Is there an Advantage in Using Triclosan containing Dentifrice?

Group 1
Agustin, Andres, Aquitania, Aradanas, Asama, Austria, Bagasan, Bantegui, Bare, Bondoc, Borlagon, Buyawe, Cabrera, Cheung

TRICLOSAN
Triclosan (2,4,4-trichloro-2-hydroxydiphenyl ether) - Broad-spectrum, non-ionic, antibacterial/antimicrobial agent incorporated in soaps and cosmetics.

http://i.ivillage.com/uk_en/competitions/images/colgate_main.jpg

Triclosan Toothpastes versus Fluoride Toothpastes: Are they Different?

Ragy et. al, 2001

OBJECTIVE

Determine whether Triclosan Toothpastes could be shown to be more effective than conventional fluoride toothpaste when utilized in a twice daily home use for two months.

Effect of Triclosan/copolymer-containing Toothpaste on the Association between Plaque and Gingival Bleeding: a Randomized Controlled Clinical Trial
Muller et. al, 2006

OBJECTIVE
To study longitudinal associations between plaque and gingival bleeding and multilevel variance/covariance structures after introducing triclosan-containing toothpaste.

The Effectiveness of a Toothpaste containing Triclosan and Polyvinylmethyl ether maleic acid copolymer in Improving Plaque Control and Gingival Health
Davies et. al, 2004

OBJECTIVE
To compare the effectiveness of triclosan/copolymer and fluoride dentifrices in improving plaque control and gingival health.

METHODOLOGY

METHODOLOGY
Ragy et al Description 8-week trial Muller et al Davies et al 10-week, randomized, two- Sixteen trials provided data arm, double masked, for the analysis controlled clinical trial Sources Cochrane controlled trials register MEDLINE (1986March 2003) EMBASE (1986March 2003) *** Personal files and the reference lists of all articles were checked for further studies Selection Criteria (trials) Random allocation of participants

METHODOLOGY
Ragy et al Description 8-week trial Muller et al Davies et al 10-week, randomized, Selection Criteria (trials) At least 6 months in two-arm, double duration masked, controlled Participants were adults clinical trial with plaque and gingivitis comparing a dentifrice containing 0.3% triclosan, 2% copolymer and 0.243% sodium fluoride in silica base with a fluoride dentifrice for plaque or gingivitis Unsupervised use of dentifrices for at least 6 months Primary outcomes- plaque and gingivitis after 6 months

METHODOLOGY
Ragy et al Description 8-week trial Muller et al 10-week, randomized, two-arm, double masked, controlled clinical trial Davies et al Data Collection and Analysis 1.Two reviewers independently extracted information Scoring of plaque in the chosen trials also used the Quigley-Hein plaque index and the Loe-Sillness gingival index For each plaque and gingivitis index , the mean differences for each study were pooled as weighted mean differences with the appropriate 95% confidence intervals using the random effect models

METHODOLOGY
Ragy et al Description
8-week trial

Muller et al

Davies et al

10-week, randomized, Data Collection and two-arm, double masked, Analysis controlled clinical trial 2. Disagreements were resolved by discussions 3. Quality assessments of the trials were also carried out

METHODOLOGY
Muller et al N Groups 34 (Females) Control Group = 17 Test Group = 17 19-28 yrs old 22.2 + 1.4 yrs Ragy et al 30 (both sexes) Group A = 10 Group B = 10 Group C = 10 18-35 yrs old 21 yrs

Age Mean Age Teeth examined

Participants

Mean no. of teeth examined All teeth except for the third molars is 28.7 + 2.7 with a few and teeth with prosthetic crowns or exceptions (first molars due cervical restorations to caries), teeth had been extracted for orthodontic reasons Volunteers from the 5th and 6th dental students and dental hygienists

METHODOLOGY
Muller et al Inclusion Criteria Ragy et al 1. Female 1. A participant must demonstrate clinical 2. Mild plaque-induced gingival signs of gingivitis disease (slight gingival edema 2. Baseline mean erythrosine disclosed and redness in certain areas) plaque score of >1.5 (Quigley and Hein 3. Minimum amounts of plaque index) supragingival calculus (CLS) 3. Mean gingivitis score of >1.0 (Loe and Sillness gingival index)

