-treatment) and after completing the product usage (post treatment).

The impressions were poured with epoxy resin material. The buccal surfaces of the two upper central incisors were evaluated. The buccal surfaces of central incisors were gold sputtered and then mounted in metallic stubs. All the study material was labeled with the subject number, tooth number and the evaluation day. 192

Observations under the SEM were made on changes in porosity, precipitations, erosive process, destruction and depression areas, with the formation of craters and exposure of enamel rods. Photographs of the scans were taken. Two different evaluators who were blinded to the test product did the observations and scoring. The scoring was done independent of one another.

The scoring was done at constant magnifications (x500, x2000 and x5000). Four readings were made on each tooth, dividing the surface into four quadrants (figure 1). The reading was performed in the centre of each quadrant. All the scores were collected and evaluated according with the scores (figure 2) and the location. The SEM scores were done by two independent graders using a scoring system of 0-4.

Due to small sample size, non-parametric methods were used to explore the data (figures 3-6). In addition to the visual observation models were poured in epoxy die and 3D laser profilometry was done on all samples. Delta Ra data was obtained and statistical differences from baseline were determined.

RESULTS Scores from the visual evaluation of the SEM data indicated that there was little evidence of any increased surface roughness in either group following treatment (Table 1). This is based on the visual evaluation of two independent calibrated evaluators. Evaluations were based on a

comparison between baseline (no treatment) and after 21 days of exposure. It should be noted that all evaluations indicated that the roughness noted was superficial with no deep roughness observed.

193

The profilometry data (table 2) shows a good biological diversity with both products producing a similar but insignificant change in surface roughness. Differences between groups showed no statistical significance using a nonparametric analysis, the Wilson rank sum test. This produces a P-value =0.69 which indicates that neither treatment had any adverse effects on the surface morphology the teeth examined. These results confirm the data presented in table 1.

DISCUSSION This study represents the first paper to evaluate enamel following tooth whitening using both visual analysis and laser profilometry. There have been other studies to evaluate the hard tissue effects of tooth whitening. These have employed microhardness and SEM analysis of the enamel surfaces
15 14,

. In this study the use of a visual scoring system for changes on enamel morphology indicated that

there were no significant changes from the baseline in either the 6% Hydrogen Peroxide gel group or the 2.5% Sodium Chlorite group. It is important to note that in all evaluations the roughness observed was superficial in nature and that all teeth varied slightly at baseline. This is expected given the variability of enamel clinically and these observations are only relevant when compared within the sample. In order to confirm our SEM visual evaluation Laser profilometry was done for both groups. Measurements were compared using baseline (before treatment) and following 21 days of exposure. Samples were analyzed for differences from baseline for both the 6% hydrogen peroxide and the 2.5% Sodium Chlorite groups. There is no statistical difference between the baseline and 21 day samples. This is true for both tooth whitening systems. In both groups the 21 day dosing has no effect on surface roughness of the exposed teeth. In conclusion this study indicates that 21 day exposure to two different tooth whitening systems had no observable or measurable adverse effects on enamel.

Tables and figures: 194

Figure 1 Figure 2: Figure 3: Figure 4: Figure 5: Figure 6: Table 1: Table 2:

Four readings were made on each tooth, dividing the surface into four quadrants Scoring scales for SEM evaluation Samples of SEM 2,000X with roughness score 0 Samples of SEM 2,000X with roughness score 1 Samples of SEM 2,000X with roughness score 2 Samples of SEM 2,000X with roughness score 3 Average scores per group by quadrant Laser profilometry Ra analysis

Figure 1:

A

B

C

D

Figure 2: SEM Scores Score 0 Score 1 Score 2 Score 3 Score 4 no visible surface roughness 5-25% of the surface displays roughness 25-50% of the surface displays roughness 50-75% of the surface displays roughness 75-100% of the surface displays roughness

195

Figure 3:

Figure 4:

196

Figure 5:

Figure 6:

197

Table 1:

Quadrant A Average per Group 500X Baseline GROUP I 0 0 14-Day 0.4 0 21-Day 0.2 0.2 Baseline 1.4 1.6 2000X 14-Day 1.6 1.6 21-Day 0.8 0.4

GROUP II

198

Quadrant B Average per Group 500X Baseline
GROUP I 0.2 0.2

2000X 21-Day
0 0

14-Day
0.4 0.2

Baseline
1.6 1.6

14-Day
1.8 1.6

21-Day
1 0.6

GROUP II

Quadrant C Average per Group 500X Baseline
GROUP I 0.4 0.4

2000X 21-Day
0 0

14-Day
0.4 0.6

Baseline
2 2

14-Day
1.8 1.4

21-Day
0.6 0.6

GROUP II

Quadrant D Average per Group 500X Baseline
GROUP I 0.8 0.6

2000X 21-Day
0 0

14-Day
0.4 0.2

Baseline
2.2 1.2

14-Day
1.6 1.6

21-Day
0.6 0.6

GROUP II

199

Table 2:

Specimen Treatment 5 Group I 12 Group I 20 Group I 24 Group I 32 Group I Mean Value

Baseline 0.5192 0.2458 0.1815 0.2189 0.3545 0.30398

21 day 0.7154 0.3715 0.2208 0.2034 0.2613 0.35448

Delta Ra 0.1962 0.1257 0.0393 -0.0155 -0.0932 0.0505

Specimen Treatment 1 Group II 3 Group II 4 Group II 25 Group II 27 Group II Mean Value

Baseline 0.1305 0.2588 0.2792 0.3158 0.3365 0.26416

21 day 0.1976 0.2505 0.2748 0.3244 0.3 0.26946

Delta Ra 0.0671 -0.0083 -0.0044 0.0086 -0.0365 0.0053

REFERENCE 1. Haywood VB, Heymann HO. Nightguard vital bleaching. Quintessence Int 1989;20: 173-6. 2. Goldstein RE. In-office bleaching: where we came from, where we are today. J Am Dent Assoc 1997; 128: 11S – 15S 3. Burrell KH. ADA supports vital tooth bleaching – but look for the seal. J Am Dent Assoc 1997 128:3S-5S. 4. Croll TP, Sasa IS. Carbamide peroxide bleaching of teeth with dentinogenisis imperfecta discoloration: report of a case. Quintessence Int 1995; 26:683-6 5. Frazier KB. Nightguard bleaching to lighten a restored, nonvital discolored tooth. Compend Contin Educ Dent 1998; 19:810-3 6. Small BW. The application and integration of at-home bleaching into private dental practice. Compend Contin Educ Dent 1998;19:799-806 200

7. Kugel G, Perry RD, Hoang E, Scherer W. Effective tooth bleaching in 5 days: using a combined in-office and at-home bleaching system. Comp Contin Educ Dent 1997; 18:378-83. 8. Li Y. Toxicological considerations of tooth bleaching using peroxide-containing agents. J Am Dent Assoc 1997; 128:31S-36S 9. Leonard RH. Efficacy, longevity, side effects, and patient perceptions of nightguard vital

bleaching. Compend Contin Educ Dent 1998; 19: 177-780 10. Haywood VB, Leonard RH, Dickinson GL. Efficacy of six months of nightguard vital bleaching of tetracycline-stained teeth. J Esthet Dent 1997;9: 13-9 11. Haywood VB, Leonrd RH, Nelson CF, Brunson WD. Effectiveness, side effects, and long-term status of nightguard vital bleaching. J Am Dent Assoc 1994; 125 1219-26 12. Gegauff AG, Rosenstiel SF, Langout KJ, Johnston WM. Evaluation of tooth color change from carbamide peroxide gel. J Am Dent Assoc 1993;124:65-72. 13. Rotstein I. Dankner E. Goldman A. Heling I. Stabholz A. Zalkind M. Histochemical analysis of dental hard tissues following bleaching. Journal of Endodontics. 22(1):23-5, 1996 Jan. 14. White DJ. Kozak KM. Zoladz JR. Duschner HJ. Gotz H. Effects of Crest Whitestrips bleaching on surface morphology and fracture susceptibility of teeth in vitro. Journal of Clinical Dentistry. 14(4):82-7, 2003.

15. Spalding M. Taveira LA. de Assis GF. Scanning electron microscopy study of dental enamel
surface exposed to 35% hydrogen peroxide: alone, with saliva, and with 10% carbamide peroxide. Journal of Esthetic & Restorative Dentistry: Official Publication of the American Academy of Esthetic Dentistry. 15(3):154-64; discussion 165, 2003.

Summary and Discussion

In Chapter 1, as an introduction to the main topic of this study, a major aspect of modern dentistry was presented. The area of tooth whitening, although one of the fastest growing and affecting millions of patients, it relies on a weak base of scientific evidence. The actual mechanism of action of hydrogen peroxide on enamel and dentin is presumed to be an oxidation process that affects both enamel and dentin. The assumption is that because the radicals have unpaired electrons, they are extremely electrophylic and unstable and will attack most other organic molecules to achieve stability, generating other radicals. These radicals can react with most unsaturated bonds, resulting in disruption of electron conjugation and a change in the absorption energy of the organic 201

molecules in tooth enamel. Simpler molecules that reflect less light are formed, creating a successful whitening action. This process occurs when the oxidizing agent (hydrogen peroxide) reacts with organic material in the spaces between the inorganic salts in tooth enamel. This assumption is difficult to prove. Our data supports the idea that there must be significant penetration of the peroxide into dentin and that once it reaches the dentin it is in a form that is able to oxidize the organic material causing a lightening effect. The early work on tetracycline staining supports the idea that there is a penetration of the free radical. These studies relied on small sample sizes and incorporated high dose delivery systems. The causes of both intrinsic and extrinsic staining were reviewed following the section on penetration of hydrogen peroxide. This was done to support the belief that these intrinsic stains require significant penetration in order for these to be lightened.

It is interesting that so little is known about the concentration and dose response during the whitening process. The assumption has been that the higher the concentration the better the effect. It has also been assumed that a dose of 30-50 mg was required to whiten teeth. We examine in this thesis the use of a novel low dose delivery system using 9-11 mg of carbamide peroxide on a polyethylene strip.

