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Section 5B

Non-Surgical Pocket Therapy: Pharmacotherapeutics

Connie Hastings Drisko*

'Department of Periodontics, Endodontics, and Dental Hygiene, University of Louisville, Louisville, Kentucky


1. What evidence exists for the use of top-
ical, crevicular, and systemic antimicrobial Gingivitis and Periodontitis are primarily
agents in the treatment of gingivitis and Peri- bacterial infections caused by diverse
odontitis? groups of microorganisms.1 5 The prevalence
2. What evidence supports the use of anti- and severity of these diseases can be re-
inflammatory agents in periodontal therapy? duced by mechanical plaque removal or a
3. What evidence supports that anti-mi- variety of systemic and topically applied an-
crobial agents directed toward periodontal timicrobial agents aimed at selectively re-
pathogens are effective in the treatment of moving or inhibiting pathogenic bacteria.6 8
periodontal diseases? Mechanical removal, both surgical and non-
4. What are the indications and contra- surgical, is time-consuming, operator and
indications of each agent? patient-dependent, and difficult to master.
5. What are the measurable endpoints The use of chemotherapeutic agents as ad-
and outcomes of each treatment? juncts to mechanical and surgical debride-
6. What evidence supports the role of ment is compelling. In addition to innovative
each agent in periodontal treatment? anti-infective treatment modalities, consid-
7. What research now underway is likely erable research efforts have been focused on
to prove effectivefor the pharmaceutical man- non-steroidal anti-inflammatories and chem-
agement ofperiodontal diseases? ically modified tetracyclines. A variety of top-
8. What evidence exists that the results of ical and systemic agents that can block the
pharmaceutical treatment are sustained? pathway and progression of periodontal dis-
9. How does the clinician know when the ease have been studied for their efficacy in

treatment is no longer effective? the prevention and treatment of Periodonti-

10. How does the pharmaceutical treat- tis, as is evidenced by numerous reports
ment for gingivitis differ from that for Peri- published within the last 10 years of labo-
odontitis? ratory and animal experiments as well as

11. What are the benefits/risks to the pa- human clinical trials.9 12
tient for each treatment? The following review encompasses the ap-
12. In what future directions should clini- plication of pharmacotherapeutics in non-
cal practice/research go? surgical therapy. A broad-based search of the
literature from 1988 to the present was con-
ducted and full length papers published in
English in refereed journals that met previ-
ously-established criteria for the conduct of
good clinical trials and laboratory based re-
search were examined. Over 2,000 articles
Ann Periodontol 1996;1:491-566. were reviewed from 1979 to present, and

Vol. 1, No. 1, November 1996

492 Drisko

426 publications from 72 journals are in- using new or existing systemic preparations
cluded in this review. A complete review of of anti-inflammatories and anti-infectives
the literature prior to 1989 was not within capable of halting or reversing the rate of
the scope of this paper, however, selected ar- periodontal disease progression. Research-
ticles published before 1989 were included ers have particularly focused on the treat-
to provide historical background and clari- ment of recurrent and refractory Periodon-
fication as needed. A limited number of well- titis. Some of these new agents are available
documented case reports are also included in the United States, and others are not.
if they represented unique therapeutic uses Several of the products reviewed in the 1989
of antimicrobial agents. World Workshop are still under development,
Publications were selected and ranked pending marketing approval from their re-
based on the premise that relevant random- spective world-wide regulatory agencies, and
ized controlled clinical trials received priority are included here if additional evidence has
followed by longitudinal studies, controlled been published since the 1989 workshop.
and uncontrolled case studies, and animal The purpose of the review is to present rel-
or laboratory-based investigations. Evidence evant evidence published since the 1989
tables were constructed from the selected Workshop on the use of topical, crevicular,
articles, with the highest ranking relevant and systemic antimicrobial agents in the
studies positioned at or near the beginning non-surgical treatment of gingivitis and Per-
of each table. An attempt was made to rep- iodontitis, and to provide a summary of
resent all papers equally, but due to the sig- recent evidence regarding the use of anti-in-
nificant amount of new data and to space flammatory agents in periodontal therapy.
limitations, some authors' work and contri- The topics will be presented in the following
butions to this large body of evidence could order:
not be acknowledged. Other papers were ex- • Irrigation methods and devices used for
cluded if they did not add new information the supra- and subgingival delivery of
to the existing literature, or when the data therapeutic agents
presented were not complete enough for crit- • Topical and systemic non-steroidal anti-
ical interpretation and evaluation. inflammatories
Pharmacotherapeutics reviewed here in- • Local delivery of topical and sustained-re-
clude topical, crevicular and systemic lease antimicrobials
agents. New topically applied antimicrobials • Use of systemic antibiotics in non-surgical
and anti-inflammatories developed since the periodontal therapy.
1989 World Workshop include dentifrices,
mouthrinses, varnishes, gels, ointments,
films, inserts, strips, chips, bioresorbable IRRIGATION METHODS AND
polymers, and irrigation solutions. Denti- DELIVERY DEVICES
frices containing antigingivitis agents such
as stannous fluoride, Chlorhexidine, and tri- The primary purpose of irrigation is to
closan will not be included in this review, nonspecifically reduce the bacteria and their
since antigingivitis agents incorporated in by-products that lead to the initiation or
toothpaste and mouthrinses are primarily progression of periodontal diseases. Supra-
preventive in nature and are discussed in gingival irrigation allows for the disruption
detail in Section 3 (Prevention). However, and dilution of marginal bacteria and their
those mouthrinses and other antimicrobial by-products which helps to prevent or treat
agents used in irrigating solutions and in- gingivitis. Subgingival irrigation interferes
corporated into topical and sustained-re- with the complex ecosystem required for the
lease delivery devices that are therapeutic in initiation and continued destruction of the
nature are included in the review. compromised periodontium in the suscepti-
Systemic agents have also been tested in ble host. The literature presented here ex-
experimental protocols designed to treat emplifies an important fact that, like all
more severegeneralized periodontal disease, other therapeutic modalities, irrigation has

