Jan Lindhe. Clinical Periodontology

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THE USE OF ANTISEPTICS IN PERIODONTAL THERAPY • 475

able and no long-term evaluations have been per-

formed.

Amine alcohols

This group of compounds does not truly fit into an

antimicrobial or antiseptic category; indeed they ex-

hibit minimal effects against microbes. Octopenol was

first shown to be effective as an antiplaque agent but

was withdrawn for toxicological reasons. Delmopinol

followed and at 0.1% and 0.2% in mouthrinses was

shown to be effective as a plaque inhibitor and an-

tigingivitis agent in short-term no oral hygiene and

long-term home use studies (Collaert et al. 1992, Mo-

ran et al. 1992b, Claydon et al. 1996). Side effects

include tooth discoloration, transient numbness of the

mucosa, particularly the tongue, and burning sensa-

tions in the mouth. The mode of action of delmopinol

can be debated but, in part, appears to be the inhibition

in formation or disruption of the matrix of early

plaque forming bacteria. No products are available at

present.

Acidified sodium

chlorites (for review see Yates et al.

1997)

This agent does not sit well with any particular group

listed in Table 22-1; however, depending on the acid

chosen and the conditions of the reaction between the

acid and the sodium chlorite, a varied and complex

range of reaction products can ensue. Under ideal

conditions for antimicrobial benefits sodium chlorite

is reacted with a protic acid to produce chlorous acid,

which then liberates a range of higher oxidant species

but contains minimal amounts of chlorine dioxide.

These higher oxidant species have a broad range of

antimicrobial action against bacteria, fungi, yeast and

viruses and products are available in the US within

the veterinary and food industry, both as a preventive

for mastitis in cows and for the preservation of frozen

poultry. Experimental mouthrinses have been tested

in short-term plaque regrowth studies and salivary

bacterial count investigations (Yates et al. 1997). Sur-

prisingly, given that the acid and sodium chlorite are

mixed immediately before rinsing, and that the dura-

tion of the chemical reaction would be limited to the

rinsing time, three experimental formulations were

shown to be as good as chlorhexidine against plaque

regrowth and showed the same substantivity as chlor

hexidine. Although not tested in longer-term studies,

side effects, particularly staining and alternation of

taste, would appear unlikely with the acidified so-

dium chlorite mouthrinses. Unfortunately, the low pH

of the formulations would be expected to cause some

dental erosion and this has been proven in studies

situ

(Pontefract et al. 2001). Such erosion, which was

found comparable to that of orange juice

in situ,

would

tend to obviate the long-term continuous use of such

agents. However, acidified sodium chlorite mouthrin-

ses could find application in preventive dentistry

similar to those to be described for chlorhexidine (see

the section "Clinical uses of chlorhexidine" later in

this chapter). The erosive effects would not, in short

to medium-term use, reach clinically significant lev-

els. To date no commercial products are available.

Other

antiseptics (for review see Addy 1986)

A number of antiseptics/antimicrobial agents have

been studied for plaque inhibition. Most have been

found to have little or no effect

in vivo;

a few have been

formulated in mouthrinse products including povi-

done iodine and hexetidine. Povidone iodine at 1%

has a substantivity of only 60 minutes (Addy & Wright

1978) and lacks appreciable plaque inhibitory activity

(

Addy et al. 1977) or action in acute infections such as

acute ulcerative gingivitis (Addy & Llewelyn 1978),

for

which it is recommended. Povidone iodine is

largely

without side effects but as a rinse has potential

affect thyroid function adversely (Wray et al. 1978).

Hexetidine, a saturated pyrimidine, at 0.1% was

shown to have limited plaque inhibitory action (Ber-

genholtz & Hanstrom 1974) and no evidence for anti-

plaque activity when used as an adjunct for oral hy-

giene (Chadwick et al. 1991). The action of hexetidine

against plaque appears enhanced by zinc salts (Saxer

& Muhlemann 1983) but data are derived only from

short-term studies. Side effects for hexetidine include

tooth staining and mucosal erosion, although both are

uncommon (Bergenholtz & Hanstrom 1974). Never-

theless, mucosal erosion is markedly increased in in-

cidence if the concentration is raised to 0.14% (Bergen

holtz & Hanstrom 1974). A mouthrinse product con-

taining 0.1% hexetidine is available in some European

countries.

Conclusions

•

Effective antimicrobial antiplaque agents show pro-

longed persistence of action in the mouth (

substan

tivity). Chlorhexidine is the most effective

anti-

plaque agent to date. Stannous fluoride and

tri

closan oral hygiene products are available with

proven antiplaque activity. The long established

mouthrinse, based on essential oils, has some evi-

dence for adjunctive antiplaque activity.

•

The limited information on natural products, for

example herbal formulations, is not encouraging

and the root extract sanguinarine has been with-

drawn because of the potential to cause precancer-

ous oral lesions.

•

The amine alcohol, delmopinol, appears effective

but products are not available.

•

Acidified sodium chlorite appears as effective as

chlorhexidine but the acidic nature of the rinse may

obviate oral hygiene products ever coming to the

marketplace.

•

Combinations of agents sometimes provide addi-

tive or synergistic action, but with the exception of

triclosan, few products are available.

476 •

CHAPTER 22

Fig. 22-2. Chlorhexidine molecule.

Fig. 22-3. Brown discoloration of the teeth of an individ

ual rinsing twice a day for 3 weeks with a 0.2% chlor

hexidine mouthrinse.

Fig. 22-4. Brown discoloration of the tongue of an indi

vidual rinsing twice a day for 2 weeks with a 0.2%

chlorhexidine mouthrinse.