A review of the evolution of tooth whitening demonstrates the field is not new. The review of the literature also shows that there a number of systems available for tooth whitening. The most common bring the night guard vital bleaching method. Other systems have been more recently introduced such as the polyethylene strip and paint-on products. The area of light activated bleaching as indicated in the introduction remains one of the most controversial areas in this field. This is due to the poor quality of many of these studies the results have been questioned. The mechanism of action of these light (and heat) activated systems is addressed along with the evidence that the assumed increased breakdown of the hydrogen peroxide and thus increased efficacy would require temperatures the would be detrimental to vital teeth. 202

Finally; the issue of adverse events and possible side effects were reviewed. The toxicological side effects seem to be minimal however tooth sensitivity can be quite significant. Studies have shown that sensitivity occurs in 55 to 75% of the treatment groups. The placebo groups also experienced 20-30% sensitivity. The causes of tooth sensitivity are poorly understood. It is most often seen as the result of tooth dehydration.

In Chapter 2 a randomized, single-center, double-blind, parallel-group, placebo controlled trial evaluating the whitening efficacy and safety of 2-week, twice daily use of a 5.3% hydrogen peroxide tooth-bleaching gel delivered on polyethylene film. This system employed a low dose delivery of 9-11 mg of carbamide peroxide gel. Efficacy was based on change in Vita® shade scores from baseline to the end of treatment. Baseline Vita® shade scores were similar for the two treatment groups. Scores were 8.18 (D-4 to A-3) and 8.28 (D-4 to A-3), and, on average, ranged from A-2 to C-4 and from A-2 to A-4 in the active and placebo groups, respectively. Sixty-four percent of teeth treated in the active group started at scores of C-2 or whiter. Thirty-three patients in each group completed treatment. Use of the peroxide-containing gel led to a mean change in baseline Vita® shade score of –3.70 ± 0.35, compared with a change of –0.87± 0.24 after use of a placebo gel. After adjustment for baseline scores, the mean difference in shade change between the peroxide gel–treated group and placebo-treated group was –2.85 ± 0.41 (P < 0.0001). Both treatments were generally well tolerated. Adverse effects after treatment were minimal and were observed in less than 10% of subjects in either treatment group. The main findings in these participants were papillary swelling, minor cervical inflammation, and a superficial cervical lesion. This was the first study to examine the use of such a thin film of hydrogen peroxide gel in tooth whitening. Prior to the research dentist would us a night guard fabricated to a stone model of the patient and contoured at the margins Spacer was routinely used on the facings of the teeth to insure that a high dose of material could be delivered to the teeth with the assumption that this was necessary to have a significant amount of material in contact with the teeth for tooth whitening to 203

occur. This study was the first to demonstrate that a low dose (9-11 mgs) but higher concentration 5.3 % hydrogen peroxide applied for 30 minutes twice daily resulted in significant lightening when compared to placebo control. This study was controversial since this delivery system was easy to apply, effective, minimal adverse events and did not require the fabrication of a tray and therefore had the potential to be used as over-the-counter product.

In Chapter 3 the question of concentration response using a low dose (4-11 mg) delivery system was addressed employing digital image analysis of treatment groups in order to analyze the CIELAB tooth color values for b* (yellow – blue), L* (lightness), and a* (red – green).17 Change values were calculated for any given post-baseline visit. The objective of this study was to evaluate the peroxide concentration whitening response following self-directed use of whitening strips over a 28-day period.

A randomized, double-blind, parallel group clinical study was conducted. Thirty-seven healthy adult volunteers were randomly assigned to one of three groups based on tooth color at screening – 1.8% hydrogen peroxide strips (HPS), 3.3% HPS or 5.3% HPS. Subjects applied the assigned maxillary strips twice per day for 30 minutes over 28 days. Tooth color was evaluated at day 7, 14 & 28 from digital images of the maxillary 6 anterior teeth using a standard method. Treatments were compared using analysis of covariance (adjusting for baseline), or analysis of variance at a 0.05 level of significance.

The results of this study demonstrated hydrogen peroxide at concentrations ranging from 1.85.3% resulted in significant (p < 0.05) color improvement versus baseline as early as Day 7. There was a clear concentration-response for all color parameters (b*, L* and E*) at all time points, favoring the higher concentrations. While the concentration-whitening relationship approached a linear response at Day 7, continued treatment resulted in incremental color improvement. All three 204

peroxide concentrations were well tolerated, and no subjects discontinued early due to a treatmentrelated adverse event.

The research provides clear evidence of a peroxide concentration whitening response. Whitening efficacy was greatest for the highest concentration group (5.3% hydrogen peroxide), while the intermediate concentration group had an intermediate response. Not surprisingly, this effect most approached linearity at the earliest time point (Day 7). At that time, adjusted mean b* for was – 1.43, –0.84, and –0.44 in the higher, intermediate and lower concentration groups, respectively. Relative to the lowest concentration strip, this represented a 225% improvement in whitening for the 5.3% strip (a 194% increase in concentration), and a 91% improvement in whitening for the 3.3% strip (a 83% increase in concentration).

Despite the concentration differences (there was nearly a three-fold difference between the lowest and highest concentration tested in this research), all three strips tested in this research carried a low total amount of peroxide. The total amount of hydrogen peroxide on each pre-dispensed strip ranged only from 3.6-10.6 mg. Relative to some tray-based systems, which may deliver up to 2 grams of bleaching gel, total peroxide delivered with any of these strips was remarkably low. This likely contributed to the low overall adverse event rate seen in this trial. This new clinical research provides evidence of a concentration gradient for whitening response following use of a low peroxide dose strip whitening system. As such, this may represent a first example of concentration ranging for one of the self-directed bleaching systems. More importantly, the research also provides evidence of the sensitivity and robustness of the measurement method – in this instance – digital imaging.

The study in Chapter 3 compliments the earlier work done in Chapter 2. In Chapter 2 we discussed the introduction of a low dose novel delivery system and we demonstrate its effectiveness vs contro 205

using a value-ordered shade guide. In Chapter 3 we determine that there is a concentration response when measured digitally using this low dose system. This research adequately differentiated multiple concentrations from low to high over time. With b* as an endpoint, the study demonstrated a nearly linear concentration response relationship, with measured efficacy differences at Day 7 that reasonably modeled the real concentration differences between groups. As such, the research provides important evidence of the validity of this method and endpoint for practice-relevant evaluation of vital bleaching technologies.

In Chapter 4 we evaluated the effectiveness of light-curing (heat conversion) vs. no light-

curing (no heat conversion) of a 35% hydrogen peroxide in-office tooth whitening system. Heat conversion is used as a means of speeding up the breakdown and thus increasing the efficacy of the hydrogen peroxide oxidation process. This was one of the first controlled studies to evaluate light activated bleaching.

Twenty patients with sound medical history (without tooth sensitivity) participated in this randomized, parallel clinical evaluation. Only six maxillary anterior teeth with discoloration and a tooth shade of A3 or darker were selected. Patients received a complete prophylaxis and were evaluated for initial (baseline) shade by three independent evaluators, precalibrated at 85% rater reliability in determining shades before the experiment began. Participants received a 20-minute chairside whitening treatment with a 35% hydrogen peroxide agent using a reflective resin barrier for gingival isolation. During the whitening treatment, the 35% hydrogen peroxide agent was light activated with a halogen curing light on teeth Nos. 6 through 8 (Group I), but was not light-activated on teeth Nos. 9 through 11 (Group II). All patients returned 24 hours after the whitening application for shade evaluation. Although there were isolated instances (7 out of 20 patients) of greater degrees of lightening in the light-curing group, there was no statistically significant difference using 206

the Mann-Whitney U test (P > .05). This study indicates that light-curing is optional with this 35% tooth whitening system.

Of the 20 patients in this study, 7 patients experienced an increase in lightening of the split arch protocol with an average lightened increase of 1.714 shades as compared to the non–light-cured side. This was not a significant clinical change. Any shade difference as noted by the light-activated side was most likely a result of dehydration resulting from heat generated by the halogen curing light. Statistically, there was no significant difference between the light-activated side when compared to non–light-activated side.

The results contradict other studies, which have indicated that light activation causes an increased whitening effect as used with hydrogen peroxide whitening agents

The study in Chapter 5 is complimentary to that in Chapter 4. The purpose of this study was to compare the efficacy of color changes of two in-office tooth whitening systems, a 15% Hydrogen peroxide light activated system and a 38% non-light activated hydrogen peroxide system. In this split-arch, randomized, parallel, blinded clinical evaluation six maxillary anterior teeth (N=60) A-2 or darker were selected using the value order Vita Shade Guide. Patients received one-hour light-activated chair side treatment using 15% H2O2 teeth 6-8 (Group I), teeth 9-11 received a 38% H2O2 system for 1 hr without a light (Group II). Before and after treatment images were taken. L*, a* and b* and Vita shades were measured. The Olympus C2500L high resolution digital camera is utilized for sampling. To ensure proper color analysis an extended procedure of sampling nine locations on the central incisor, lateral incisors of the maxillary and mandibular arches was completed. This data is then averaged
207

to find a mean color and standard deviation of color on each tooth. A Gaussian blur filter was applied during post processing which does an averaging of color over the digitally sampled photo. All digital images were then analyzed to yield L*, a* and b* data Patients returned after 2 weeks for final shade evaluation.

The L*, a* and b* data indicates that both BriteSmile and Opalescence Xtra Boost whitened teeth to statistically significant level (P=.01) for L* 3.6 (BriteSmile), 3.8 (Xtra Boost) and b* -6.0 (BriteSmile), -5.0 (Xtra Boost) equivalent to between 3 and 6 shades as determined on a Vita shade guide. The two whitening systems were not statistically significantly different from pre-bleaching to two weeks post-bleaching. The Vita Shade Guide results showed that both in-office tooth whitening systems were effective. Group I averaged 5.9 ± 2.5 and Group II 3.97 ± 2.33 shade changes immediately after treatment. At the 2-week recall, Group I scored an average of 4.6 ± 2.14 and Group II 4.6 7± 2.3 shade changes, compared to the pre-bleaching shades. A paired sample t-test revealed statistically significant difference (p<0.0001) between Groups I and II immediately after bleaching, with Group I performing better. At the 2-week recall, however, only Group I showed a significant rebound (p=0.0002). At the completion of the study, there was no significant difference between Groups I and II (p=0.7826). The clinical observation using a value ordered Vita Shade Guide was confirmed using digital analysis of L*, a*, b* color values
15

. In addition the digital camera was calibrated for each image.