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 493

both limitations and benefits. This review gator versus a syringe and found that pro-
encompasses many new studies investigat- fessionally administered saline irrigation
ing various aspects of supragingival and with a pulsed mono-jet subgingival irrigator
subgingival irrigation including: new devices system to be even more effective than the sy-
and methods of delivery by clinicians and ringe/needle treatment regardless of the so-
patients; effect on plaque toxicity; depth of lution used.
solution penetration; various chemothera-
peutic agents employed; ultrasonics and an-
timicrobials; safety; and bacteremia associ- Patient
ated with irrigation. Applied Home Irrigation
Supragingival home irrigation. Several stud-
ies have shown that water or other antimicro-
bial medicaments provide an increased reduc-
Professional Application tion of gingivitis and bleeding on probing
Delivery devices. Professional delivery of (BOP) over normal oral hygiene alone in main-
supragingival irrigation primarily uses two tenance patients (Table 1).17-19
different systems; direct irrigation using a
hand-held syringe or mechanical irrigation Subgingival home irrigation. A wide array
of subgingival irrigation devices have been
using a special pumping device that produces used in patient applied home irrigation. Pa-
a stream of irrigant with regular intermittent
tients seem to comply with recommendations
breaks resulting in a pulsating effect. A va- to use home jet Irrigators, and find them rel-
riety of irrigator tips including cannulas and atively easy to use (Table l).2°-23 Macaulay
soft hollow rubber tips have been developed
and Newman had patients use a pulsed
and modified for home or professional use
with irrigation delivery systems. mono-jet subgingival irrigation system, once
Professional application with pulsed irri- daily for 4 weeks and found the treatment to
be effective in controlling subgingival plaque
gation. Boyd et al.13 evaluated subgingival for at least 2 months after the end of a 1-
irrigation using a pulsed jet irrigator with ei- month period of active treatment.19
ther a standard tip or a cannula on an oral
Wolff et al.24 studied the mono-jet subgin-
irrigator and found that irrigation with the
cannula tip penetrated farther into both me- gival irrigation system and concluded that, if
dium (3.5 to 6.0 mm) and deep (> 6 mm) patients delivered antimicrobial agents sub-
pockets than did irrigation with the stan- gingivally between maintenance visits, ad-
dard pulsating tip. Larner and Greenstein14 ditional reductions in the clinical signs as-
studied three different irrigator tip designs: sociated with inflammatory periodontal dis-
ease were evident. In another study, 3-
a 24 gauge single side-port cannula, mono-
month use of a pulsed mono-jet subgingival
jet subgingival tip (0.955 mm tip with a sin-
gle end port), and a 23 gauge cannula with irrigation system (tip placed slightly under
a single end port. They determined that the
the gingival margin) was effective in reducing
cannula type tip on the oral irrigator had gingival inflammation regardless of the an-
timicrobial irrigant used (Table l).25
significantly greater penetration than did the
mono-jet subgingival system. It appears that both supra- and subgingi-
Professional application with a hand held val home irrigation is effective. It should be
syringe. Early work by Hardy et al.15 dem- kept in mind, however, that as with any oral
onstrated clearly that placing an irrigating hygiene device, the device is only as good as
needle 3 mm within periodontal pockets the operator, and beneficial results vary
with a hand-held syringe provides an effi- widely from patient to patient. While supra-
cient and predictable means of reaching the gingival irrigation can be performed by pa-
apical subgingival plaque border with an ir- tients with a moderate degree of success,
rigating solution. More recently, Itac and subgingival irrigation in particular may pose
Serfaty16 studied the clinical effectiveness of technical difficulties for patients with limited
subgingival irrigation with a pulsed jet irri- dexterity.