CHLORHEXIDINE

Chlorhexidine is available in three forms, the diglu-

conate, acetate and hydrochloride salts. Most studies

and most oral formulations and products have used

the digluconate salt, which is manufactured as a 20%

V/V concentrate. Digluconate and acetate salts are

water-soluble but hydrochloride is very sparingly sol-

uble in water. Chlorhexidine was developed in the

1940s by Imperial Chemical Industries, England, and

marketed in 1954 as an antiseptic for skin wounds.

Later, the antiseptic was more widely used in medi-

cine and surgery including obstetrics, gynecology,

urology and presurgical skin preparation for both

patient and surgeon. Use in dentistry was initially for

presurgical disinfection of the mouth and in endodon-

tics. Plaque inhibition by chlorhexidine was first in-

vestigated in 1969 (Schroeder 1969), but the definitive

study was performed by Loe and Schiott (1970). This

study showed that rinsing for 60 seconds twice per

day with 10 ml of a 0.2% (20 mg dose) chlorhexidine

gluconate solution in the absence of normal tooth

cleaning, inhibited plaque regrowth and the develop-

ment of gingivitis. Numerous studies followed, such

that chlorhexidine was one of the most investigated

compounds in dentistry (for review see Jones 1997).

Chlorhexidine is a bisbiguanide antiseptic, being a

symmetrical molecule consisting of four chlorophenyl

rings and two biguanide groups connected by a cen-

tral hexamethylene bridge (Fig. 22-2). The compound

is a strong base and dicationic at pH levels above 3.5,

with two positive charges on either side of a hex-

amethylene bridge (Albert & Sargeant 1962). Indeed,

it is the dicationic nature of chlorhexidine, making it

extremely interactive with anions, which is relevant to

its efficacy, safety, local side effects and difficulties

with formulation in products.

Toxicology, safety and side effects

The cationic nature of chlorhexidine minimizes ab-

sorption through the skin and mucosa, including from

the gastrointestinal tract. Systemic toxicity from topi-

cal application or ingestion is therefore not reported,

nor is there evidence of teratogenicity in the animal

model. Even in intravenous infusion in animals, chlor

hexidine is well tolerated and has occurred acciden-

tally in humans without serious consequences. Hy-

persensitivity reactions including anaphylaxis have

been reported in fewer than 10 people in Japan and

resulted from the application of non-proprietary

chlorhexidine products to sites other than the mouth.

There was insufficient information to confirm that the

reactions were actually due to chlorhexidine.

Neurosensory deafness can occur if chlorhexidine is

introduced into the middle ear and the antiseptic

should not be placed in the outer ear in case the

eardrum is perforated. The antiseptic has a broad

antimicrobial action, including a wide range of Gram-

positive and Gram-negative bacteria (Wade & Addy

1989). It is also effective against some fungi and yeasts

including candida, and some viruses including HBV

and HIV. Bacterial resistance has not been reported

with long-term, oral use, or evidence of supra-infec-

tion by fungi, yeasts or viruses. Long-term oral use

resulted in a small shift in the flora towards the less

THE USE OF ANTISEPTICS IN PERIODONTAL THERAPY • 477

sensitive organisms but this was rapidly reversible at

the end of the 2-year study (Schlott et al. 1976).

In oral use as a mouthrinse, chlorhexidine has been

reported to have a number of local side effects (Flotra et

al. 1971). These side effects are:

Brown discoloration of the teeth and some restora-

tive materials and the dorsum of the tongue (to be

discussed further) (Figs. 22-3 and 22-4).

Taste perturbation where the salt taste appears to

preferentially affected (Lang et al. 1988) to leave

food and drinks with a rather bland taste.

Oral mucosal erosion (Fig. 22-5). This appears to be

an idiosyncratic reaction and concentration de-

pendent. Dilution of the 0.2% formulation to 0.1%,

but rinsing with the whole volume to maintain dose,

usually alleviates the problem. Erosions are

rarely

seen with 0.12% rinse products used at 15 ml

volume.

Unilateral or bilateral parotid swelling (Fig. 22-6).

This is an extremely rare occurrence and an expla-

nation is not available.

Enhanced supragingival calculus formation. This

effect may be due to the precipitation of salivary

proteins on to the tooth surface, thereby increasing

pellicle thickness and/or precipitation of inorganic

salts on to the pellicle layer. Certainly pellicle form-

ing under the influence of chlorhexidine shows an

early and highly calcified structure (Leach 1977).

Chlorhexidine also has a bitter taste, which is difficult

to mask completely.

Chlorhexidine staining

The mechanisms proposed for chlorhexidine staining

can be debated (Eriksen et al. 1985, Addy & Moran

1995, Watts & Addy 2001) but have been proposed as:

Degradation of the chlorhexidine molecule to re-

lease parachloraniline

Catalysis of Maillard reactions

Protein denaturation with metal sulfide formation

Precipitation of anionic dietary chromogens.

Degradation of chlorhexidine to release parachlora-

niline appears not to occur on storage or as a result of

metabolic processes. Also, alexidine, a related bis-

biguanide, does not have parachloraniline groups, yet

causes staining identical to that of chlorhexidine

(Addy

& Roberts 1981). Non-enzymatic browning re-

actions (

Maillard reactions) catalysed by chlorhexidine are a

theoretical possibility (Nordbo 1979);

however,

evidence is indirect, circumstantial or inconclusive (

Eriksen et al. 1985). The theory does not con

sider the

fact that other antiseptics and metals such as

tin, iron

and copper also produce dental staining.