METHODOLOGY
Muller et al Exclusion Criteria 1. Any indication for antibiotic prophylaxis Pregnancy or lactation as revealed by the volunteer Any long-term medication with a possible effect on gingival inflammation Any non-plaque-induced gingival disease Destructive periodontal disease with a possible exception of localized gingival recession Extensive tooth restoration or tooth replacement Smoking 1. Ragy et al Requirement for antibiotic medication, antibiotic therapy 7 days prior to the start of study, have used any tetracycline antibiotic during the previous 6 weeks History of hypersensitivity to dentifrices with triclosan Unable to comply with study appointment schedule Untreated caries or chronic periodontitis requiring prompt treatment Used a Chlorhexidine-containing rinse for at least 2 months before the start of the study and must also refrain from using such a rinse during the study Received any dental treatment in the past week, or be on an extensive oral hygiene program Be pregnant diabetic or immunosuppressed

2.
3.

2. 3.

4. 5.

4.
5.

6. 7.

6.

7.

METHODOLOGY
Muller et al
Experimental Design

Ragy et al
Divided randomly into 3 groups of 10 TRICLOSAN TOOTHPASTES 1. Group A: Colgate total (triclosan- 0.3%, NaF- 0.33%, Gantrez copolymer, 2%) 2. Group B: Gingilacer (triclosan 0.3%, zinc citrate 0.5%, Na MFP 1.13g 1500ppm) FLUORIDE TOOTHPASTE 3. Group C: Colgate regular (NaF 0.1% w/w, and MFP 0.76% w/w, dicalcium phosphate)

Simple randomization was accompanied by assigning computer generated random numbers to volunteers by an independent periodontist (E.K.).

METHODOLOGY
Muller et al Ragy et al
All the baseline subjects were given thorough prophylaxis to remove plaque, calculus, and stains INSTRUCTIONS GIVEN AFTER SELECTION AND GROUPING OF PARTICIPANTS 1.Brush twice daily for 8 weeks Using the toothpaste assigned to them Using the horizontal scrub technique, for 2 mins Using a soft toothbrush 2.Do not use any oral hygiene products other than those assigned for the study 3.Recall visits at 4th and 8th weeks when plaque and gingivitis were recorded according to the criteria used at the baseline Toothbrushes and unused toothpastes were returned during these visits to check if the patients are compliant

Experimental Design

a prophylaxis session was provided 1 week before the trial no attempt was made to improve the oral hygiene of the volunteers. Instead, they were advised not to alter their oral hygiene habits. If the volunteer uses a triclosan-containing toothpaste or mouthwash she was asked to change it to a brand not containing triclosan

METHODOLOGY
Muller et al Ragy et al
All the baseline subjects were given thorough prophylaxis to remove plaque, calculus, and stains INSTRUCTIONS GIVEN AFTER SELECTION AND GROUPING OF PARTICIPANTS 1.Brush twice daily for 8 weeks Using the toothpaste assigned to them Using the horizontal scrub technique, for 2 mins Using a soft toothbrush 2.Do not use any oral hygiene products other than those assigned for the study 3.Recall visits at 4th and 8th weeks when plaque and gingivitis were recorded according to the criteria used at the baseline Toothbrushes and unused toothpastes were returned during these visits to check if the patients are compliant

Experimental Design

The first 3 examinations conducted every other week were considered the preparatory phase. (individual site-specific associations between plaque levels and bleeding on probing, and a possible hawthorne effect were studied) After 4 weeks examination participants received neutral containers with , according to the randomization process, either placebo toothpaste (Colgate maximum cavity protection no triclosan) or verum toothpaste (Colgate Total 0.3% triclosan) During the experimental phase, three further examinations took place every other week