Vol. 1, No. 1, November 1996

494 Drisko

Table 1. Irrigation with pharmacological agents

Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =

Gingivitis: Professional Irrigation

Clark et al.72 Randomized double-blind, con- Professional subgingival irri- Patients also used a daily Relevant; 9
1989 trolled parallel arm gation every 3 weeks with rinse of the test or control
90/101 completed povidone-iodine and hydrogen solutions. Examiner repro-
Length 24 weeks
peroxide antibacterial sys- ducibility not reported.
tem significantly reduced
BOP by 70% compared to a
34% reduction in the water
or hydrogen peroxide con-

Gingivitis: Home Irrigation

Flemmig et al.18 Randomized single-blind, con- Daily supragingival home ap- All 3 treatments were effec- Relevant; 9
1990 trolled parallel arm plication of 0.06% CHX tive in reducing gingival in-
USA N 175/222
showed significantly better flammation compared to
Length 6 months
reduction in gingival inflam- brushing, with the greatest
mation (42.5%) compared to effects in the CHX irrigation
tooth brushing. Water irriga- group. Water irrigation and
tion and CHX rinse bid CHX rinsing were equal,
equally reduced gingival in- but less effective than CHX
flammation by 23.2% and irrigation in gingivitis reduc-
24.1%. PD were significantly tion. No examiner repro-
reduced with CHX irrigation ducibility data reported.
compared to rinse and tooth-
brushing. Plaque was signif-
icantly reduced in the CHX
groups compared to tooth-
brushing. Calculus and stain
were significantly increased
in both CHX groups com-
pared to water irrigation and
Newman et al.65 Randomized single blind, con- Compared to toothbrushing, The authors suggest that Relevant; 9
1990 trolled parallel arm daily home irrigation with the frequent sampling of
88/105 completed 0.06% CHX was the most ef- subgingival plaque may
(microbiology from Length 6 months
fective in significantly reducing have had some treatment
Flemmig et al.18) the total CFU, the percent effect and may account for
Gram-negative anaerobic rods, small differences between
and black-pigmented Bactero- groups.
ides. Twice daily rinse with
CHX also reduced subgingival

Chaves et al.27 Randomized single-blind, con- Home applied supragingival The authors comment that Relevant; 9
1994 trolled, parallel arm irrigation with 0.04% CHX or water irrigation is capable
104/125 completed rinsing with 0.12% CHX in of reducing gingival inflam-
Length =
6 months addition to toothbrushing re- mation without significantly
sulted in 30 to 35% reduction altering supragingival plaque
of plaque in gingivitis sub- accumulation in gingivitis
jects. Prevotella intermedia patients.
was significantly reduced in
the CHX and water irrigation
groups but not CHX rinse or
brushing. All groups had a
significant reduction in bleed-
ing compared to brushing.
PD were unchanged.

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 495

Table 1. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =
Ciancio et al.22 Randomized, double-blind, Home applied supragingival The control irrigation signif- Possibly
1989 split mouth controlled irrigation with a phenolic icantly reduced plaque, relevant; 7
USA N 61/66 completed
mouthrinse once a day re- gingival crevicular fluid vol-
Length 6 weeks =
sulted in significant reduction ume, and bleeding on prov-
in plaque, total bacterial cell ocation, confirming the
counts, and gingivitis com- efficacy of irrigation with or
pared to a vehicle control. without an antimicrobial in
No significant differences treating gingivitis. Longer
were noted in PD and attach- studies should be con-
ment gains between groups. ducted to assess the long-
term effect of irrigation with
a phenolic-based mouth-
rinse on gingivitis.

Brownstein et al.1 Randomized, double-blind, Once daily supragingival Daily supragingival irriga- Possibly
1990 controlled, split mouth paral- home irrigation with 0.06% tion appears to be an effec- relevant; 7
USA lel arm CHX and CHX rinse (0.12%) means to reduce gin-
N =
44/48 completed significantly reduced plaquegivitis, regardless of whether
Length =
2 months and gingival bleeding by scaling was performed
about 40% in moderate to prior to irrigation. No repro-
severe gingivitis patients. ducibility data reported.
Bleeding was further re- Longer monitoring periods
duced with CHX irrigation would be desirable in this
compared to placebo irriga- type study to see the longer-
tion. term effect of treatment.