Protein

denaturation produced by chlorhexidine with the

interaction of exposed sulfide radicals with metal

Fig. 22-5. Mucosal erosion occurring following a few

days of rinsing twice a day with a 0.2% chlorhexidine

mouthrinse.

Fig. 22-6. Bilateral parotid swelling following a few

days of rinsing with a 0.2% chlorhexidine mouthrinse.

ions is also theoretically possible (Ellingsen et al. 1982,

Nordbo et al. 1982) but there is no direct evidence to

support this concept. Again, the theory does not take

into account similar staining by other antiseptics and

metal ions. Laboratory and clinical studies also could

not reproduce this process (Addy et al. 1985, Addy &

Moran 1985). Precipitation of anionic dietary chromo-

gens by cationic antiseptics, including chlorhexidine

and polyvalent metal ions as an explanation for the

phenomenon of staining by these substances, is sup-

ported by a number of well-controlled laboratory and

clinical studies (for reviews see Addy & Moran 1995,

Watts & Addy 2001). Thus, the locally bound antisep-

tics or metal ions on mucosa or teeth can react with

polyphenols in dietary substances to produce stain-

ing. Beverages such as tea, coffee and red wine are

particularly chromogenic, but other foods and bever-

ages will interact to produce various colored stains.

These reactions between chlorhexidine and other cat-

478 • CHAPTER 22

ionic antiseptics and polyvalent metal ions with chro-

mogenic beverages can be performed within the test

tube. Interestingly, most of the precipitates formed

between polyvalent metal ions and chromogens have

the same color as their sulfide salts. It is for this reason

that original theories considered that staining, seen in

individuals exposed to these polyvalent metal ions,

usually in the workplace, was due to metal sulfide

formation. Again, laboratory and clinical experiments

have failed to produce such interactions.

It is perhaps the staining side effect that limits

long-term use of chlorhexidine in preventive dentistry

(

Flotra et al. 1971) and occurs with all correctly formu

lated products including gels, toothpastes and sprays.

Indeed, the staining side effect can be used to assess

patient compliance in the use and activity of formula-

tions. In the latter case laboratory and clinical studies

on staining have revealed a proprietary chlorhexidine

mouthrinse product to be inactive (Addy & Wade

1995, Renton-Harper et al. 1995). Interestingly, this

particular chlorhexidine product was reformulated in

the UK to produce an active formulation (Addy et al.

1991), but the manufacturers maintained the original

formulation within France when both laboratory and

clinical studies confirmed markedly reduced poten-

tial of the product to cause staining in the laboratory,

and plaque inhibition in the clinic (Addy & Wade

1995, Renton-Harper et al. 1995).

Mechanism of action

Chlorhexidine is a potent antibacterial substance but

this alone does not explain its antiplaque action. The

antiseptic binds strongly to bacterial cell membranes.

At low concentration this results in increased perme-

ability with leakage of intracellular components in-

cluding potassium (Hugo & Longworth 1964, 1965).

At high concentration, chlorhexidine causes precipi-

tation of bacterial cytoplasm and cell death (Hugo &

Longworth 1966). In the mouth chlorhexidine readily

adsorbs to surfaces including pellicle-coated teeth.

Once adsorbed, and unlike some other antiseptics,

chlorhexidine shows a persistent bacteriostatic action

lasting in excess of 12 hours (Schiott et al. 1970). Ra-

dio-labelled chlorhexidine studies suggest a slow re-

lease of the antiseptic from surfaces (Bonesvoll et al.

1974a,b) and this was suggested to produce a pro-

longed antibacterial milieu in the mouth (Gjermo et al.

1974). However, the methods could not determine the

activity of the chlorhexidine, which was almost cer-

tainly attached to the salivary proteins and desquam-

ating epithelial cells and therefore unavailable for

action. Consistent with the original work and conclu-

sions (Davies et al. 1970), a more recent study and

review suggested that plaque inhibition is derived

only from the chlorhexidine adsorbed to the tooth

surface (Jenkins et al. 1988). It is possible that the

molecule attaches to pellicle by one cation leaving the

other free to interact with bacteria attempting to colo-

nize the tooth surface. This mechanism would, there-

fore, be similar to that associated with tooth staining.

would also explain why anionic substances such as

sodium lauryl sulfate based toothpastes reduce the

plaque inhibition of chlorhexidine if used shortly after

rinses with the antiseptic (Barkvoll et al. 1989). Indeed,

a more recent study has demonstrated that plaque

inhibition by chlorhexidine mouthrinses is reduced if

toothpaste is used immediately before or immediately

after the rinse (Owens et al. 1997). These inhibitory

effects on chlorhexidine activity by substances such as

toothpastes can be modeled using the chlorhexidine

tea staining method, which shows reduced staining

activity by the chlorhexidine solutions resulting from

an interaction with toothpaste (Sheen et al. 2001).

Plaque inhibition by chlorhexidine mouthrinses

appears to be dose related (Cancro et al. 1973, 1974,

Jenkins et al. 1994) such that similar effects to that seen

with the more usual 10 ml, 0.2% solution (20 mg) can

be achieved with high volumes of low concentration

solutions (Cumming & Loe 1973, Lang & Ramseier-

Grossman 1981). It is worth noting, however, that not

inconsiderable plaque inhibition is obtained with

doses as low as 1—5 mg twice daily (Jenkins et al. 1994).

Also, and relevant to the probable mechanism of ac-

tion, topically applying 0.2% solutions of chlor-

hexidine only to the tooth surface, including by the

use of sprays, produces the same level of plaque inhi-

bition as rinsing with the full 20 mg dose (Addy &

Moran 1983, Francis et al. 1987a, Jenkins et al. 1988,

Kalaga et al. 1989a).