Unlike other studies, the teeth of the one side were kept moist during bleaching, thus minimizing the effect of dehydration that can occur while the other lateral side was being bleached. This might explain why our data does not show the dramatic results reported in another paper. It is reasonable to conclude that with the increase in temperature, dehydration did occur, which was subsequently followed by rehydration. Therefore, in spite of the initial perception that an increase in whitening

208

took place, the 2-week post-operative evaluation did not demonstrate a difference, which was confirmed by an absence of a statistically significant difference between the two materials. This data is particularly relevant since the use of light activated bleaching has been gaining in popularity in the US. This is partially due to the fact that there are few well controlled, independent studies in the field. In a study that we just completed at our University but the (data yet unpublished) we used a metal halide (Zoom) light N=30 patients and we once again found no value to use of a light in bleaching.

In Chapter 6 we address the issue of hydrogen peroxide penetration as well as mechanism of action by examining the efficacy of a low dose delivery system on bleaching tetracycline-stained teeth. We incorporate a patient population with documented intrinsic staining so that we could evaluate the ability of the low dose gel to penetrate to the dentin. This clinical article reviews the efficacy of a new 6.5% hydrogen peroxide tooth-whitening gel strip for bleaching teeth that have been intrinsically stained from tetracycline. Given the severity of the staining in the cases presented during this conducted clinical trial, the resulting efficacy is dramatic.

A randomized clinical trial compared the efficacy of two at-home vital bleaching systems on tetracycline-stained teeth. Daily bleaching was conducted over two months. Eligibility was limited to healthy adult volunteers who had 16 or more natural teeth, including at least 3 gradable maxillary incisors with significant tetracycline staining. Individuals demonstrating tooth sensitivity or an immediate need for dental treatment were excluded from participation in this trial. The 40 randomized subjects included 30 assigned to the strip group and 10 assigned to the tray group. The study population ranged from 22 to 70 years of age. Approximately half of the sample presented with moderate to severe tetracycline staining (levels II through IV), one third of whom had the more severe banding that is occasionally reported following childhood antibiotic use. While tobacco use was uncommon (15% of the sample), 95% of the study participants consumed coffee, 209

tea, or cola beverages daily. Treatment groups were generally well balanced with respect to demographic and behavioral parameters and tetracycline stain levels. Efficacy was assessed using a standard 16-step value-oriented tooth shade guidec used in dentistry to match artificial crowns to the natural dentition. Shade assessments were performed in a neutral-colored dental operatory under color-balanced lighting conditions by a trained and calibrated examiner. Tolerability was assessed by intraoral examination and subject report at each study visit.

Individual shade scores were determined by ordering the 16 shades arranged from dark to light according to the rank ordering suggested by the manufacturer. To account for unusually dark colors (often seen with tetracycline stain) or white colors (often seen post-bleaching), this 16-step guide was supplemented by 2 additional values (C4+ and B1-) representing shades darker than C4 or lighter than B1. Effectiveness was determined by calculating the change in shade scores from baseline at each post-treatment visit. Using this method, a decrease in numeric shade score represented an increase in tooth whiteness. Treatment groups were compared using analysis of covariance with the baseline shade as the covariant. Comparisons to baseline were 1-sided, while between-group comparisons were 2-sided using a 5% significance level. Both treatments were effective overall in improving the shade of tetracycline-stained teeth. Relative to baseline, the 2 groups averaged approximately 4 to 6.5 units of shade improvement after 2 months of treatment. Observed changes were greater on average after 2 months as compared to 1 month. Response was faster in the strip group. During the first month’s treatment, individuals in the strip group averaged greater than a 4-unit reduction in tooth shade, which represented a highly statistically significant (P < .0001) improvement vs. baseline. In contrast, subjects in the tray group averaged less than a 1-shade reduction during the first month, not differing statistically from baseline (P > .10). Adjusting for baseline, the strip group averaged 2.6 to 3.2 units more shade reduction compared with the tray group control. With respect to between-group comparisons, the strip group experienced statistically significantly superior reductions (P < .01) in shade compared with the tray group at both the 1- and 2-month time points. 210

This study confirms early observations of the need for extended contact time in many tetracyclinestained patients. After 2 months of daily treatment, involving approximately 60 hours of strip use or 120 hours of tray use, no subjects had yet reached the predetermined bleaching cutoff (B1-). In these subjects, additional time may be necessary to affect maximum color change. Previous reports suggest a minimum of 2 months of treatment, hence the time point elected in this study. This data demonstrates the difficulty, regardless of the delivery system, in bleaching tetracyclinestained teeth. This confirms that the peroxide does penetrate to the dentin and that the oxidation process affects the color of the stained dentin. It also confirms that this is a slow process and requires extended exposure.

Chapter 7 is the continuation of the 2 month study described in Chapter 6. Chapter 6 was the published data from the first 2 month of this 6 month study. A variety of indications exist for bleaching single or multiple teeth, including tetracycline staining. The primary objective of this study was to evaluate clinical response following extended daily use of a trayless 6.5% hydrogen peroxide tooth bleaching gel on tetracycline stain. In this research, 10% carbamide peroxide in an at-home daytime tray delivery system was used for comparison purposes. As in Chapter 6 this is a single-blind clinical trial, subjects were randomly assigned to a Strip group (30 subjects) or a Tray group (10 subjects) following screening for tetracycline staining. Subjects used their respective products for approximately 6 months, with clinical safety and efficacy measurements taken at the end of each month. The strip product was used for 30 minutes, twice daily (maxillary arch only). The tray product was used for 2 hours daily (maxillary arch only). Treatment efficacy was determined by the tooth color change from baseline using an expanded Vita Shade guide. The Strip group averaged greater shade reduction compared to the day wear Tray group at the Months 1, 2, and 3 visits, respectively. After Month 3, there were no significant between-group differences in shade. Of the subjects in the Strip group, 65% reached B1 tooth color by Month 6, while 43% of subjects in Tray group obtained this result after 6 months. Both treatments were generally well tolerated. Mild and transient tooth 211

sensitivity (40-47%) and oral irritation (30-47%) were the most common adverse events associated with daily bleaching, yet neither affected study participation. Both the 6.5% H2O2 experimental bleaching strip and daywear marketed tray-based carbamide peroxide system provided significant tooth whitening in subjects with tetracycline stain. The Strip group obtained the results in a shorter time compared to the daywear tray group.

In this study, onset of shade improvement was earlier, and the magnitude of the change was greater with strips compared to trays. Through Month 3, the strip group exhibited a statistically significant (p < 0.05) 1.3 to 3.2 shade improvement relative to the tray control. What accounted for the significant between-group differences in shade improvement seen early in treatment? One

likely explanation is that twice a day use of a strip for 30 minutes applied a higher concentration of peroxide more frequently compared to 2-hours of continuous tray use of the lower concentration carbamide peroxide gel. Other factors could have contributed to these findings, including the small sample size in the tray group, differences in the tetracycline staining at baseline, and/or compliance (strips versus the day wear regimen used for the trays). However, shade guides represent an imperfect measure of efficacy, especially for complex clinical presentations like those seen with tetracycline staining. As such, the comparative effectiveness of outcomes must be evaluated with caution because causality cannot be assessed from multi-factorial research like this clinical trial. This study provides new evidence of an expanded safety in-use with strip-based tooth whitening. Both bleaching systems in this trial were well tolerated with daily use over a 6-month treatment period. No subjects in either group discontinued treatment early due to product-related adverse events. For the tray system, these findings corroborate other reports of safe continuous daytime use of 10% carbamide peroxide on tetracycline stain
23,24

. The research provides additional

assurance of the clinical safety of this 10% carbamide peroxide tray system with conventional use over a few weeks, and longer term use for treatment of tetracycline staining. For the strip system, the findings provide first evidence of in-use clinical safety with extended treatment. Long term clinical trials of this duration may be particularly relevant in establishing clinical safety associated 212

with routine treatment, as a research model that evaluates extreme (intentional or unintentional) use. Such research may only be appropriate with populations such as this one, where long-term treatment is common and/or necessary to achieve a desired endpoint, where ethical and experimental controls are adequate to interpret outcomes, and where rigorous and sufficient exit criteria are established to assure in-use safety. Under these conditions, longer duration trials

represent a ―torture test‖ of sorts, offering additional insight on short-term clinical safety. Tetracycline staining is complex, and may necessitate extensive esthetic intervention. Vital

bleaching with professional tray or strip systems can yield an evident improvement in appearance within a few weeks. This non-invasive treatment may need to continue over an extended period. Some individuals will show favorable response after 3-4 months, after which treatment may be discontinued. Duration may be difficult to predict, given the variable clinical manifestations of

tetracycline staining. This study confirms that hydrogen peroxide will penetrate enamel and oxidize dentin. Even with long term exposure to these various whitening regimens no adverse results were noted.

In Chapter 8 we explore a new delivery system for tooth whitening. This is one of the first studies to do a direct comparison of two paint-on delivery systems. The latest inclusion to OTC products is a Brush technique. This technique is non-tray based paint on application. These products include a 19% sodium percarbonate film (5.3% hydrogen peroxide) along with an 18% carbamide peroxide paint-on gel. The advantages to the paint- on products are ease of use as well as the elimination of the need for a tray. These systems also limit gingival exposure. There is little data on efficacy of these products. The objective of this trial was to compare the safety and whitening efficacy of an experimental liquid strip (four weeks of use) to Colgate Simply White (three weeks of use). This was a randomized, controlled, double-blind, parallel, single-center study. Fifty (50) generally healthy subjects who desired to have their teeth whitened were enrolled in the study. Subjects who qualified for the study based on the results of their Baseline visit were randomly assigned to one of 213

two treatment groups. Data was obtained using a HC2500 CCD high resolution digital camera manufactured by Fuji. It was equipped with a Fujinon A8x12BMD, 1:2.8/12-96mm zoom lens and a linear polarizer to permit cross-polarized light. Two 150-watt lights located on each side of a CCD camera provided the lighting. The unit was connected to a personal computer which recorded and analyzed the images. Prior to daily use, the system was calibrated to assure proper operation. Additionally, a color standard was centered and imaged every hour, and then was removed prior to imaging subjects. Maxillary anterior facial surfaces were measured for tooth color using the digital image technology. One color value (L* a* b*) was generated from the complete surface of the measured teeth.