METHODOLOGY
Muller et al Ragy et al
All the baseline subjects were given thorough prophylaxis to remove plaque, calculus, and stains INSTRUCTIONS GIVEN AFTER SELECTION AND GROUPING OF PARTICIPANTS 1.Brush twice daily for 8 weeks Using the toothpaste assigned to them Using the horizontal scrub technique, for 2 mins Using a soft toothbrush 2.Do not use any oral hygiene products other than those assigned for the study 3.Recall visits at 4th and 8th weeks when plaque and gingivitis were recorded according to the criteria used at the baseline Toothbrushes and unused toothpastes were returned during these visits to check if the patients are compliant

Experimental Design

METHODOLOGY
Muller et al Ragy et al

Clinical Examination

The principal investigator carried out all examinations Clinical periodontal examinations were recorded at six sites of every tooth present Periodontal probing depth (PPD) and clinical attachment level (CAL) were measured with a pressure-controlled probe to the nearest millimetre

Scoring indices were performed by a single clinical examiner 4 surfaces per tooth (buccal, mesiobuccal, lingual, mesio-lingual) Williams #11 round graduated periodontal probe

METHODOLOGY
Muller et al Ragy et al

Clinical Examination

After probing facial surfaces of each quadrant, gingival bleeding was assessed on a 0-2 scale (Bleeding Index, BI) 0 : no bleeding 1 : Slight (single spot) 2 : Profuse (whole sulcus filled immediately with blood) Probing was continued at palatal sites Presence of calculus (CLS) was recorded and plaque disclosed with a plaque revelator

The clinical scoring used to assess gingivitis was the Loe-Silness gingival scoring index (1963 as modified by Talbott et al (1977) 0: Absence of inflammation 1: Mild inflammation (moderate glazing, redness, edema, and hypertrophy without bleeding on probing) 2: Moderate inflammation (moderate glazing, redness, edema, and hypertrophy with bleeding upon probing) 3: Severe inflammation (redness and hypertrophy, a tendency for spontaneous bleeding, and ulceration)

METHODOLOGY
Muller et al Ragy et al

Clinical Examination

The amount of plaque was estimated using criteria of the plaque index system by Silness and Loe (PLI)
0 : no plaque in gingival area 1 : film of plaque adhering to the free gingival margin. The plaque may only be recognized by running a probe across the tooth surface at the entrance of the gingival sulcus 2 : moderate accumulation of soft deposits within the gingival sulcus, on the gingival margin and/or adjacent tooth surface which can be seen by the naked eye.

The clinical scoring procedure used to assess plaque formation was the Turesky modification (1970) of the Quigly-Hein (1962)index scores plaque formation on a numerical scale of 0-5
0 : No visible plaque present 1: Separate flecks of plaque at the cervical margin of the tooth. 2: A thin, continuous band of plaque (up to 1mm) at the cervical margin 3: A band of plaque wider than 1mm but covering less than 1/3 of the surface 4: Plaque covering at least 1/3 but less than 2/3 of the surface 5: Plaque covering more than 2/3 of the surface

METHODOLOGY
Muller et al Ragy et al

Statistical Analysis

Primary outcome variable was the association between plaque amount and BOP in a steady-state plaque environment. Null hypothesis was that triclosan-containing toothpaste doesnt change the association Ecological analysis of correlation between bleeding and PLI Multivariate multilevel models

Covariance Analysis: to determine if there was any overall treatment effect; baseline=covariate No further pairwise comparisons (overall treatment P value was>10 for both plaque and gingival indices

RESULTS

Ragy et. al., 2001

Baseline averages of the whole mouth plaque index scores were initially very similar to each other ranging from 2.652.73. At the end of the 8th week mean values were 2.45, 2.33 and 2.5 for Col. Total, gingilacer and Col. regular respectively

Table 1: summary of the whole mouth plaque index scores (mean+/- SD)

Baseline 4 weeks 8 weeks

Col. Total 2.73+/- 0.23 2.46+/- 0.29 2.45+/- 0.34

Gingilacer 2.65+/-0.31 2.37+/-0.25 2.33+/-0.33

Col. Regular 2.71+/-0.32 2.5+/-0.41 2.5+/-0.38

There were no statistically Table 2: Least square means of plaque index scores significant Week Treatment 95% Confidence interval differences in mean lower upper Pplaque scores value between groups at 4 Col. Total 2.42 2.32 2.52 either the 4th or > 0.2 Gingilacer 2.40 2.30 2.30 8th weeks Col. Regular 2.49 2.39 2.39
8 Col. Total Gingilacer Col. Regular 2.44 2.37 2.43 2.30 2.27 2.34 2.30 2.27 2.34 > 0.2