Chlorhexidine products

Chlorhexidine has been formulated into a number of

products.

Mouthrinses

Aqueous alcohol solutions of 0.2% chlorhexidine were

first made available for mouthrinse products for twice

daily use in Europe in the 1970s. A 0.1% mouthrinse

product also became available; however questions

were raised over the activity of the 0.1% product and

in some countries the efficacy of this product is less

than would be expected from a 0.1% solution (Jenkins

et al. 1989). Later, in the US, a 0.12% mouthrinse was

manufactured but to maintain the almost optimum 20

mg doses derived from 10 ml of 0.2% rinses, the prod

uct was recommended as a 15 ml rinse (18 mg dose).

The studies revealed equal efficacy for 0.2% and 0.12%

rinses when used at appropriate similar doses

(

Segreto et al. 1986).

Gel

A 1% chlorhexidine gel product is available and can

be delivered on a toothbrush or in trays. The distribu

tion of the gel by toothbrush around the mouth ap-

pears to be poor and preparations must be delivered

to all tooth surfaces to be effective (Saxen et al. 1976).

THE USE OF ANTISEPTICS IN PERIODONTAL THERAPY • 479

In trays the chlorhexidine gel was found to be particu

larly effective against plaque and gingivitis in handi-

capped individuals (Francis et al. 1987a). The accept-

ability of this tray delivery system to the recipients

and the carers was found to be poor (Francis et al.

198Th). More recently, 0.2% and 0.12% chlorhexidine

gels have become available.

Sprays

0.1% and 0.2% chlorhexidine in sprays are commer-

cially available in some countries. Studies with the 0.

2% spray have revealed that small doses of approxi

mately 1-2 mg delivered to all tooth surfaces produces

similar plaque inhibition to a rinse with 0.2% mouth-

rinses (Kalaga et al. 1989a). Sprays appear particularly

useful for the physically and mentally handicapped

groups, being well received by individuals and their

carers (Francis et al 1987a,b, Kalaga et al. 1989b).

Toothpaste

Chlorhexidine is difficult to formulate into toothpaste

for reasons already given and early studies produced

variable outcomes for benefits to plaque and gingivitis

(

Gjermo & Rolla 1970, 1971, Johansen et al. 1972,1975).

More recently, a 1% chlorhexidine toothpaste with and

without fluoride was found to be superior to the con-

trol product for the prevention of plaque and gingivi-

tis in a 6-month home use study (Yates et al. 1993).

However, stain scores were markedly increased as

was supragingival calculus formation, and the manu-

facturer did not produce a commercial product. For a

short time a commercial product was available, hav-

ing been shown to be efficacious for both plaque and

gingivitis (Sanz et al. 1994). Although effective, chlor-

hexidine products based on toothpaste and sprays

produce similar tooth staining to mouthrinses and

gels; taste disturbance, mucosal erosion and parotid

swellings tend to be less or have never been reported.

Varnishes

Chlorhexidine varnishes have been used mainly for

prophylaxis against root caries rather than an anti-

plaque depot for chlorhexidine in the mouth.

Conclusions

•

Chlorhexidine to date is the proven most effective

antiplaque agent for which commercial products

are available to the public.

•

Chlorhexidine is free from systemic toxicity in oral

use, and microbial resistance and supra-infection

do not occur.

•

Local side effects are reported which are mainly

cosmetic problems.

•

The antiplaque action of chlorhexidine appears de-

pendent on prolonged persistence of antimicrobial

action in the mouth (substantivity).

•

A number of vehicles for delivering chlorhexidine

are available, but mouthrinses are most commonly

recommended.

•

Extrinsic dental staining and perturbation of taste

are variably the two side effects of chlorhexidine

mouthrinse usage which limit acceptability to users

and the long-term employment of this antiseptic in

preventive dentistry.

CLINICAL

USES OF

CHLORHEXIDINE

Despite the excellent plaque inhibitory properties of

chlorhexidine, widespread and prolonged use of the

agent is limited by local side effects. Moreover, be-

cause of the cationic nature of the chlorhexidine and

therefore its poor penetrability, the antiseptic is of

limited value in the therapy of established oral condi-

tions including gingivitis, and is much more valuable

in the preventive mode. A number of clinical uses,

some well researched, have been recommended for

chlorhexidine (for reviews see Gjermo 1974, Addy

1986, Addy & Renton-Harper 1996a, Addy & Moran

1997).

As an adjunct to oral hygiene and professional

prophylaxis

Oral hygiene instruction is a key factor in the treat-

ment plan for patients with periodontal disease and

as part of the maintenance program following treat-

ment. Adequate plaque control by periodontal pa-

tients is therefore essential to successful treatment and

the prevention of re-occurrence of the disease. Chlor-

hexidine should therefore increase the improvement

in gingival health through plaque control, particularly

following a professional prophylaxis to remove exist-

ing supra and immediately subgingival plaque. There

is, however, a potential disadvantage of using such an

effective chemical plaque control agent at this stage of

the periodontal treatment plan. Thus, following oral

hygiene instruction, it is normal, usually by the use of

indices, to quantify the improvement in plaque con-

trol by patients so instructed and, in particular, the

improvement at specific sites which previously had

been missed by individual patients. By virtue of the

excellent plaque control effects of chlorhexidine, the

response to oral hygiene instruction cannot be accu-

rately assessed since the antiseptic will overshadow

any deficiencies in mechanical cleaning. Indeed, as the

original research demonstrated, patients could main-

tain close to zero levels of plaque following a profes-

sional prophylaxis without using any form of me-

chanical oral hygiene (Loe & Schiott 1970).