Periodontitis: Professional Irrigation

Nylund & Egelberg5' Randomized controlled split Subgingival professional irri- The saline irrigation was as Possibly
1990 mouth gation in furcations with 5% effective as the antimicro- relevant; 6
USA/Sweden N 20=
TCN every 2 weeks for 3 bial irrigation, suggesting
Length 3 months=
months (total of 6) resulted in that irrigation alone may be
no significant differences in an effective adjunctive
clinical parameters with the treatment for furcation ar-
test solution compared to sa- eas. It is not clear if the ex-
line. aminer was blinded to the
subject's treatment. No ex-
aminer reproducibility data
Southard et al.57 Randomized single-blind, con- 2% CHX irrigations per- Microbial reductions were Possibly
1989 trolled, 4 quadrant split mouth, formed 4 weeks consecu- further extended to 11 relevant; 7
8 tively resulted in equal PD weeks in the CHX + SRP
Length =
15 weeks reductions for SRP, CHX ir- group. Treatment in gen-
rigation and SRP + CHX ir- eral was further enhanced
rigation. SRP + CHX reduced with the combined therapy.
P. gingivalis significantly No examiner reproducibility
more than scaling or irriga- reported. The rather re-
tion alone. Attachment gains markable results from this
were significant for all but the small pilot study suggest
no treatment group. CHX ir- that high concentrations of
rigation alone (1.9 mm) had CHX and multiple irriga-
the highest attachment tions may have enhanced
gains, then SRP + CHX (1.7 clinical and microbial im-
mm) followed by SRP alone provement. The require-
(1.6 mm). ment for multiple office
visits may pose a potential
compliance problem for the
bleeding on probing. CHX =
Chlorhexidine. MET =
metronidazole. SRP scaling and root planing,
colony forming units. Gl =
gingival index. PD =
probing depths. TCN tetracycline.

Vol. 1, No. 1, November 1996

496 Drisko

Table 1. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =

Schlagenhauf et al* Randomized controlled split 0.1% CHX or saline profes- Generalized advanced Per- Possibly
1990 mouth (4 treatments) sionally applied irrigation iodontitis was maintained relevant; 7
N =
30 (once a month for 5 months) equally as well in this study
Length 6 months
following SRP or no treat- with multiple professional
ment resulted in equal clini- applications of saline, CHX,
cal and microbiological or SRP alone. No examiner
changes when scaling and ir- blinding or examiner repro-
rigation were compared. Irri- ducibility reported. Al-
gation with saline and CHX though this technique could
was as effective as SRP. enhance maintenance and
There were no significant dif- provide an alternative to
ferences between saline and SRP, the need for monthly
CHX irrigations. patient visits may detract
from the usefulness of the
Christersson et al.53 Randomized controlled split 10% TCN irrigation for 5 The results of this pilot Possibly
1993 mouth minutes resulted in thera- study are intriguing; how- relevant; 7
Part I 4; Part II 11
= =
peutic levels of antibiotic re- ever, the potential damage
Length Part I 3 weeks;
= =
leased into the crevicular to soft and hard tissue as
Part II =
6 months fluid for at least 1 week in well as pulpal tissue needs
scaled or unsealed single to be evaluated. This study
rooted teeth. When 10% did not report blinding or
TCN, 5-minute irrigation was reproducibility of the ex-
compared to saline in scaled aminer. The extended ex-
sites, both significantly re- posure time and increased
duced Gl, and had attach- concentration of the TCN
ment gains of 1.8 mm for test appears to be significantly
and 1.0 mm for control at 6 associated with influence
months. Significantly greater on these rather remarkable
attachment gain was seen in clinical results. Clinically
the test at both 3 and 6 significant improvements
months compared to control. after only one 5-minute
therapy is a highly desira-
ble potential therapeutic
outcome that should be ex-
plored further.
Periodontitis: Home Irrigation
Newman et al.17 Randomized controlled, sin- Zinc sulfate rinse used as an Supragingival home ap- Relevant; 9
1994 gle-blind, multi-center paral- irrigant did not reduce clinical plied water irrigation signif-
USA, Italy, France, and lel arm parameters beyond that icantly improved clinical
Germany N =
155/175 achieved with water alone. parameters in a group of
Length 6 months
There were statistically sig- treated Periodontitis main-
nificant, but clinically small, tenance patients. Examiner
improvements in PD when reproducibility was achieved
water irrigation was com- by calibrating all examiners
pared to oral hygiene alone. at all centers to the same
study monitor.
Flemmig et al.'' Randomized controlled, sin- Daily home applied irrigation Water irrigation enhanced Relevant; 9
1994 gle-blind, parallel arm with buffered 0.3% acetylsal- the periodontal health of
Germany N =
56/60 completed icylic acid (ASA) or water re- treated Periodontitis main-
Length 6 months
sulted in significant reduc- tenance patients where
tions in Gl scores but only buffered ASA did not ap-
water reduced bleeding on pear to have any adjunc-
probing. tive effect. Control was in
this case better than the
test pharmacological agent.