The gingival index for the whole mouth showed no difference between products during the 4th and 8th weeks

Table 3: Summary of the whole mouth gingival index scores (mean +/-SD) 3:
Baseline 4 Weeks 8 Weeks Col. Total 1.62+/-0.26 1.09+/-0.34 1.05+/-0.30 Gingilacer 1.76+/-0.40 1.15+/-0.37 1.04+/-0.31 Col. Regular 1.63+/-0.34 1.11+/-0.37 1.06+/-0.38

There was no significant statistical difference in gingivitis score between the groups at either 4 or 8 weeks

Table 4:Least square means of gingival index scores Week Treatment 95% Confidence interval mean lower upper Pvalue 4 Col. Total 1.11 1.0 1.21 > 0.2 Gingilacer 1.04 0.95 1.15 Col. Regular 1.07 0.97 1.18 8 Col. Total 1.08 0.97 1.16 > 0.2 Gingilacer 0.97 0.86 1.08 Col. Regular 0.04 0.93 1.16

Although the difference in plaque scores among the three groups was not found to be statistically significant, there was a decrease in plaque scores for all three groups between the baseline and 4th week. A similar pattern was observed in the gingival index of all three groups. No statistical significance was noted, but a decrease in gingival index was observed for all three groups from baseline to week 4.

Muller et. al., 2006

Volunteers: 34 32 (due to examination stress after week 4) Volunteers: mild-moderate plaque-induced gingivitis with few sites with increased PPD of >4mm at partially erupted 8s No loss of attachment (only due to few facial areas with gingival recession)

TABLE 1. CLINICAL PERIODONTAL CONDITIONS OF THE STUDY POPULATION AT THE ONSET AND ALTERATIONS 6 WEEKS AFTER
INTRODUCING EXPERIMENTAL TOOTHPASTES ARE PRESENTED

NO SIGNIFICANT DIFFERENCE BETWEEN GROUPS

NEITHER AT BASELINE NOR AT THE END OF THE STUDY

THE DIFFERENCE WERE SMALL WITHIN GROUPS ALTHOUGH

BLEEDING TENDENCY ATTENUATED IN BOTH GROUPS

ECOLOGICAL APPROACH

ECOLOGICAL APPROACH

Table 2. Correlation between individual mean plaque and BI after week 4

Preparatory Phase Control Group Yes Experimental Phase Yes

Test Group

Yes

No

ECOLOGICAL APPROACH

MULTIVARIATE MULTILEVEL MODELS

Table 3. Fixed effects estimates during Prep

Any increase in the PLI by 1 score inc in the odds of BOP by 34-44%

MULTIVARIATE MULTILEVEL MODELS

Table 3. Fixed effects estimates during Prep

Any 1 mm increase of PPD inc by 60% BOP odds ratio

MULTIVARIATE MULTILEVEL MODELS

Table 4. Random part of multivariate four-level model

TABLE 4. RANDOM PART OF MULTIVARIATE FOUR-LEVEL MODEL

Biserial correlation for BOP Level 2 (site) Level 3 (tooth) Very low: 0.11-0.13 Larger: 0.3 Estimated extrabinomial parameters Below 1; (+) underdispersion Below 1

Level 4 (subject)

Highest: 0.7-0.9

Below 1

Constraining the model to fit binomial variation at the lowest level did not substantially alter any of the other parameter estimates (not shown).