At the Week 4 visit, only the Experimental Film group was effective in whitening teeth as measured by mean change in L* (lightness) from Baseline (p-value < 0.0001 from Table 7). The Experimental Film group provided more than 4 times greater improvement in lightness (L*) when compared to the Colgate Simply White group with estimated means and standard errors of 1.065± 0.135 and 0.263 ± 0.146, respectively. The treatment comparison for L* was statistically significant (p-value = 0.0003 from Table 12). Only the Experimental Film group effective in whitening teeth as measured by mean change in a* (redness) from Baseline (p-value = 0.0003 from Table 8). The Experimental Film group provided more than 3.8 times greater improvement in redness (a*) when compared to the Colgate Simply White group with estimated means and standard errors of –0.397 ± 0.072 and –0.104 ± 0.078, respectively. The treatment comparison for a* was statistically significant (p-value = 0.0099 from Table 13). Both treatments were effective in whitening teeth as measured by mean change in W* (composite whiteness) from Baseline with p-values ≤ 0.0029 (Table 9). The Experimental Film group provided more than 4.2 times greater improvement in composite whiteness (W*) when compared to the Colgate Simply White group with estimated means and standard errors of –1.385 ± 0.146 and –0.325 ± 0.158, respectively. The treatment comparison for W* was 214

statistically significant (p-value < 0.0001 from Table 14). Both treatments were effective at increasing overall color change (E*) with p-values < 0.0001 (Table 10). The Experimental Film group provided more than 1.9 times greater overall color change (E*) when compared to the Colgate Simply White group with estimated means and standard errors of 1.534 ± 0.147 and 0.788 ± 0.160, respectively. The treatment comparison for E* was statistically significant (p-value = 0.0020 from Table 15). This study indicated that the 19% sodium percarbonate film (5.3% hydrogen peroxide) paint-on whitening product was affective in whitening teeth, however neither system tested was as affective as the tray or strip systems previously tested.

In Chapter 9 we explore the rebound that occurs post bleaching as well as methods to limit its affect. A randomized, parallel, examiner-blind clinical study was conducted to examine the ability of 2 toothbrushes to maintain teeth whitening after at-home bleaching. Forty subjects used a 15% carbamide peroxide tray bleaching system at home for 2 weeks per the manufacturer’s instructions and then were randomly assigned to use either the Sonicare® Advance power toothbrush or a manual toothbrush as part of their home oral hygiene routine for 6 months. The color of the labial surfaces of the subjects’ maxillary anterior dentition was assessed before bleaching and immediately, 2 months, 3 months, and 6 months after bleaching. Color was assessed by comparison with Vita® Classical shade tabs and by digital image analysis in the CIE L*a*b* color space. Both groups demonstrated a rebound effect at the 2-month visit and beyond, with mean Vita shade scores significantly higher than immediately after bleaching. At the 6-month evaluation, there was a significant difference in the amount of rebound in each group. Specifically, the rebound of the Sonicare brush group was on average 1.12 Vita shades less than that of the manual brush group. The 6-month difference was confirmed through digital image analysis, with the Sonicare brush group 4.8 L* units lighter, corresponding to 2 Vita shades, and 2.1 b* units less yellow than the manual brush group. This clinical trial demonstrates that the Sonicare Advance toothbrush better maintains whitening after bleaching treatment than a manual toothbrush. 215

The analyses of the digital images and the Vita shade data both show the Sonicare toothbrush to be superior to a manual toothbrush at maintaining whitening 6 months after bleaching. While this is the first study examining the effect of Sonicare on maintaining whitening, there are other data on the effect of a manual toothbrush. Matis and colleagues, for example, report an increase of 5.2 L* units and 2.9 shade guide units only 6 weeks after a 2-week bleaching regimen using 15% carbamide peroxide. Our results show a more modest but still measurable rebound effect for manual brushing. The estimated 6-month Vita shade difference between groups was larger in the digital analysis (2 Vita shades) than in the Vita shade analysis (1.12 Vita shades). This difference in estimates may be the result of the varying precision and accuracy of the 2 efficacy measures. We additionally note that the ordering of the Vita Classical shade guide does not follow the order suggested by digital image analysis of the shade tabs. In particular, ranking the tabs by decreasing luminance L*, that is the pure value axis of the L*a*b* color sphere, suggests not only that the color tabs are incorrectly ordered but also that the color change between tabs is nonlinear. Similar observations have been reported by O’Brien and colleagues and Paravina and colleagues. These factors also may contribute to the difference in estimates between the 2 efficacy measures. This study is important in a number of ways. It confirms that post bleaching rebound occurs as soon as 1 month after bleaching and this rebound continues at a slower rate up to 6 month. Secondly this data questions the degree of rebound reported in other studies. Finally this study brings in question the adequacy of the value ordered shade guide in its present form for bleaching studies.

In Chapter 10 an in vitro study was performed to measure the temperature increase in pulp chamber produced by Zoom light (mercury halide) and to investigate the influence of this light in conjunction with the application of bleaching gel on the intrapulpal temperature. The Zoom! Light was designed specifically for tooth bleaching. The results achieved by this study indicate that although previous reports showed significant temperature rise on the tooth surface our results demonstrate that the intrapulpal temperature increases only slightly during the exposure time. Therefore the Zoom light was found to cause only a slight increase in intrapulpal temperature. The 216

use of the light and gel demonstrated a significantly higher temperature increase than the light alone. However, this increase is still lower than the necessary to cause pulpal damage (5.5 °C). The sensitivity noted during light activated bleaching is most probably increase dehydration on the surface of the tooth. This may relate to 5°C surface temperature change previously reported on the enamel surface. Finally this study supports the clinical observation that light activated bleaching does not result in long term pulp damage and it suggests that the sensitivity noted during light activated tooth whitening may be the result of dehydration and not pulpal irritation.

In Chapter 11 an exploratory study was done to assess any surface morphological changes in tooth enamel after treating with a currently marketed hydrogen peroxide strip bleaching system and a currently marketed sodium chlorite tray-based system using an SEM Investigation. This study represents the first paper to evaluate enamel following tooth whitening using both visual analysis and laser profolometry. In this study the use of a visual scoring system for changes on enamel morphology indicated that there were no significant changes from the baseline in either the 6% Hydrogen Peroxide gel group or the 2.5% Sodium Chlorite group. It was also noted that in all evaluations the roughness observed was superficial in nature and that all teeth varied slightly at baseline. The laser profilometry data indicated that there is no statistical difference between the baseline and 21 day samples. This is true for both tooth whitening systems. In both groups the 21 day dosing has no effect on surface roughness of the exposed teeth. Using two different measurement techniques the results from both tests have the same conclusion that 21 day exposure to two different tooth whitening systems had no observable or measurable adverse effects on enamel.

Conclusions and Recommendations
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The following conclusions and recommendations may be drawn from our studies on tooth whitening: 1. The use of a low dose delivery system is adequate to get significant whitening. 2. The use of a polyethylene strip containing 5.3% hydrogen peroxide 30 minutes twice per day results in significant whitening. 3. This research provides clear evidence of a peroxide concentration whitening response. Whitening efficacy was greatest for the highest concentration group while the intermediate concentration group had an intermediate response. This effect most approached linearity at the earliest time point (Day 7). 4. This clinical research provides evidence of a concentration gradient for whitening response following use of a low peroxide dose whitening system. As such, this may represent a first example of concentration ranging for one of the self-directed bleaching systems. There is a measurable concentration affect during bleaching. 5. The use of a light and/or heat to speed up the oxidation process in tooth whitening is of no benefit. This was tested using the Halogen. Gas Plasma and Metal Halide light sources. Dehydration appears to cause the initial improvement that is noted immediately post bleaching. 6. The use of a mercury halide light for tooth whitening does not result in pulpal temperatures that would cause irreversible pulp damage but might be able to result in dehydration of exposed teeth. 7. Our data demonstrates the difficulty, regardless of the delivery system, in bleaching tetracycline stained teeth. This confirms that the peroxide does penetrate to the dentin and that the oxidation process affects the color of the stained dentin. It also confirms that this is a slow process and requires extended exposure. 8. Long term exposure (6 month continuous use) to either 10% carbamide peroxide in a tray system or 6.5% hydrogen peroxide strip resulted in no serious adverse events. This study

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represents the largest sample size for this type of study and the first to use the strip delivery system. 9. Paint-on whitening systems vary in effectiveness and none of those tested equal the efficacy found with the tray or strip systems. 10. Post bleaching rebound occurs as soon as 1 month after bleaching and this rebound continues at a slower rate up to 6 month. 11. The adequacy of the value ordered shade guide in its present form for bleaching studies is inadequate. This ordering on the shades is incorrect when checked using digital L*a*b* analysis. The ADA needs to re-evaluate its requirement for this method of evaluation in order to obtain ADA approval for tooth whitening systems. 12. Tooth whitening systems tested had no observable or measurable adverse effects on enamel.

Acknowledgements
I wish to express my sincere gratitude to all who contributed to this work.

Prof. Dr Marco Ferrari who has supported me in many ways both as a friend and fellow researcher. He has encouraged me to complete this thesis and pushed me to become a better scientist, as he pushes himself. He has always been there when I have needed advise and I value him dearly. Prof. Dr C.L. Davidson who has inspired me as a researcher and who I am always trying to emulate in both my research and in my life. Dr. Robert Gerlach, my good friend and fellow researcher. We have spent many hours discussing our projects and he is a constant source of advice and friendship. Dr’s Ferreria and Sharma who are wonderful young investigators always willing to help and always wanting to learn. 219

Isabella Desir, my staff assistant, who is willing to put in long hours and always with a smile. To my family that has always been there when I need them and support me in every way. To my wife, Karen, who has been with me through it all and is a constant source of inspiration to me. My children, Kurt and Chrissy; they put life in perspective. My family is most important to me and I apologize to all of them for the hours of travel and study that have kept me from them.

I would also to thank the members of the committee, Prof Piero Tosi, Rector of the University of Siena, to Prof Alberto Auteri, Dean of the Faculty of Medicine, University of Siena, to Prof Egidio Bertelli, vice-Dean of the Faculty of Medicine and Director of the Department of Dental Science, and to Prof Marco Ferrari, Pro-Rector for international affairs and President of Dental School, University of Siena for their support with this thesis.