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 497

Table 1. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =

Jolkovsky et alz Randomized, single-blind con- Daily home applied marginal Professional and home ap- Relevant; 9
1990 trolled, parallel arm irrigation (soft hollow rubber plication of CHX appeared
58/60 completed tip) with 0.04% CHX follow- to enhance the mainte-
Length =
3 months ing a single professional nance of periodontal health
0.12% CHX resulted in sig- in a group of treated Per-
nificant PD reductions and iodontitis patients. Exam-
Gl for both the CHX and wa- iner reproducibility not re-
ter control. C. rectus and ported.
black-pigmented Bacteroides
were significantly reduced in
the CHX group.

Listgarten et al.' Randomized, double-blind con- Subgingival daily home irri- Significant patient drop-out Possibly
1989 trolled gation with tetrapotassium may have affected results. relevant; 6
24/40 completed peroxydiphosphate (PDP) in Irrigation with water alone
Length 2 months
a group of scaled and un- was effective in reducing
treated Periodontitis patients clinical and microbial pa-
resulted in significant de- rameters in a group of
creases in plaque, Gl scores, untreated Periodontitis pa-
and PD, and increases in at- tients; however, scaling
tachment gains in the scaled plus irrigation was signifi-
plus irrigation groups. Pla- cantly better. No examiner
cebo solution was not signif- reproducibility data re-
icantly different than test. ported.
Unsealed groups had clini-
cally moderate but statisti-
cally significant reduction in
plaque and gingivitis but not
PD or attachment gains.
Fine et al.34 Randomized, double-blind, con- Daily subgingival home irri- Patient home irrigation with Relevant; 8
1994 trolled gation with a phenolic-based an over-the-counter mouth-
50 mouthrinse resulted in signif- rinse was adjunctive in the
Length =
42 days icant reduction in supragin- management of chronic
gival plaque, BOP, and adult Periodontitis by re-
redness compared to a water ducing the subgingival mi-
control. Putative pathogens croflora and the supragin-
and black-pigmented Bacter- gival plaque and gingivitis
oides were significantly re- in this very short-term
duced by the test agent. study. No reproducibility
data reported, but the
study groups were bal-
anced for smoking, gender
and age.

Linden & Newman4' Randomized, double-blind con- Daily subgingival home ap- Irrigation with placebo was Possibly
1991 trolled plied irrigation with 0.5% nearly as effective as the relevant; 7
UK N =
19 MET in a syringe for 28 days antimicrobial solution in
Length =
84 days resulted in no significant dif- maintaining health in a
ferences between placebo group of chronic Periodon-
and test solutions. Both titis maintenance patients.
groups showed marked im-
provement but the MET
group had proportionately
more sites.

bleeding on probing. MET =
colony forming units. PD =
probing depths.
Chlorhexidine. SRP =
scaling and root planing.
Gl =
gingival index. TCN =

Vol. 1, No. 1, November 1996

498 Drisko

Table 1. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =

Vignarajah et al.2' Randomized, double-blind con- Subgingival home daily irri- The effect of therapy lasted Possibly
1989 trolled, parallel arm gation with 0.1% CHX re- about 3 months in the relevant; 7
UK N 13/14 completed
sulted in statistically signifi- group of Periodontitis sub-
Length 168 days
cant reductions in plaque jects during maintenance
scores, PD, and the papillary following full mouth perio-
bleeding index at day 84, but dontal debridement. Ex-
not at day 168. aminer reproducibility sta-
tistics reported to be k

0.62 to 0.88.

bleeding on probing. MET =
colony forming units. PD =
probing depths.
Chlorhexidine. SRP =
scaling and root planing.
Gl =
gingival index. TCN =