TABLE 5. FIXED EFFECTS ESTIMATES AFTER PREP AND DURING EXP

There was gradually increasing negative effect of test toothpaste on BOP proportions

At the end of the Exp phase, odds of BOP decreased by 30% in the Test Group (OR 0.71%. 95% Confidence Interval 0.56-0.9, p= 0.005)

TABLE 6. SUBJECT VARIATION

Week 4

Week 8-10

Level 1

0.6

0.2

MULTIVARIATE MULTILEVEL MODELS WITH PLI AND CLS AS RESPONSES

Test

toothpaste had no significant (no reducing) effect on PLI Test toothpaste had a small, albeit not significant (negative), effect on LCS

Owing to highly localized occurrence of CLS, the model revealed considerable underdispersion at the site level, making the assumption of Binomial distribution questionable. When level 4 (tooth) was removed from the model, extrabinomial variation was essentially reduced. In contrast to the bleeding scores, biserial correlations for CLS were high (about 0.6) at the site level

TABLE 7. ASSOCIATION: BOP AND PLI

At the end of the Exp phase, Association between BOP and Plaque Scores: Test Group < Control Group ( =8.39, p<0.05)

ADVERSE EFFECTS
One only, but disappeared after termination of the experiment Benign migratory glossitis (painless geographic tongue)

Davies et. al., 2004

Meta- analyses for both Quigley- Hein Plaque Index and Plaque severity index:

- the triclosan/copolymer toothpaste is effective in reducing plaque.

WMD for the QHPI: -0.48 (95% CI (random effects): -0.64 to -0.32)

WMD for the Plaque Severity Index: -0.15 (95% CI (random effects): -0.20 to -0.09) * refer to fig.1, page 1031

Meta-analyses for the Loe and Silnes and gingivitis severity indices: - showed a reduction in gingivitis when comparing the triclosan/copolymer dentifrice with a fluoride dentifrice

WMD for Loe and Silnes Gingival Index: -0.26 (95% CI (random effects): -0.34 to -0.18) WMD for Gingivitis Severity Index: -0.12 (95% CI (randon effects): -0.17 to -0.08)

* Refer to fig.2, page 1032

Plaque and gingivitis severity indices demonstrated that: - the use of triclosan dentifrice reduced the proportion of surfaces with heavy plaque by 15 % and those with gingival bleeding by 12%.

It appeared that:

- The proportion of sites that had plaque was reduced from 0.31 to 0.16 (49% reduction) - the proportion of sites with bleeding was also reduced from 0.24 to 0.12 (49% reduction as well)

The Weighted Mean Difference (WMD) for the QuigleyHein Plaque Index corresponds to a 23% reduction in plaque when comparing the triclosan dentifrice with a Fluoride dentifrice.

The Weighted mean Difference (WMD) for Loe and Silness Gingival Index also corresponds to 23% reduction.

To determine publication and other biases, a funnel plot was used.

One of the funnel plots of the trials appeared asymmetrical, which was statistically significant thereby indicating some evidence of bias.

RESULTS

Ragy et. al., 2001

-There were no statistically significant differences in plaque scores between groups at either the 4th or 8th weeks - There was no significant

Muller et. al.,2006

-Difference were small within groups although bleeding tendency attenuated in both groups - Significant correlations b/n individuals mean plaque and bleeding indices were noticed in the Prep phase as well as in the Control Group thereafter, but during the Exp phase, correlations were no longer significant. - At the end of the Exp phase, the association between BOP and Plaque Scores is lower in the Test Group then the Control Group

Davies et. al, 2004

- triclosan/ copolymer
dentifrice is effective in reducing plaque
-Significant

statistical difference in gingivitis score between the groups at either 4 or 8 weeks

-Although the difference in plaque scores among the three groups was not found to be statistically significant, there was a decrease in plaque scores for all three groups between the baseline and 4th week. A similar pattern was observed in the gingival index of all three groups. No statistical significance was noted, but a decrease in gingival index was observed for all three groups from baseline to week 4.

reduction in

gingivitis
-Reduction

in the proportion of surfaces with heavy plaque and gingival bleeding

-Proportion

of sites that had plaque and sites with bleeding were both reduced as well

DISCUSSIONS

Ragy et. al, 2001

All three dentifrices demonstrated a slight reduction in gingival index scores after 4 weeks. The lack of difference between the triclosan groups and the fluoride group could be due to the relatively short duration (8 week).

Lower values for plaque as compared to the baseline were also observed for all dentifrices. The values for both triclosan dentifrices were not statistically different from those of the fluoride toothpaste.