CURRICULUM VITAE Gerard Kugel, D.M.D., M.S., F.A.C.D., F.I.C.D., F.A.G.D., F.A.D.M. 171 Burlington Street Lexington, MA 02173 (781) 861-1935 EDUCATION Tufts University School of Dental Medicine Boston, Massachusetts D.M.D., Ph.D. Program, 1981-1985 D.M.D., 1985 Sackler School of Graduate Biomedical Sciences Department of Anatomy and Cellular Biology Tufts University Boston, Massachusetts M.S., 1993

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Cornell University Graduate School of Medical Sciences Department of Neurobiology New York, NY Ph.D. candidate, 1977-1979 (transferred) Rutgers University New Brunswick, NJ B.S. Biology and Psychology 1976 Associate Dean for Research Tufts University School of Dental Medicine Boston, Massachusetts March 2001 – Present Visiting Professor, Restorative Dentistry University of Siena, Siena, Italy 1993 - Present Head of the Division of Operative Dentistry Tufts University School of Dental Medicine Boston, Massachusetts April 1988 – Present Private Practice Boston Center for Oral Health 400 Commonwealth Avenue Boston, Massachusetts 02115 September 1988 – Present

WORK EXPERIENCE

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PUBLICATIONS Kugel G, PapathanasiouA, Williams III A J, Anderson C, Clinical Evaluation of Chemical And Light-Activated Tooth Whitening Systems, Compendium Accepted July 2004. Ferrari M, Kugel G, Cagidiaco M C, Barker M L, Gerlach R W, Clinical Trial Evaluating the Peroxide Concentration Response of Whitening Strips Over 28 Days, Am J Dent. In Press Kugel G, Gerlach R W, Aboushala A, Susana Ferreira-Martin, Marco Ferrari,The Long term use of 6.5% Hydrogen Peroxide Bleaching Strips on Tetracycline Stain: A controlled Clinical Study, J of Esth and Rest Dent, May-04. Accepted Kugel G, What You Need to Know When Choosing a Material, Dentist’s Money Digest, pages 24-25, April 2004 Kugel G, Aboushala A, Sharma S, Ferreira S, Anderson C, Maintenance of Whitening with a Power Toothbrush After Bleaching Treatment, Compendium, Vol. 25, No. 2, pages 119131, February 2004. Ferreira S, Kugel G, A Simple Review of LED Curing Lights, Contemporary Esthetics and Restorative Practice, pages 52-56, November 2003. Aboushala A, Kugel G, Meta N, Using a Novel Bite Plate to Alleviate Chronic Bruxism Symtoms, Contemporary Esthetics and Restorative Practice, Vol 7, No. 10 Pages 72-78, October 2003 Zhang Q, Rosenberg M, Kugel G, Agarwal R, Phillips j, Kumar S, Effect of Nitrous Oxide on Intracellular Events of GT1-7 GnRHsecreting Neurons, Anesth Prog 50:53-61, 2003 Zhang Q, Bratton G, Agarwal R, Calise D, Kugel G, Wan Y, Kumar A, Lead-induced cell singnaling cascades in GT1-7 cells, Brain Research Bulletin, 61, pages 207-217, 2003 Kugel G, Perry R, Restoring Anterior Maxillary Dentition Using Alumina and Zirconia –Based, Compendium, Vol. 24, No. 8, pages 569-580, August 2003. Zhang Q, Bratton G, Agarwal R, Calise D, Kugel G, Wan Y, Kumar A. Lead-induced cell signaling cascades in GT1-7 cells, Brain Research Bulletin Vol. 61, No. 207-217, April 2003

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Kugel G, Over-the-Counter Toothwhitening Systems, Compendium Vol. 24, No 4A. April 2003 Fabianelli A, Kugel G, Ferrari Marco, Efficacy of self-etching primer on sealing margins of Class II restorations, American Journal of Dentistry Vol 16, No.1, pages 37-41, February 2003. Kugel G, Perry R, Direct Composite Resins: An Update, Compendium. Vol. 23, No. 7. July 2002. Kugel G, Boghosian A. Impact of the Sonicare® Toothbrush on Plaque and Gingivitis, Compendium. Vol. 23, No. 7. July 2002. Suppl. 1 Kugel G, Boghosian A. Effects of the Sonicare® Toothbrush for Specific Indications, Compendium. Vol. 23, No. 7. July 2002. Suppl. 1 Papathanasiou A, Kastali S, Perry R, Kugel G, Clinical Evaluation of a 35% Hydrogen Peroxide In-Office Whitening System, Compendium. Vol. 23, No. 4. April 2002. Perry R, Kugel G, Success with Inlays/Onlays: The Seven Essentials, Compendium. Vol 23, No. 3. March 2002. Gheewalla E, Perry R., Kugel G, Effects of Three Electric Toothbrushes on Orthodontic Bracket Retention, Journal of Clinical Orthodontics, Volume XXXVI No. 2, January 2002 Fabianelli A, Kugel G, Ferrari M. Efficacy of self-etching primer on sealing margins of CI II restorations. American Journal of Dentistry. Accepted 2002. Ferrari M, Cagidiaco M, Kugel G, Dolci G. Evaluation concentration response after 4 weeks treatment with a flexible, polyethylene whitening strips. Compendium/Special Issue Volume 22, No. 2, 2001. Kugel G, Aboushala A, Zhou X, Gerlach R. Daily Use of Whitening Strips on Tetracycline-Stained Teeth: Comparative Results After 2 Months. Compendium Volume 22, No. 2, 2001.

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Kugel, G., Garcia-Godoy F., Direct Esthetic Adhesive Restorative Materials A Review. The Indian Dentist, No. 7-13, 21, April – June 2001 Papathanasiou A., Bardwell D, Kugel G., A Clinical Study Evaluation a New Chairside and Take-Home Whitening System. Compendium of Continuing Education in Dentistry, Volume 22, No. 4:289-300, April 2001 Goracci C., Gheewalla R., Kugel G., Ferrari M., Orthodonticrestorative treatment of chipped or worn incisors. American Journal of Dentistry, Volume 14, No. 50-55, February, 2001 Kugel G., Provisional Esthetic Enhancements Following Initial Treatment to Correct Anterior Wear, Esthetic Technique, Volume 1, No. 1:3-7, April 2001 Leinfelder K, Kugel G., Flowable Compomers, Dialogues in Esthetic Dentistry, Volume 2, No. 1:7-8, April 2001 Javaheri DS, Kugel G., Janis JN. Current Status of At-Home Bleaching. Practical Procedures and Aesthetic Dentistry, Volume 13, No. 1:10-13, January/February 2001 Perry R, Kugel G. Two-Year Clinical Evaluation of a HighDensity Posterior Restorative Material. Compendium of Continuing Education in Dentistry, Volume 21,No. 12:10671080, December 2000 Weinstock E, Skoulas A, Kugel G, Aboushala A. The Myth of Dentist-Patient Confidentiality. Compendium of Continuing Education in Dentistry, Volume 21, No. 12:1056-1064, December 2000 Kugel G. Direct and Indirect Adhesive Restorative Materials: A Review. American Journal of Dentistry, Volume 13, Special Issue, No. 35-40, November, 2000.

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Kugel G, Garcia-Godoy F. Direct and Indirect Esthetic Adhesive Restorative Materials: A Review. Dental News, Volume VII, Number 3:29-39, 2000 Perry R, Kugel G, Kunzelmann KH, Flessa HP, Estafan D. Composite Restoration Wear Analysis: Conventional Methods vs. Three-Dimensional Laser Digitizer. JADA, Vol. 131, No. 10:, p.1472-1477, October 2000. Papathanasiou A, Bardwell D, Kugel G. Combining In-Office and Take-Home Whitening Systems. Contemporary Esthetics and Restorative Practice. Vol. 4. No. 8: 88, September 2000 Kugel G, Garcia-Godoy, F. Direct Esthetic Adhesive Restorative Materials: A Review. Contemporary Esthetics and Restorative Practice. Vol. 4. No. 9: 6-10, September 2000. Kugel G, Kastali S. Tooth-Whitening Efficacy and Safety: A Randomized and Controlled Clinical Trial. Compendium 21, S29, 16-21, July 2000 Kugel G. Nontray Whitening. Chairside: Compendium. Vol. 21, No. 6, 524-528, June 2000. Kugel G, Ferrari M. The Science of Bonding: From First to Sixth Generation. JADA, Vol. 131:20S-25S, June 2000.
Kugel G, Perry R, Ferrari M, Lalicata P. Disinfection and Communication Practices: A Survey of U.S. Dental Laboratories. JADA, Vol. 131:786-792, June 2000.

Zervou C, Kugel G, Leone C, Zavras A, Doherty E. Enameloplasty Effects on Microleakage of Pit and Fissure Sealants Under Load: an In-Vitro Study. The Journal of Clinical Pediatric Dentistry. 24(4): 279285, April 2000 Ferrari M, Mannocci F, Mason PN, Kugel G, In vitro leakage of resin-bonded all-porcelain crowns. Journal of Adhesive Dentistry, 1:3:233-242, 1999. Kugel G, Swift EJ, Sorenson JA, Dunne JT, Tucker JH. A prospective clinical evaluation of electronically mixed polyvinyl siloxane impression materials. Compendium, S24:2-22, 1999.

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Petridis H, Hirayama H, Kugel G, Habib C, Garefis P. Shear bond strength of techniques for bonding esthetic veneers to metal. Journal of Prosthetic Dentistry, 82:5:608-614, 1999. Ferrari M, Cagidiaco MC, Kugel G, Davidson CL. Clinical evaluation of a one-bottle bonding system for desensitizing exposed roots. American Journal of Dentistry, 12:5:243-249, 1999. Kugel G, Perry R, Hoang E, Hoang T, Ferrari M. Dyract Compomer: Comparison of Total Etch vs. No Etch Technique. Journal of the Academy of General Dentistry, Volume 46, Number 6:604-606, Nov-Dec 1998. Kugel G. Clinical Testing of Surefil. Journal of International Dental Symposia, 5:7, 1998. Ferrari M, Mason PN, Fabranelli A, Mannocci F, Kugel G, Davidson CL. Influence of Tissue Characteristics at Margins on Leakage of Class II Indirect Restorations, Accepted, American Journal of Dentistry, 1998. Ferrari M, Kugel G. Handling of Composites in Posterior Teeth, Compendium, 19:879-892, 1998. Kugel G, Ferrari M. AelitefloTM. To Base or Not to Base, There Is No Question!, Restorative Quarterly, 1:7, April 1998. Karuri AR, Kugel G, Engelking LR, Kumar MSA. Alterations in Catecholamine Turnover Rate in Specific Regions of the Rat Brain Following Acute Exposure to Nitrous Oxide, Brain Research Bulletin, 45:557-561, 1998. Kugel G, Minimale Präpartion für Frontzahnrestaurationen (Minimal Preparation for Anterior Restorations), Phillip Journal, 14:383-384, 1997. Donly K, Vargas M, Meckes M, Sharma A, Kugel G, Hurley E. InVitro Comparison of Restoration Wear and Tensile Strength Following Extended Brushing with Sonicare and Manual Toothbrushes, Journal of Clinical Dentistry, 8:1:30-35, 1997. Zammitti S, Habib C, Kugel G. Use of Environmental Scanning Electron Microscopy to Evaluate Dental Stain Removal, Journal of Clinical Dent, 8:1: 20-25, Winter 1997.