Effect on Plaque Toxicity They also found no difference in penetrabil-

ity within either group between proximal, fa-
Brownstein et al.26 suggested that the ef- cial, or lingual surfaces or between furcated
fect of irrigation on gingival bleeding and to and non-furcated teeth, which is in agree-
a lesser extent plaque may be due to the fol- ment with Eakle et al.31 Braun and Ciancio30
lowing factors: 1) change in plaque compo- reported penetration of 90% for sites 6 mm
sition; 2) flushing out of the inflammation- or less in depth and 64% for pockets 7 mm
inducing factors; and 3) a physical change or deeper when the tip was professionally in-
in tissue integrity (Table 1). Others have hy- serted 1 to 2 mm into the pocket.
pothesized that irrigation may involve spe- Eakle et al.31 studied penetrability when
cific host-parasite alterations in the subgin-
the disclosing solution irrigation was applied
gival environment or that perhaps the inad- with a supragingival irrigator at either a 45°
vertent mechanical stimulation of the
or a 90° angle to the gingival margin. They
gingiva may in some way be beneficial (Table concluded there was no significant differ-
J 27,28
ence between the two methods of applica-
Penetration In a recent study,16 pocket irrigation was
Pitcher et al.29 reported that disclosing so- carried out with both a pulsed jet irrigator
lutions failed to reach the apical extent of and syringe placed within 1 mm of the prob-
the periodontal sulcus with mouthrinses ing depth. The pulsed jet irrigator provided
and with direct irrigation using a hand held better debridement and superior clinical and
bacterial results than did the syringe.1632
syringe. Direct irrigation of pockets > 5 mm
with a hand held syringe, while more effec- However, the deepest penetration to date
tive than rinsing, resulted in penetration of has been presented in an important study by
1.8 mm versus only 0.2 mm for rinsing. Hardy et al.,15 demonstrating complete pen-
etration when an irrigating syringe tip was
Other investigators evaluated the differ-
ences in penetrability with newly designed placed 3 mm subgingivally into both shallow
cannula tips in a powered irri- and deep pockets. This is the only study that
gator.13 29.30
Boyd et al.13 determined disclos- reports 100% penetration with an irrigation
ing solution delivered in a cannula-type technique.
irrigator tip inserted half the depth of the Lamer and Greenstein14 evaluated the ef-
pocket in medium and deep periodontal fect of calculus and irrigator tip design on
pockets penetrated farther than solution de- depth of subgingival irrigation. They deter-
livered with a standard supragingival tip. mined that deep pockets (7 to 10 mm) with

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharrnacotherapeutics 499

calculus had less dye penetration. This was irrigant used.25 The implication of this and
not found to be true at shallower sites of 4 other studies is that the physiologic flushing
to 6 mm, where the presence of calculus did of the pocket itself may comprise the pri-
not impede dye penetration for any of the mary therapeutic effect of irrigation, regard-
tips. In the 7 to 10 mm deep pockets, when less of the irrigant used. However, the
calculus was present, the use of the can- following studies show a wide spectrum of
nula-type probe tip resulted in greater dye beneficial effects when antimicrobials and
penetration than any others tested. antiseptics are used in irrigating solutions in
Greenstein33 has suggested that the pen- conjunction with periodontal debridement,
etration depth of the irrigant might be un- supportive periodontal treatment, or home
derestimated in studies using the level of the care.
periodontal ligament (PDL) to represent the Chlorhexidine. Chlorhexidine (CHX) has
base of the pockets. He proposed that, al- been shown to possess a broad spectrum of
though the PDL is easily detected on ex- topical antimicrobial activity. It is this prop-
tracted teeth and provides a reproductible erty, in addition to the safety, effectiveness,
reference point, measurements taken from substantivity, lack of serious side effects,
the PDL do not take into account that his- and lack of toxicity, that has allowed it to be
tologically, the coronal aspect of the junc- used extensively in dentistry—usually as a
tional epithelium corresponds to the base of mouthrinse. Chlorhexidine activity in the
the pocket. Since the junctional epithelium oral cavity is promoted by binding to plaque,
is approximately 1 mm coronal to the level salivary pellicle, oral mucosa, and hard
of the periodontal ligament, studies using structures and its release for up to 24 hours
the periodontal ligament as their reference makes it a highly substantive product. Re-
would have overestimated the probing depth versible side effects that can occur with pro-
by approximately 1 mm, and thus underes- longed use of Chlorhexidine in the oral cavity
timated the solution penetration by about 1 include staining of hard tissues and some
mm. Subgingival irrigation may penetrate dental materials, altered taste sensation, su-
more deeply than previously thought. Since pragingival calculus accumulations, and
calculus impedes irrigation in deep sites, pa- less commonly, a mild mucositis.54
tients should be instructed to use irrigation Recent literature is dominated by studies
after initial debridement has been completed comparing the effects of different concentra-
to obtain the most benefit from irrigation tions of CHX used with supragingival irri-
therapy. gation on plaque and gingivitis. Decades of
It would appear that maximum results are research have proven that Chlorhexidine, at
obtained if the irrigant reaches the base of 0.2% or less, is highly predictable in reduc-
the pocket either by cannula on a pulsed ir- ing supragingival plaque accumulation and
rigator or by inserting a blunt irrigating nee- gingival inflammation.
dle on a hand held syringe at least 3 mm Minimum inhibitory concentration (MIC)
subgingivally. of CHX was tested against a range of 52 bac-
teria commonly isolated from subgingival