Postoral surgery including periodontal surgery or

root planing

Chlorhexidine may be used postoperatively since it

offers the advantage of reducing the bacterial load in

the oral cavity and preventing plaque formation at a

time when mechanical cleaning may be difficult be-

cause of discomfort. In periodontal surgery, periodon-

tal dressings have largely been replaced by the use of

480 • CHAPTER 22

chlorhexidine preparations, in particular mouthrin-

ses, since healing is improved and discomfort reduced

(

Newman & Addy 1978, 1982). Regimens vary but

chlorhexidine should be used immediately post treat-

ment and for periods of time until the patient can

re-

institute normal oral hygiene. Depending on the

appointment schedule, chlorhexidine could be used

throughout the treatment phase and for periods of

weeks after completion of the treatment plan. If dress

ings are used, chlorhexidine is of limited value to the

postoperative site since it does not penetrate beneath

the periodontal dressings (Pluss et al. 1975). The idea

of full mouth disinfection using chlorhexidine both

supra and subgingivally has recently been assessed by

one group of researchers (Quirynen et al. 1995). In the

event, few adjunctive benefits could be shown and it

appeared that the more dominant factor was the time

over which the non-surgical treatment plan was com-

pleted. Thus, root planing performed totally within 24

hours was more effective than root planing completed

over more conventional periods of several weeks (for

review see Quirynen et al. 2001).

For patients with jaw fixation

Oral hygiene is particularly difficult when jaws are

immobilized by such methods as intermaxillary fixa-

tion. Chlorhexidine has been shown to reduce mark-

edly the bacterial load, which tends to increase during

jaw immobilization, and improve plaque control

(Nash

& Addy 1979).

For oral hygiene and gingival health benefits in the

mentally and physically handicapped

Chlorhexidine has been found particularly useful in

institutionalized mentally and physically handi-

capped groups, improving both oral hygiene and gin-

gival health (Storhaug 1977). Spray delivery of 0.2%

solutions was found particularly useful and accept-

able to patients and care workers (Francis et al.

1987a,b, Kalaga et al. 1989b).

Medically compromised individuals predisposed

oral infections

A number of medical conditions predispose individu-

als to oral infections, notably candidiasis. Chlor-

hexidine is effective as an anticandidal agent but is

most useful when combined with specific anticandi-

dal drugs, such as nystatin or amphoteracin B (Simon

etti et al. 1988). Indications for chlorhexidine use com

bined with anticandidal drugs have been for the pre-

vention of oral and systemic infections in the immu-

nocompromised, including those with blood dy-

scrasias, those receiving chemotherapy and/or radio-

therapy and notably bone marrow transplant patients

(

Ferretti et al. 1987, 1988, Toth et al. 1990). The value

of chlorhexidine appears greatest when initiated be-

fore oral or systemic complications arise. A chlor-

hexidine spray was also found to produce sympto-

matic/psychological oral care benefits in the termi-

nally ill (Dobbins et al. 1992).

High-risk caries

patients

Chlorhexidine rinses or gels can reduce considerably

the streptococcus mutans counts in individuals who

are caries prone. Additionally, and interestingly, chlor

hexidine appears synergistic with fluoride and com-

bining chlorhexidine and fluoride rinses appears

beneficial to such at risk individuals (Dolles & Gjermo

1980, Lindquist et al. 1989).

Recurrent oral ulceration

Several studies have shown that chlorhexidine

mouthrinses and chlorhexidine gels reduce the inci-

dence, duration and severity of recurrent minor

aphthous ulceration (Addy et al. 1974, 1976, Hunter &

Addy 1987). The mechanism of action is unclear but

may relate to a reduction in contamination of ulcers

by oral bacteria, thereby reducing the natural history

of the ulceration. Regimens have included three times

daily use of chlorhexidine products for several weeks.

Interestingly, one study showed that triclosan rinses

reduce the incidence of recurrent mouth ulcers (Skaare

et al. 1996). There have been no controlled studies of

chlorhexidine in the management of major aphthous

ulceration or other oral erosive or ulcerative condi-

tions, although anecdotally chlorhexidine appears in

effective. Again, this may reflect the low therapeutic

potential of this and other antiseptics.

Removal and

fixed orthodontic appliance wearers

Plaque control in the early stages of orthodontic ap-

pliance therapy may be compromised and chlor-

hexidine can be prescribed for the first 4-8 weeks.

Additionally, chlorhexidine has been shown to reduce

the number and severity of traumatic ulcers during

the first 4 weeks of fixed orthodontic therapy (Shaw

et al. 1984).

In denture stomatitis

Chlorhexidine has been recommended in the treat-

ment of candidal associated infections; however, in

practice even applying chlorhexidine gel to the fitting

surfaces of denture produces, in many cases, slow and

incomplete resolution of the condition. Again, chlor-

hexidine is less effective in the therapeutic mode and

it is more advantageous to treat denture stomatitis

with specific anticandidal drugs and then employ

chlorhexidine to prevent recurrence. The denture itself

can be usefully sterilized from candida by soaking in

chlorhexidine solutions (Olsen et al. 1975a,b).