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Samadzadeh A, Aboushala A, Hurley E, Kugel G. A Comparison of Fracture Strength Between PMMA and Resin-Based Provisional Restorations Reinforced with Plasma-Treated Woven Polyethylene Fiber, Journal of Prosthetic Dentistry, 78:5:447-450, November 1997. Kugel G, Perry R, Putignamo A, Ferrari M. Valutazione clinica a due anni dello spectrumTPH nel restauro di lesioni cariose in cavità di classe II in denti permanenti.. Quintessence International, Settembre/Ottobre 1997. Ferrari M, Kugel G. Handling of Composites in Posterior Teeth, Compendium, 19:879-892, 1998. Kugel G. Buying Right, Journal of the Massachusetts Dental Society, 46:2:12-14, October 1997. Perry RD, Kugel G, Habib CM, McGarry P, Settembrini L. A Two Year Clinical Evaluation of TPH for Restoration of Class II Carious Lesions in Permanent Teeth, General Dentistry, 45: 4:344-349, July/August 1997. Ferrari M, Mannocci F, Cagidiaco MC, Kugel G. Short-Term Assessment of Leakage of Class V Composite Restorations Placed In Vivo, Clinical Oral Investigation, 1:2:61-64, June 1997. Kugel G, Perry R, Hoang E. Effective Tooth Bleaching in 5 Days: Using a Combined In-Office and At-Home Bleaching System, Compendium, 18:4:378-383, April 1997. Abdel-Latif M, Kugel G, Norris L, Kabani S. Nd: Yag Laser and Conventional Techniques in Bone Surgery, Cairo Dental Journal, 13:1:225-230, 1997. Kugel G. Classification and Application of Cementation Alternatives, Signature: The Art and Science of Modern Dentistry, Fall 1997. Ferrari, M, Cagidiaco, Kugel G, Davidson CL. Dentin Infiltration by Three Adhesive Systems in Clinical and Laboratory Conditions, American Journal of Dentistry, 9:6:240-244, December 1996. Weiner RS, Weiner LK, Kugel G. Teaching the Use of Bases and Liners: A Survey of North American Dental Schools, JADA, 127:11:1640-1645, November 1996.

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Kugel G, Perry RD, Habib CM, McGarry P. A Two Year Clinical Evaluation of Pertac Hybrid for Restoration of Class II Carious Lesions in Permanent Teeth, Compendium, November 1996. Ferrari M, Cagidiaco MC, Kugel G. Leakage of Class V Resin Composite Restorations Placed in Vivo, American Journal of Dentistry, October 1996. Aboushala A, Kugel G, Hurley E. Class II Composite Resin Restorations Using Glass-Ionomer Liners: Microleakage Studies, Journal of Clinical Pediatric Dentistry, 21:1:67-70, Fall 1996. Agawal RK, Kugel G, Karuri A, Gwosdow AR, Kumar, MSA. Effects of Low and High Doses of Nitrous Oxide on Preproenkephalin on RNA and Its Peptide Methionine Enkephalin Levels In the Hypothalamus, Brain Research, 730:1,2:47-51, August 1996. Ferrari M, Cagidiaco MC, Kugel G. All -Ceramic Fixed Restorations: A Preliminary Clinical Evaluation, Practical Periodontics Aesthetic Dentistry, 8:1:73-80, Jan-Feb 1996. Habib C, Smith S, Kugel G, Aboushala A. Dimensional Stability of Elastomeric Impressions After Long-Term Disinfection, Journal of Prosthetic Dentistry, January 1996. Ferrari M, Kugel G. IPS - Empress Crowns: Clinical Reports, Practical Periodontics and Aesthetic Dentistry, 1996. Kugel G, Bardwell DN. Restoration of a Class V Lesion Using a New Compomer Material, Signature: The Art and Science of Modern Dentistry, 14-17, November 1995. Kugel G. The Changing Face of Oral Health Care, Feature Article, Tuftonia, 27, Spring 1994. Ferrari M, Dalloca L, Kugel G, Bertelli E. An Evaluation of the Effect of the Adhesive Luting on Microleakage of the IPS Empress Crowns, Practical Periodontics and Aesthetic Dentistry, 6:4:15-24, May 1994. Fischman SL, Kugel G, Truelove RB, Nelson BJ, Cancro LP. The Motivational Benefits of a Dentifrice Containing Baking Soda and Hydrogen Peroxide Used, The Journal of Clinical Dentistry, 3:3 8892, 1992.

228

Russell DA, Kugel G. Preceptor Program: An Alternative Mode of Instruction for the Slowly Progressing Dental Student, Journal of Dental Education, 55:1:36-37, January 1991. Champion MA, Kugel G, Gruskowski C. Evaluation of a New Intraoral Isolation Device, Operative Dentistry, 16:181-185, 1991. Kugel G, Zive M, Agawal RK, Beumer JR, Kumar AM. Effects of Nitrous Oxide on the Concentration of Opioid Peptides, Substance P, and LHRH in Brain and -Endorphin in the Pituitary, Anesthesia Progress, 38:206-211, 1991. Kugel G, Letelier M, Zive H, King JC. Nitrous Oxide and Infertility, Anesthesia Progress, 37:4:176-180, July 1990. Kugel G, Zive M, Norris L. Nitrous Oxide and Occupational Exposure, Journal of the Society for the Advancement of Anesthesia in Dentistry, 7:10:266-276, May 1990. Kugel G, Zive M, Norris L. N2O/O2 - It's No Laughing Matter, Review Article, Journal of the American Analgesia Society, 24:1:14-16, March 1990. Kugel G, Norris L, Zive M. Nitrous Oxide; Occupational Exposure: It's Time to Stop Laughing. Anesthesia Progress, 36:6:252-257, 1989. King J C, Kugel G, Zahniser D, Wooledge K, Damassa D, Alexsavich B. 3-D Analyses Reveal Changes in Populations of LHRH Cell Bodies Following Gonadectomy, Peptides, 8:721-735, August 1987. King JC, Lechan RM, Kugel G, Anthony ELP. Acrolein: A Fixative for - Immunocyto-chemical Localization of Peptides in the Central Nervous System, The Journal of Histo-chemistry and Cytochemistry, 31:1:62-68, January 1983.

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ABSTRACTS

Perry R, Kugel G, Shrama S, Ferreira S, Clinical Evaluation of a LED Curing Light, Journal of Dental Research, 83: 540 March 2004 Kugel G, Ferreira S, Sharma S, Barker M L, Garlach R W, Comparison of Daytime and Nighttime Brush-Applied Whitening Systems, Journal of Dental Research, 83:1912 March 2004 Papathanasiou A, Kastali S, Clinical Evaluation of a New AdhesiveComposite System, Journal of Dental Research, 83:538 March 2004 Petkevis J, Alfaro M, Doherty E H, Kugel G, Kanca J, Self-etch adhesive bond strength at two time intervals, Journal of Dental Research, 83: 465 March 2004 Bedi A, Hirayama H, Kugel G, Forgione A G, Surface Roughness and Irregularities of Castings using Different Iinvestment Techniques, Journal of Dental Research, 83: 1680 March 2004 Kugel G, Papathanasiou, Clinical Evaluation of Two Different In-office Tooth Whitening Systems, Journal of Dental Research, 28: 897 March 2003 Aboushala, A, Kugel G, Sharma S, Ferreira S, SonicareToothbrush Whitening Effect after Bleaching Treatment, Journal of Dental Research, 82: 614, March 2003 Anderson C, Kugel G, Aboushala, A, Sharma S, Ferreira S, Rebound Evaluation of Post-Bleaching Maintenance Utilizing Manual and Electric Toothbrushes; Quantitative Assessment by Digital Photography, Journal of Dental Research, 82: 605, March 2003 Kugel G, Aboushala, A, Zhou X, Gerlach R Six-month Continuous Use of Two At-home Professional Bleaching Systems on Tetracycline Stain, Journal of Dental Research, 82: 32, March 2003 Anderson C, Kugel G, Ferreira S, Aboushala, A, Sharma S, Six-month Rebound Evaluation of Subjects Treated with a 15% Carbamide Peroxide Gel; Quantitative Assessment by Standard Digital Photography, Journal of Dental Research, 82: 1303, March 2003 Perry R, Papathanasiou A, Kugel G, Davidiian E, A Comparison of Two Flowable Composite Materials in Posterior Restorations Journal of Dental Research, 82: 256, March 2003