Irrigating Solutions plaque and was reported to be between 8

and 500 ug/ml.55 At 250 ug/ml all the sub-
Water. The majority of studies reviewed gingival isolates from subjects presenting
utilize some type of a placebo agent as a con- with Periodontitis lesions, were inhibited.
trol including water,23,25,34-37 quinine sul- Overall the MIC was below the level that can
fate,19 38 40 or saline.1416-41-53 It is important to be achieved by topical application of CHX.
note that the majority of the studies con- However, in vivo serum protein may inhibit
cluded that water provided an equal, and CHX and prolonged exposure may be nec-
sometime superior, beneficial result when essary before low dose concentrations are ef-
compared to other test medicaments. For ex- fective.55 It is not surprising that the interest
ample, Jolkovsky et al. found an improve- in Chlorhexidine is still strong, and its po-
ment of the GI at 3 months regardless of the tential efficacy is being explored using dif-

Vol. 1, No. 1, November 1996

500 Drisko

ferent concentrations in various subgingival weeks did not appear to augment the affects
delivery systems for the treatment of Perio- of the non-surgical periodontal therapy.
dontitis. Braatz et al.58 reported similar results when
Stabholtz et al.56 irrigated subgingivally their patients performed daily home irriga-
one time with 0.12% CHX solution prior to tion for 24 weeks with 2.0% Chlorhexidine
extraction and tested the tooth root for any following an initial scaling and root planing.
residual antimicrobial activity. No antimi- It is not clear why there are such significant
crobial activity was found. In contrast, when differences between the results of these
teeth irrigated with 50 mg/ml (5%) of tetra- studies and those of Southard et al., but it
cycline hydrochloride (TCN) were compared is assumed that different levels of disease
to 0.12% CHX or saline irrigated teeth, TCN activity or disease severity were present at
revealed significantly greater residual anti- the time of treatment and could account for
microbial activity for 12 days than the 0.12% the lack of agreement between studies, par-
CHX treated teeth, and significantly more ticularly when others have shown irrigation
activity for 16 days than the saline irrigated with weaker concentrations of CHX, and
teeth. even saline, have been shown to be effective
Further research should include investi- in reducing periodontal inflammation and
gations using higher concentrations of probing depths.2151 Stanley et al.55 proposes
Chlorhexidine and longer application times that the highly effective oral hygiene in the
to determine if this would affect the sub- Braatz et al.58 and MacAlpine et al.48 studies
stantivlty and antimicrobial activity of Chlor- may have masked the effect of the 2.0% CHX
hexidine on roots. It would seem reasonable irrigation.
to assume that the substantivity, or binding 0.2% Chlorhexidine. When a 15-second
to the root surface, would be increased with CHX irrigation or 1-minute rinse with 0.2%
higher concentrations of Chlorhexidine and Chlorhexidine was compared to saline, it was
longer exposure times, resulting in a more concluded that irrigation with Chlorhexidine
profound reduction of antimicrobial activity, was more effective at reducing plaque vitality
similar to that of 5% TCN. than rinsing with Chlorhexidine.51 Both the
2.0% Chlorhexidine. Southard et al.57 have CHX rinse and CHX irrigation treatments
tested the hypothesis that multiple profes- were more effective than their respective sa-
sional irrigations with higher concentrations line controls. Walsh et al. found similar re-
of CHX has a significant adjunctive effect sults in a double-blind study, where 0.2%
when performed alone or in conjunction with Chlorhexidine was used twice a day for 56
periodontal debridement (Table 1). In their days in an oral irrigator, and was able to re-
study, 4 weekly irrigations with 2.0% Chlor- duce plaque deposition, periodontal inflam-
hexidine irrigation, with and without scaling mation, and probing depths.21 On the
and root planing (SRP) reduced clinical pa- contrary, others have reported no additional
rameters and the level of Porphyromonas gin- benefit from using a single subgingival ap-
givalis in > 6 mm probing depths that bled plication of 0.2% Chlorhexidine.1938 Tseng
on probing. Meticulous root planing was an and Newcomb47 showed that when scaling
effective treatment through a 7-week period, and root planing had been thoroughly carried
but irrigation with 2.0% Chlorhexidine alone out immediately prior to irrigation, a single
was nearly as effective. Combined therapy application of 0.2% Chlorhexidine did not en-
using SRP plus 4 weekly CHX irrigations re- hance gingival healing, or delay recoloniza-
sulted in significant attachment gains and tion of pockets by certain microorganisms.
reduction of P. gingivalis for longer time pe- Wennström et al.41 are in full agreement and
riods (up to 11 weeks) compared to no treat- reported earlier that professionally performed
ment, scaling and root planing alone, or periodic subgingival irrigation with Chlorhex-
irrigation alone. In contrast, MacAlpine et idine used alone, or in combination with
al.48 determined irrigation with 2.0% Chlor- thorough mechanical debridement, failed to
hexidine, saline, or tetracycline immediately produce a significant therapeutic effect. It
following SRP and every other week for 24 did not induce changes in total viable