Immediate preoperative chlorhexidine rinsing and

irrigation

This technique can be used immediately prior to op-

erative treatment, particularly when ultrasonic pol-

ishing or high-speed instruments are to be used. Such

preoperative rinsing markedly reduces the bacterial

load and contamination of the operative area and

operator and staff (Worral et al. 1987). Additionally, in

susceptible patients, irrigation of chlorhexidine

around the gingival margin reduces the incidence of

THE USE OF ANTISEPTICS IN PERIODONTAL THERAPY • 481

bacteremia (MacFarlane et al. 1984). However, this

should be seen only as an adjunct to appropriate

systemic antimicrobial prophylaxis.

Subgingival irrigation

Numerous antimicrobial agents have been used as

subgingival irrigants in the management and treat-

ment of periodontal diseases (for reviews see

Wennstrom 1992, 1997). Alone, irrigation with antimi

crobial agents produces effects little different from

using saline and of short duration, suggesting that the

action is a washing-out effect. Irrigation combined

with root planing appears to provide no adjunctive

benefits.

Conclusions

•

There are a significant number of indications for

the use of chlorhexidine in preventive dentistry,

most of

which rely on the antimicrobial properties

of the

antiseptic and its duration of action.

•

The most valuable chemical plaque control uses of

chlorhexidine are in the short to medium term when

mechanical tooth cleaning is not possible, difficult

or inadequate and during which time local side

effects are likely to be minimized.

•

Chlorhexidine is more effective as a preventive

rather than a therapeutic agent and therefore must

be of questionable value as a subgingival adjunct in

the treatment of periodontitis (see next chapter).

EVALUATION OF CHEMICAL

AGENTS AND PRODUCTS

(for reviews see Addy et al. 1992, Addy 1995, Moss et

al. 1995, Addy & Moran 1997)

The number and use of oral hygiene products has

grown enormously in recent years and, as an example,

hundreds of millions of pounds per year are spent on

oral hygiene products in the UK. There can be no

doubt that the oral hygiene industries, through their

collaboration and research with the dental profession

and their promotion of their products have, in no

small way, contributed to the improvement in dental

health seen in many countries. However, claims for

efficacy of oral hygiene products are frequently made

and it is essential that these are supported by scientific

evidence. Without such evidence the profession and

the public may be confused or misled. The dental

profession is, however, faced with a large number of

oral hygiene products supported by huge quantities

of varied promotional literature and media advertis-

ing, which makes impossible, in many cases, any valid

judgement or assessment of the efficacy or value of

individual products to specific patient groups or the

public as a whole. Even those with specialized inter-

est, and research experience in specific aspects of oral

hygiene product evaluation, must find validation

based on published literature a daunting task. This is

made all the more difficult since what constitutes

proof of efficacy is not generally agreed even amongst

so-called experts. Few countries of the world have

central control over what evidence is required before

efficacy clearance can he made and there are very few

guidelines suggesting requirements for proof of effi-

cacy for oral hygiene products.

The scientific evaluation of dental products, and for

that matter preventive and therapeutic agents in

medicine as a whole, is a relatively modern concept

but today must be the backbone on which to base

claims of efficacy. Anecdotal and case reports, uncon-

trolled studies and data listed as "held on file" by

manufacturers, whilst interesting, should not be used

as the basis for efficacy claims. Blind, randomized,

controlled clinical and laboratory studies must be the

methods used today to obtain data on the activity of

agents, formulations and products. Terminology and

phraseology in product claims also needs to be care-

fully reviewed and assessed. Perhaps the greatest area

for criticism must be the implied claim by the manu-

facturer and/or the inferences left to be drawn from

promotional material by the dental profession or pub-

lic. A classic scenario for which there is precedence can

be stated as follows: A is the cause of B, C reduces A,

leaving the inference to be drawn that C can control B.

Perhaps nowhere is this more apparent than in the use

of agents which are known to control plaque, and

therefore it can be implied, without evidence, they

must control gingivitis. The now familiar claim would

be "this product reduces plaque, the major cause of

gum disease". Similarly, creative arithmetic is not in-

frequently used to give inflated impressions of effi-

cacy Proportional differences, rather than actual dif-

ferences, are not infrequently quoted, as are percent-

ages of percentages giving hundreds of percent im-

provements over another product or control, yet the

actual benefit is a fraction of the scoring index used.

Finally, "piggy back" claims are not uncommon, when

known active ingredient is formulated into a new

product and equivalent efficacy to established prod-

ucts is assumed. In respect of terminology for oral

hygiene products, the European Workshop on Perio-

dontology in 1996 defined certain terms (Lang & New

man 1997):

• Antimicrobial agents:

Chemicals that have a bacte-

riostatic or bacteriocidal effect

in vitro

that alone

cannot be extrapolated to a proven efficacy

in vivo

against plaque.

• Plaque reducing/inhibitory agents:

Chemicals that

have

only been shown to reduce the quantity

and/or

affect quality of plaque, which may or may

not be

sufficient to influence gingivitis and/or car

ies.

• Antiplaque agents:

Chemicals that have an effect on

plaque sufficient to benefit gingivitis and/or caries.

• Antigingivitis agents:

Chemicals which reduce

gingival inflammation without necessarily influ-

482 • CHAPTER 22

encing bacterial plaque (includes anti-inflamma-

tory agents).

Thus the fact that antimicrobial agents such as anti-

septics kill or inhibit the growth of bacteria does not

necessarily mean they will be effective plaque inhibi-

tors (Gjermo et al. 1970). Also, the mere incorporation

of a known antiplaque agent into a formulation is not

a guarantee of efficacy because inactivation by other

ingredients may occur.