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Watts R, Joffre E, Doherty E, Kugel G, Shear Bond Strength Investigation of an Experimental Self-etching Bonding System, Journal of Dental Research, 82: 566, March 2003 Anderson C, Kugel G, Perry R, Garcia-Godoy F, Evaluation of an Experimental One-Step Composite Polishing System, Journal of Dental Research, 81: 1267, March 2002 Anderson C, Sethi S, Kugel G, Perry R, Garcia-Godoy F, Comparison of Surface Gloss and Time by Three Composite Polishing Systems, Journal of Dental Research, 81: 1273, March 2002 Kugel G, Aboushala A, Zhou X, Gerlach R W, Use of Whitening Strips on etracycline: Results after four months, Journal of Dental Research, 81: 2442, March 2002 Kim M S, Reusch B, Hoffmann H, Doherty E H, Kugel G, Surface Wettability of Saliva and Blood Plasma During Setting of Impression Materials, Journal of Dental Research, 81: 2660, March 2002 Nguyen T, Doherty E H, Aboushala A, Kugel G, Perry R, Effect of Chemomechanical Caries Removal System on Microleakage of Composite Resin Restorations, Journal of Dental Research, 81: 3391, March 2002 Anderson C, Kugel G, Rebound Evaluation of Tetracycline Stained Subjects Treated with a 6.5% Hydrogen Peroxide Gel; Quantitative Assessment by Standard Digital Photography, Journal of Dental Research, 81: 3488, March 2002 Perry R, Gheewalla E, Kugel G, A Comparison of Three Electric Toothbrushes on Orthodontic Bracket Retention, Journal of Dental Research, 80: 590, 2001 Kim MS, Doherty EH, Kugel, G, Flow Under Pressure of Four Impression Materials Using Shark-Fin Device, Journal of Dental Research, 80: 624, 2001 Kastali S, Papathanasiou A, Perry R, Kugel G, Clinical Evaluation Of A Light To Heat Activated Bleaching System, Journal of Dental Research, 80: 926, 2001

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Kugel G, Kastali S, Sagel P, Gerlach R, Six-Month Clinical Response with Whitening Strips: Comparison to Placebo, Journal of Dental Research, 80: 1174, 2001 Lokko NN, Kugel G, Habib C, Doherty E, Rand W, In Vitro Bond Strength Evaluation of Resin, Modified Glass Ionomer Cements, Journal of Dental Research, 80: 1304, 2001 Verdier A, Kugel G, Habib C, Comparison of Surface Finish Produced on Resin Composites following Extended Brushing With A Manual Toothbrush and Sonicare, Journal of Dental Research, 80: 1337, 2001 Perry R, Kugel G, Aboushala A, Two-Year Clinical Evaluation of a HighDensity Posterior Restorative, Journal of Dental Research, 79:158, 2000. Fabianelli A, Vichi A, Kugel G, Ferrari M, Influence of Self-etching Priming Bonding Systems on Sealing Ability of Class II Restorations: Leakage and SEM Evaluation, Journal of Dental Research, 79:305, 2000. Bardwell D, Habib C, Kugel G, Mehta N, Leone C, Microleakage of Previously Restored Class II Restoratives After Exposure to 10% Carbamide Peroxide, Journal of Dental Research, 79:306, 2000. Kastali S, Papathanasiou K, Perry R, Kugel G, Clinical Evaluation of a New Hybrid Composite, Journal of Dental Research, 79:333, 2000. Zervou C, Kugel G, Leone C, Zavras A, Doherty E, White G.E., Enameloplasty and Load Effects on Microleakage of Sealants (in vitro), Journal of Dental Research, 79:1688, 2000. Papathanasiou K, Kastali S, Perry R, Kugel G, Clinical Evaluation of Light Cured Flowable Compomere in Class V Restorations, Journal of Dental Research, 79:1735, 2000. Rassovsky M, Hirayama H, Habib C, Kugel G, The Expansion of Various Luting Agents Used to Cement Post & Core: An in vitro study, Journal of Dental Research, 79:2327, 2000. Naidu K, Kugel G, Habib C, Class II Composite Restorations: Microleakage Using Three Different Curing Systems, Journal of Dental Research, 79:2466, 2000.

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Habib C, Kugel G, Effect of Aging on Three Enamel Dentin Adhesive Systems, Journal of Dental Research, 79:2475, 2000. Aboushala A, Kugel G, Efthimiadis N, Korchak M, Efficacy of a Computer-controlled Injection System of Local Anesthesia, in vivo, Journal of Dental Research, 79:2775, 2000. Aboushala A, Mehta N, Forgione A, Kugel G, Chapman R. Vertical Dimension and Electromyography of Masseters in Complete Denture Patients, Journal of Dental Research, 78:2911, 1999. Nam C, Kugel G, Habib C. Changes in Enamel Surfaces After Take Home Bleaching Treatment in vitro, Journal of Dental Research, 78:1695, 1999. Perry R, Kugel G. One-Year Clinical Evaluation of a High-Density Posterior Restorative, Journal of Dental Research, 78:1628, 1999.

Lalsingh C, Hurley E, Hassan M, Trushkowsky R, Kugel G, Leone C. Effects of Curing Lights on Microleakage in Class V Composite Restorations, Journal of Dental Research 78:1601, 1999. Papathanasiou A, Kastali G, Kugel G, Bardwell D, Hurley E. Microleakage Evaluation of Three Class II Composite Restorative Techniques in vitro, Journal of Dental Research 78:1600, 1999. Hurley E, Aboushala A, Perry R, Kugel G. Microleakage in Class II Restorations Using a New Posterior Composite, Journal of Dental Research 77:487, June 1998. Drukteinis S, Hurley E, Perry R, Kugel G. The Performance of Aluminum Oxide and Cojet Microetchant Systems, Journal of Dental Research 77:506, June 1998. Gheewalla E, Perry R, Kugel G. Effect of Powered Toothbrushes on Orthodontic Bracket Adhesion in vivo, Journal of Dental Research, 77:506, June 1998.

233

Kugel G, Karuri A, Kumar MSA. Alterations in the Cathecholamine Turnover Rate in Specific Regions of Rat Brain Following Acute Exposure to Nitrous Oxide, Journal of Dental Research 77:921, June 1998. Ferrari M, Mason PN, Fabianelli A, Kugel G, Davidson CL. Influence of Different Margin Substrates on Leakage of Class II Indirect Restorations, Journal of Dental Research 77:2248, June 1998. Aboushala A, Kugel G, Perry R, Leone C. Resin-Ionomer Restoration of Molar Furcations in Humans, Journal of Dental Research 77:2573, June 1998. Ferrari M, Cagidiaco MC, Kugel G, Davidson CL. Clinical Evaluation of SB1 Root Desensitization with/without Acid Etching. Journal of Dental Research 77:2586, June 1998. Ferrari M, Mannocci F, Innocenti M, Kugel G, Davidson CL. Clinical Evaluation of Dyract AP and Fuji IX to Build up Abutments for Porcelain Crowns, Journal of Dental Research 77:2598, June 1998. Kastali S, Kugel G, Perry R, Papathanassiou A. Combined In-Office and At-Home Bleaching Systems: An Evaluation, Journal of Dental Research 77:2604, June 1998. Perry R, Kugel G, Kastali S. Evaluation of a Non-Hydrogen Peroxide At-Home Bleaching System, Journal of Dental Research 77:2605, June 1998. Kugel G, Squier C. Fact vs. Fiction: The Transfer of Scientific Knowledge into the Dental Curriculum, Journal of Dental Research 77:4, March 1998. Aboushala A, Mehta N, Forgione A, Kugel G, Chapman R, Clark RE. Vertical Dimension and Electromyography of Sternocliedomastoids in Complete Denture Patients, Journal of Dental Research, 77:456, March 1998. Chafka A, Mehta N, Kugel G, Hayes C, Forgione A. Effect of Graded Increases in Vertical Dimension on Cervical Flexor Strength, Journal of Dental Research 77:735, March 1998. Kugel G, Lalicata PJ, Perry R. Survey of U.S. Dental Impression Materials and Techniques, Journal of Dental Research, 76:1343, March 1997.
234

Daryabegi Y, Perry R, and Kugel G. Differences Shear Bond Strength of Three Dentin Bonding System, Journal of Dental Research, 76:1387, March 1997. Fu A, Mehta N, Forgione A, Clark E, Hayes C, Kugel G. Abdallah E. Maxillomandibular Relationship in TMD Patients Before and After Short Term Bite Plate Therapy, Journal of Dental Research, 76:2363, March 1997. Hoang E, Kugel G. and Perry R. Combined in Office and Home Applied Bleaching System, Journal of Dental Research, 76:2476, March 1997. Perry R, Kugel G, McGarry P, Hurley E. An In Vivo Subcutaneous Investigation of a Resin-Ionomer, Journal of Dental Research, 76:2499, March 1997. Aboushala A, Mehta N, Forgione A, Kugel G. Chapman R. and Clark RE. Vertical Dimension Effects on Strenocleidomastoid Strength in Complete Denture Patients, Journal of Dental Research, 76:3185, March 1997. Bahram R, Aboushala A, Kugel G, Perry R. Compomer Effects on Microleakage in Class II Composite Resin Restorations, Journal of Dental Research, 76:3236, March 1997. Druktenis S, McGarry P, Aboushala A, Kugel G, Habib C. Effect of Adhesives on Microleakage Between Dentin and Light Cured Glass Ionomer Liners, Journal of Dental Research, 76:3238, March 1997. Yau L, Perry R, Kugel G. Three Body Wear of Light Cured Flowable Composites, Journal of Dental Research, 76:3276, March 1997. McSweeney T, Perry R, Aboushala A. Kugel G. Different Liners in Class II Composite Resin Restorations, Journal of Dental Research, 76:3283, March 1997. Vaughn V, Kugel G, Perry R, Noonan ST. Measuring Flow of Elastomeric Impression Materials Using the Shark Fin Device, Journal of Dental Research, 76:3292, March 1997. Ferrari M, Cagidiaco MC, Kugel G, Davidson CL. Dentin Infiltration by Three Adhesive Systems in Clinical and Laboratory Conditions, American Journal of Dentistry, 9:6, December 1996.
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Habib C, Smith C, Kugel G, Aboushala A. Comparison of Dimensional Stability of Elastomeric Impression After Immersion Disinfection, Journal of Dental Research, 75:357, March 1996. Sharma A, Kugel G, Hurley E. Evaluation of the Effect of Sonic and Manual Toothbrushes on Cemented Crowns, Journal of Dental Research, 75:361, March 1996. Samadzadeh A, Aboushala A, Kugel G. A Comparison of Fracture Strengths Between PMMA and Resin-Based Provisional Restorations Reinforced with Plasma-Treated Woven Polyethylene Fiber, Journal of Dental Research, 75:369, March 1996. Marcus A, Bender G, McGarry P, Kugel G. Comparison of Dental Cements Shear Bond Strength to a Semi-Precious Alloy Surface In Vitro, Journal of Dental Research, 75:398, March 1996. Vaughn V, Bardwell D, Kugel G, Perilli. Follow-Up Comparing Three Polishing Systems to Glazed Porcelain Utilizing Profilometry, Journal of Dental Research, 75:1038, March 1996. McSweeney T, Perry R, Kugel G. Profilometry Comparison of Polished Porcelain. Journal of Dental Research, 75:1039, March 1996. Bhatt A, Gheewalla E, Perry R, Kugel G. Comparison of a Compomer and Resin Cement for Bonding of Orthodontic Bracket, Journal of Dental Research, 75:1259, March 1996. Perry R, Kugel G, Kunzelmann KH, Flessa HP, Mehi A, Hickel R. A Composite Study of Wear Analysis Methods of In-Vivo Posterior Composite Restorations, Journal of Dental Research, 75:1910, March 1996. Lee K, Aboushala A, Kugel G. Microleakage of Class II Composite Resin Restorations Using Different Placement and Light Cure Techniques In Vitro, Journal of Dental Research, 75:2168, March 1996.