Zinc citrate and Triclosan

Significant reductions in plaque accumulation Better able to maintain gingival health Complementary and additive effects in vivo
Zinc=existing plaque Triclosan= inhibit plaque formation

Normal home use toothpaste studies are influenced by a number of factors which may mask the superiority of a particular product over the controls.

Factors True placebo toothpaste products

Product or benchmark control Antiplaque activity and antimicrobial effects Reduces ability to detect actual product differences

Fluoride

Improvement in toothbrushing

Baseline prophylaxis

Antimicrobial or antiplaque agents

Potential to disrupt homeostasis if it has:

Marked selective activity against organisms associated with health Too broad a spectrum of activity

Triclosan

Fabl gene= enyol reductase in fatty acid synthesis

Muller et. al., 2006

In the clinical trials done (6 months duration; 54-329 subjects with plaque induced gingivitis), mean plaque and gingivitis scores are consistently lower in subjects using triclosan/copolymer-containing toothpaste.

The relationship between plaque and bleeding became weaker after introducing triclosan-containing toothpaste. A further serious disadvantage of analyzing summary measures is immediate loss of most of the information usually acquired during examination of numerous periodontal sites.

 One advantage of the approach used is that it gives a direct way of looking the influence of the subjects unobserved characteristics on the response variable and hence a direct measure of the effects which are being assessed.

The study was intentionally confined to young adult female non-smokers, which demand a more in-depth discussion.
In longitudinal studies, heavy tobacco consumption may lead, at site level, to gingival bleeding unrelated to the amount of supragingival plaque pointing to smoking as an independent risk factor for gingival inflammation. Gender differences have been reported in a recent gingivitis experiment.

Prevention of the potential Hawthorne effect

After introducing experimental toothpastes, estimate probabilities for BOP gradually decreased in the test group. In addition, the site-specific causal association between BOP and PLI scores became weaker in the test group. In some studies, triclosan-related reductions of plaque and/ or gingivitis have been reported only after extended periods of usage. It is most likely that respective effects may be more consistent after longer usage only. A potential effect of higher content of fluoride in control toothpaste on gingival bleeding tendency and the association between plaque and BOP could not be ascertained.

Davies et. al., 2004

Significantly

improved the removal of supragingival plaque & gingival health:

dentifrice containing triclosan/copolymer fluoride dentifrice

Evidence

for Publication bias was found on the Gingivitis severity outcome reported

 Prophylaxis

(in 13 studies):

Effectiveness of the dentifrices to control the subsequent accumulation of plaque

No

prophylaxis (in 3 studies):

Effectiveness of the dentifrices in removing existing plaque and reducing further accumulation

 Greater

clinical significance:

Improvement in gingival health & reduction in gingival bleeding in 3 randomized-control trials of at least 3 years duration:
Ellwood et al. 1998 Rosling et al. 1997 Culliman et al. 2003

 Studies

involved 7 countries:

Findings may be generalizable around the world.

CONCLUSIONS

Ragy et al. 2001

Triclosan/copolymer or triclosan/zinc citratecontaining dentifrices have the same effect on plaque and gingivitis and therefore give no additional benefit to oral hygiene and gingival health when compared to conventional fluoride dentifrices.

Muller et al. 2006

The relationship between mean PLI and bleeding scores is weakened on subjects who used triclosan-containing dentifrices but is not altered on those who used conventional fluoride dentifrices
Triclosan-containing dentifrice decrease the likelihood of BOP at the site level while PLI and presence of CLS were not affected.

Davies et al. 2004

Triclosan/copolymer containing dentifrices provide more effective level of plaque control and periodontal health than conventional fluoride dentifrices

Ragy et al. 2001 Muller et al. 2006

A site specific attenuation of the causal association between PLI scores in subjects using triclosancontaining dentifrices could already be discerned after 6 weeks.

Davies et al. 2004

OVERALL CONCLUSION
Triclosan-containing dentifrice has a significant effect in the control of dental plaque and gingivitis. Because of its antimicrobial property, triclosan when incorporated in dentifrices contributes in the removal of existing plaque and prevention of further plaque accumulation.