This section looks at methods that have been used

to test oral hygiene products both in the laboratory

and the clinic. No one protocol can provide all the

answers, and research and development of agents into

products is a step-by-step process, hopefully culmi-

nating in a body of evidence proving efficacy, beyond

doubt, of a final product. Methods

in vitro

and

in vivo

will be summarized but animal testing will not be

discussed except to acknowledge that the use of ani-

mals is still necessary in drug development, in under-

standing the mode of action of drugs and, particularly,

in evaluating safety from a toxicological point of view.

However, the evaluation of oral hygiene products on

animals, particularly for efficacy, must be questioned

on a number of scientific and moral grounds.

Most laboratory and clinical methods have been

developed to test antimicrobial agents but methodolo-

gies are available, or present ones could be modified,

to study potential antiadhesive and plaque removal

chemicals. (For reviews see Addy et al. 1992, 1995a,b,

Addy & Moran, 1997.)

Studies in vitro

Bacterial tests

Antimicrobial tests including minimum inhibitory

concentration (MIC), minimum bactericidal concen-

tration (MBC) and kill curves can be determined.

These tests indicate the antibacterial activity and an-

timicrobial spectrum of agents and formulations

against a range of oral bacteria. Continuous culture

techniques can also be used but they may not provide

more meaningful data. It is likely that, with techno-

logical advances, laboratory models to accurately rep-

licate the plaque biofilm will become available to test

chemical plaque control agents. At present, antimicro

bial tests

in vitro

primarily only indicate activity, or

lack of it, and they are very poor predictors per se

plaque action in

vivo.

This is because, so far, methods

do not provide particularly reliable information on the

substantivity of the antimicrobial agent. Nevertheless,

antimicrobial tests are valuable for a variety of rea-

sons. With few exceptions, agents without activity

vitro

will not provide activity

in vivo.

The additive or

negative effects of ingredient mixtures can be deter-

mined. The availability of active ingredients incorpo-

rated in the product can be assessed. The adverse

influence of the oral environment can be modeled; for

example, the influence of saliva or proteins on the

antibacterial activity of agents can be tested.

Uptake measurements

One aspect of substantivity is adsorption of antimicro

bials and other potential plaque inhibitory agents on

to surfaces. This can be quantified using a variety of

substrates such as hydroxyapatite, dentine, enamel,

acrylic and other polymers. The influence of other

factors or agents on the uptake of a particular agent

can also be assessed. Such data are of interest but must

be interpreted with caution since they only measure

uptake, not activity once adsorbed. Nevertheless,

desor

tion of an agent from such surfaces can be

measured by a variety of analytical techniques thereby

giving some indication of both the adsorption profile

and the subsequent substantivity of the agent to the

substrate surface.

Other methods

Activity or availability of an ingredient in a formula-

tion can be measured or assessed. Methods include

chemical analyses; however, some methods chemi-

cally extract the agent from the formulation in its

entirety and therefore do not necessarily demonstrate

that it is freely available and active within the formu-

lation. For the cationic antiseptics and polyvalent met

al salts, their potential to bind dietary chromogens

from beverages such as tea can be used to assess the

possibility that they may cause staining

in vivo.

usefully, the test method can be employed to deter-

mine and compare the availability of the same ingre-

dient in different formulations. Such methods have

shown considerable differences in availability of

chlorhexidine and cetylpyridinium chloride in appar-

ently similar mouthrinses (Addy et al. 1995b). More-

over, how other oral hygiene products might interfere

with the activity of chemical plaque control agents,

such as toothpaste with chlorhexidine and cetylpyrid

inium chloride, has given surprisingly accurate pre-

dictions of clinical outcome (Owens et al. 1997, Sheen

et al. 2001, 2002). Again, these methods give little

indication of substantivity and therefore the staining

method

vitro

cannot be used to compare different

agents for propensities to cause staining

in vivo.

For

example, a 0.05% cetylpyridinium chloride mouth-

rinse produces comparable tea staining on a substrate

surface to a 0.2% chlorhexidine mouthrinse, yet clini

cally the amount of staining reported for chlor-

hexidine is considerably greater than that for ce-

tylpyridinium chloride and this can be explained by

the fact that the substantivity of the former is greater

than the latter.

Study methods

in vivo

A considerable number of protocols have been devel-

oped to evaluate potential antiplaque agents and

products. Ideally, because of the number of ingredi-

ents and more particularly formulations, a step-by-

step pyramid approach is taken. Thus initially, study

THE USE OF ANTISEPTICS IN PERIODONTAL THERAPY • 483

Fig. 22-7. Salivary bacterial counts

over time following mouthrinsing

with chlorhexidine, saline, so-

dium lauryl sulfate and triclosan.

Following a single rinse with

chlorhexidine, sodium lauryl sul-

fate and triclosan there is an im-

mediate large reduction in bacte-

rial counts. This continues and

persists to the 420-minute end-

point of the study for chlor-

hexidine (positive control) with a

tendency for counts to revert to-

wards baseline for triclosan and

sodium lauryl sulfate. With saline

(placebo control) there is little

change in counts over time.

designs are used which permit, if necessary, the

screening of relatively large numbers of agents and

formulations and on relatively small numbers of sub-

jects.

Depot studies

Retention of agents in the mouth may be measured by

determining the amount expectorated versus the

known dose (the buccal retention test) or by measur-

ing plaque and saliva levels of the agent over time.