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Perry R, Kugel G, Kunzelmann KH, McGarry P. Two-Year Evaluation of a Hybrid Composite for Posterior Restorations. Journal of Dental Research, 75:2181, March 1996. Prezioso A, Kugel G, Perry R. Microleakage: A Comparison of Three Chairside Ceramic Repair Kits In Vitro. Journal of Dental Research, 75:2965, March 1996. Hoang E, Perry R, Aboushala A, Kugel G. Comparison of Microleakage Using Etched and Non-Etched Techniques in Class V Restorations, Journal of Dental Research, 75:2966, March 1996. Vaughn V, Aboushala A, Habib C, Kugel G. Comparison Between Two Sealants for Reducing Class II Composite Resin Microleakage In Vitro, Journal of Dental Research, 75:3017, March 1996. Beaber W, Arbree N, Kugel G. Pilot study: A Skin Protectant for Latex-Glove-Induced Dermal Sensitivity Reaction, Journal of Dental Research, 75:3185, March 1996. Smith N, Sharma A, Habib C, Perry R, Kugel G. Comparison of a Cordless Curing Light and a Single Unit Curing Light, Journal of Dental Research, 74:495, March 1995. Vaughn V, Bardwell D, Kugel G, Perilli R. Comparing Three Polishing Systems to Glazed Porcelain Utilizing Profilometry, Journal of Dental Research, 74:220, March 1995. Resnick S, Prezioso A, Kugel G, Smith C, McGarry P. Effect of Surface Treatments on Microleakage of Composite - Ceramic Repair, Journal of Dental Research,. 74:228, March 1995. Joseph A, Perry R, Kugel G, Smith C. Effects of Varying Concentrations of 4-META on Tensile Strength on Bonding Composite to Dentin, Journal of Dental Research, 74:495, March 1995. Morrill F, Galburt R, Kugel G, Habib CM. Comparison of Bond Strength Formed Between Amalgam and Composite by Varying the Ratio of Spherical to Lathe Cut Particle, Journal of Dental Research, 74: 743, March 1995. Zammitti S, Kugel G, Habib C. Environmental Scanning Electron Microscope Study Evaluating the Efficacy of a Sonic Toothbrush, Journal of Dental Research, 74:970, March 1995.
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Mehta N, Kugel G, Lamkin J, Bansal S, Forgione A. Effectiveness of Electronic Anesthesia in Controlling Pain During Periodontal Scaling, Journal of Dental Research, 74:972, March 1995. McSweeney T, Perry R, Kugel G. Tensile Strength of Dentin Bonding Agents With Different Acid Etch Preparations, Journal of Dental Research, 74:1107, March 1995. Supnet L, Bhatt A, Aboushala A, Bardwell D, Smith C, Kugel G. Microleakage of Three Experimental Dentin Primers With Altered HEMA Concentrations, Journal of Dental Research, 74:1112, March 1995. Perry R, Kugel G, Habib C, McGarry P, Champion M. TwoYear Evaluation of a Hybrid Composite for Posterior Restorations, Journal of Dental Research, 74:1224, March 1995. Kugel G, Court MH, Agarwal RK, Kumar MSA. Effects of Nitrous Oxide on Preproenkephalia mRNA and Methionine Enkephalin, Journal of Dental Research, 74:1309, March 1995. Bahram R, Kugel G, Mclure T, Habib C. Comparison of Polishability of Three Composite Materials, Journal of Dental Research, 74:1386, March 1995. Aboushala A, Kugel G, Habib C. Microleakage Class II Composite Restorations Using Glass Ionomer Liner, Journal of Dental Research, 74:1398, March 1995. Shayegan A, Aboushala A, Kugel G. Microleakage of Class II Composite Restoration Using a Glass Ionomer, Liner and Base, Journal of Dental Research, 74:1399, March 1995. Smith N, Gheewalla E, Kugel G, Habib C. Evaluation of Effects of a Sonic Toothbrush on the Bond Strength of Bonded Orthodontic Appliances, Journal of Dental Research, 74:1414, March 1995. Ferrari M, Kugel G, Davidson CL. In Vivo and In Vitro Hybrid Layer Formation, IADR-CED Meeting, Lubiana, 1995. Habib C, Smith C, Kugel G, Aboushala A. Dimensional Stability of Elastomeric Impressions After Long Term Disinfection, Journal of Dental Research, 73:409, 1994.

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Morrill F, Galburt R, Kugel G, Zive M, Habib C. Comparison of Different Shaped Particles of Amalgam Alloy Bonded to Composite and Dentin with 4-Methacryloxyethyl Trimellitate Anhydride, Journal of Dental Research, 73:221, 1994. Bahram R, Kugel G, Zive M, Habib C, Golden M. Comparison of Bond Strength of Two Dentin Bonding Systems to Radicular Dentin, Journal of Dental Research, 73:199, 1994. Mehta N, Kugel G, Al Shuria A, Sands M, Forgione A. Effect of Electronic Anesthesia T.E.N.S. on T.M.J. and Orofacial Pain, Journal of Dental Research, 73:358, 1994. Kugel G, Smith N, Sharma A, Habib C, Perry R. A Comparison of a Cordless Curing Light and a Single Unit Curing Light, Journal of Dental Research, 73:406, 1994. Zive M, Champion M, Kugel G. Marginal Microleakage Around Tooth-Colored Inlay Systems, Journal of Dental Research, 72:307, 1993. Ghazinouri R, Zammitti S, Zive M, Kugel G, Habib C. Microleakage Using a New Technique for Posterior Composite Restorations, Journal of Dental Research, 72:308, 1993. McGarry P, Kugel G, Habib C, Perry R. Clinical Evaluation of a Small Particle Composite to Treat Root Caries & Cervical Erosions, Journal of Dental Research, 72:349, 1993. Bellucci A, Kugel G, Habib C, Zive M. Adhesion Strengths of Four Luting Agents with Various Core Buildup Materials, Journal of Dental Research, 72:361, 1993. Habib C, Kugel G, Herr K. Two-Year Evaluation of Composite Restoration of Root Surface Caries After Chemo-Mechanical Excavation, Journal of Dental Research, 72:381, 1993. Kugel G, Habib C, Zammitti S. Enamel and Dentin Surfaces After Treatment With Adhesion Conditioners Using the Environmental SEM, Journal of Dental Research, 72:387, 1993. Agarwal R, Zive M, Kugel G, Gwosdow A, Kraytsberg G, Kilpatrick D, Kumar A. Nitrous Oxide Effects on the Expression of Brain Opiate System, Journal of Dental Research, 71:913A, March 1992.
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Jong G, Zive M, Kugel G, Habib C. Surface Treatment Effects on Porcelain Composite Bonding, Journal of Dental Research, 71:1372, March 1992. Thomas K, Kugel G, Habib CM. Comparison of Dentin Surfaces after Treatment with Dentin Bonding Primers Using the Environmental Scanning Electron Microscope, Journal of Dental Research, 71:1390, March 1992. Habib C, Kronman J, Kugel G. One-year Evaluation of Composite Restoration for Root Surface Caries after ChemoMechanical Excavation, Journal of Dental Research, 71:795, March 1992. Kugel G, Achour A, Zive M. A Comparison of Marginal Microleakage Around Porcelain and Resin Inlay Systems, Journal of Dental Research, 70:990, April 1991. Habib C, Kronman J, Kugel G, Tutin, R. Dentinal Bonding and Composite Restoration of Root Surface Caries after ChemoMechanical Excavation, Journal of Dental Research, 70:1025, April 1991. Bellucci A, El Alfy H, Kugel G, Chapman R. Fracture Resistance of Porcelain Related to Polishing and Glazing. Journal of Dental Research, 70:638, April 1991. Latif M, Kugel G, Chapman R, Norris L, Kabani S, Washburn B. Techniques in Bone Surgery. Journal of Dental Research, 70:1956, April 1991. Kugel G, Rider C, Angelopoulos A, Fakitsas A. Evaluation of the Nd:YAG Contact Laser in Oral Surgery. Journal of Dental Research, 69:1172, March 1990. Zive MA, Kugel G, Beumer J, Kumar MSA. Brain Neuropeptide Changes in Rats Exposed to N20, Journal of Dental Research, 69:314, March 1990. Geshnizgani A, Kugel G, Onderdonk A, Delaney M, McDonough P, Habib C, Cisneros R. Effect of Nitrous Oxide on Oral Microorganisms, 89th Annual Meeting, American Society for Microbiology, May 1989. Kugel G, Letelier C, Atallah H, Zive M. Chronic Low Level Nitrous Oxide Exposure and Infertility, Journal of Dental Research, 68:1057, March 1989.
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Kugel G, Norris L, Zive M. Nitrous Oxide: Occupational Exposure, Journal of Dental Research, 68:1058, March 1989. Kugel G, Letelier C, Atallah H, King JC, Gilmore WC. Nitrous Oxide and Infertility, Journal of Dental Research, 67:380, March 1988. Kugel G, Rosenberg L. Effects of Nitrous Oxide Exposure on the Central Nervous System Control of Reproduction in Female Rats, Journal of Dental Research, 66:394, March 1987. King JC, Kugel G, Zahniser D, Wooledge K, Damassa D, Alexsavich B. Sex Differences in the Response of LHRH Neurons to Gonadectomy in the Rat: Three-Dimensional Computer Analyses, Society for Neuroscience, 87, May 1984. King JC, Lechan RM, Kugel G, Anthony ELP. A Fixative for Immunocyto-Chemical Localization of Peptides, Greater New York Dental Meeting, New York, New York, November 1983.

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