Such retention assessments can be misleading because

retention is only one aspect of substantivity and the

measurement techniques do not provide information

on the activity of the retained agents. Moreover, the

buccal retention test does not distinguish drug ab-

sorption from adsorption nor determine how much is

swallowed. Thus, for example, studies using radio-

labeled chlorhexidine purported to demonstrate slow

release from oral surfaces and this occurred over a

protracted period of time. However, saliva derived

from subjects following rinsing with chlorhexidine

only provided antimicrobial activity for up to 3 hours

following rinsing (Addy & Wright 1978). This is

clearly

markedly less than the known substantivity or

persistence of action of chlorhexidine in the mouth of

least 12 hours (Schiott et al. 1970). It is likely, there

fore, that the initial desorption studies using a radio-

label were merely detecting chlorhexidine adsorbed

desquamating oral surfaces, particularly the mu

cosa.

Antimicrobial tests

For antimicrobial agents only, salivary bacterial count

assessments are much more indicative of substantiv-

ity and are predictive of antiplaque action for the same

agents. The method involves measuring salivary bac-

terial counts before and at time points after a single

rinse with the agent (Fig. 22-7) and was first described

for chlorhexidine (Schiott et al. 1970). In the case of

toothpaste, the product can be either brushed or

rinsed as an aqueous slurry (Addy et al, 1983, Jenkins

et al. 1990). Agents and products produce variable

reductions in counts ranging from none, as with water,

to greater than 90% as with chlorhexidine. More im-

portantly, the duration of reduction from baseline var

ies from minutes to hours. Thus, povidone iodine only

reduces counts for approximately 1 hour, cetylpyrid-

inium chloride for 3 hours (Roberts & Addy 1981),

whereas chlorhexidine produces such effects for over

12 hours (Schiott et al. 1970). Toothpastes generally

show reductions in counts between 3 and 5 hours,

probably largely due to contained detergents and/or

specific ingredients such as triclosan (Addy et al.

1989).

Experimental plaque studies

Short-term plaque regrowth studies are perhaps the

most commonly used clinical experiments to screen

chemical oral hygiene products. They have the advan

tage of assessing the chemical action of the formula-

tion divorced from the indeterminate variable of

toothbrushing. Typically, plaque regrowth from a zero

baseline and the influence of the test agent is recorded.

Originally used for mouthrinses, the method has been

modified for toothpaste by delivering the formulation

in a tray applied to the teeth (Gjermo & Rolla 1970,

1971, Etemadzadeh et al. 1985) or as a slurry rinse

(

Addy et al.1983). Studies are usually cross-over, al-

lowing many formulations to be evaluated against

suitable controls. Study periods range from 24 hours

to several days, usually 4-5 (Harrap 1974, Addy et al.

1983). A negative control such as water and a positive

484 • CHAPTER 22

control such as chlorhexidine may be used (Fig. 22-8).

These help to position the activity of the test formula-

tions between the extremes. Also, because the results

from these controls can be predicted, their use tends

confirm or otherwise the conduct of these blind,

randomized study designs.

Experimental gingivitis studies

Experimental gingivitis studies (Loe & Schiott, 1970)

are based on the original experimental gingivitis in

man

protocol first used to demonstrate the direct eti

ological

relationship between plaque and gingivitis

(Loe et al.

1965). This latter original study did not

return subjects

to zero baseline plaque scores or gin

gival health,

whereas most subsequent methods, to evaluate oral

hygiene products, have taken this approach with

baseline parameters. Study periods usu

ally range

from 12, but more particularly 19–28 days. In the

absence of normal tooth cleaning, the development of

plaque and gingivitis are recorded under the

influence

of test and control formulations. Studies

may be either

cross-over or parallel.

Home use studies

For chemical oral hygiene products and usually tooth-

Fig. 22-8. Plaque area following the use of chlor-

hexidine, saline, sodium lauryl sulfate and triclosan

mouthrinses after 4-day periods. Considerable plaque

inhibition was afforded by chlorhexidine (positive con-

trol) when toothcleaning was suspended. Both sodium

lauryl sulfate and triclosan show significant plaque

inhibitory action compared to saline (placebo control)

albeit significantly less than chlorhexidine.

Fig. 22-9. A 6-month study of delmopinol rinses as ad

juncts to oral hygiene. Significant improvements in

plaque scores are seen in the delmopinol mouthrinse

groups at 3 and 6 months compared to placebo. A Haw

thorne effect of improved toothcleaning irrespective of

the treatment is apparent in the placebo group, particu

larly at 3 months, although this is still present at 6

months.

pastes and mouthrinses, the final evaluation requires

that they are shown to be effective against plaque and,

more particularly, gingivitis when used along with

normal mechanical tooth cleaning. Studies can be over

days or weeks but usually, in accordance with guide-

lines such as those for the American Dental Associa-

tion (Council of Dental Therapeutics 1985) they need

be 6 months or longer, particularly since safety needs

to be assessed (Fig. 22-9). Most studies are par

allel in

design. Protocols have used two approaches.

One is

perhaps more therapeutic in concept whereby

subjects

have to exhibit a certain level of plaque

and/or

gingivitis before entry (Johansen et al. 1975).

The

other is more preventive in concept and there is a

prestudy period in which subjects with gingivitis re-

ceive prophylaxis and instruction to improve their

gingival health. Those satisfactorily responding are

entered, and change in gingival health is monitored in

the test and control groups (Stephen et al. 1990). Sev-

eral factors tend to confound home use studies of oral

hygiene products and may mask a proven chemical

antiplaque action determined from short-term plaque

and experimental gingivitis studies. Most important

the so-called Hawthorne effect where subjects

knowingly involved in oral hygiene studies improve

their tooth cleaning (Fig. 22-9). Secondly, baseline pro-

phylaxes are commonly given and the influence of this

on the subsequent gingivitis levels is not known. In

mouthrinse studies used as adjuncts to tooth cleaning,