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 501

counts, anaerobes, rods, Gram-negative an- deep periodontal pockets. Clinical

micros in
aerobic rods, black-pigmented Bacteroides, improvements of 0.9 mm in attachment lev-
P. gingivalis, or motile rods and spirochetes els and 1.8 mm probing depth reductions
that were any different from the control were observed at 4 weeks which the authors
sites.59 Others reported limited, if any, ef- contributed to the marked suppression of
fects with subgingival irrigation with 0.2% Wolinella recta and other organisms.63 In an-
Chlorhexidine irrigation.60 61 other study, using the same protocol, Pep-
D'Angelo et al.62 combined daily irrigation tostreptococcus micros was not eliminated
with 0.2% CHX, scaling and root planing, following scaling and a 5-minute irrigation
and weekly sessions of professional oral hy- with 0.12% CHX.64
giene in the treatment of a child with pre- 0.06% Chlorhexidine. Chlorhexidine has
pubertal Periodontitis. In addition, they ex- been further diluted and tested by Brown-
tracted the remaining primary teeth several stein et al.26 who compared oral irrigation
months before eruption of the first perma- with 0.06% Chlorhexidine and rinsing with
nent molars. This unique treatment was ef- 0.12% Chlorhexidine to placebo in the treat-
fective in establishing a healthy environment ment of naturally occurring gingivitis over a
for the eruption of the permanent teeth, 2-month period. They concluded that deliv-
without use of systemic antibiotics. The au- ery of Chlorhexidine (0.06%) by an oral irri-
thors conclude that the elimination of the gator is effective at reducing gingival
pathogenic microflora during the primary bleeding, plaque, and Actinomyces species
dentition stage by extracting the infected and is thus an effective means of treating
teeth, plus daily local mechanical and chem- naturally occurring gingivitis. The 6-month
ical control of the irritating factors may have results of a study by Flemmig et al.18 (Table
prevented any subsequent damage to the 1) demonstrated that 0.06% Chlorhexidine
child's permanent dentition. irrigation was the most effective regimen for
0.12% Chlorhexidine. Based on the previ- reducing the plaque index (PI), gingival index
ous discussion, it is clear that there is no (GI), and BOP compared to water irrigation
consensus in the literature relative to the or a twice daily rinse with 0.12% Chlorhexi-
benefit of using Chlorhexidine irrigation to dine. Interestingly, water irrigation reduced
treat Periodontitis patients. Use of lower clinical parameters nearly the same as the
concentrations of CHX (0.12%) in a mono-jet CHX rinse. In another report on the same
pulsed irrigator have been reported by Vig- study (Table 1), Newman et al.65 reported on
narajah et al. and found to significantly the subgingival microflora of the gingivitis
enhance the probing depth reduction during patients and showed incremental beneficial
routine periodontal care20 (Table 1). Yet, oth- effects of 0.06% CHX irrigation on the mar-
ers found that single or even multiple pro- ginal and subgingival microflora of these pa-
fessional subgingival irrigations with 0.12% tients. It appears that daily home use of
Chlorhexidine immediately following SRP did diluted concentrations of CHX in an irrigator
not result in major adjunctive benefits in re- has merit as a treatment for gingivitis, but
duction of subgingival pathogens beyond the evidence does not strongly support the
that achieved by thorough scaling and root efficacy of subgingival irrigation with diluted
planing.43-44 Of interest was one study show- CHX in the treatment of Periodontitis pa-
ing subgingival irrigation of periodontal tients, except perhaps during maintenance.
pockets at 1-month intervals was equally ef- 0.04% Chlorhexidine. Using a combined
fective as scaling and root planing performed professional and home applied technique,
at the same pace. However, 0.12% Chlorhex- Jolkovsky et al.25 found a single professional
idine was no more effective than saline con- subgingival irrigation with 0.12% Chlorhexi-
trols in this group of maintenance patients dine in periodontal maintenance patients fol-
(Table l).42 Rams et al. reported failure of lowed by daily home marginal irrigation with
subgingival ultrasonic debridement followed 0.04% Chlorhexidine reduced GI, as well as a
with a prolonged 5 minute irrigation with significant reduction in Wolinella recta and
0.12% CHX to eradicate Peptostreptococcus black-pigmented Bacteroides sp. (Table 1).

Vol. 1, No. 1, November 1996

502 Drisko

Others27 found that Prevotella intermedia, Gl, study

has shown that 1.5% hydrogen per-
and BOP were reduced when toothbrushing oxide of no therapeutic value in the pre-
was combined with 0.04% irrigation with vention or treatment of an experimental
Chlorhexidine (Table 1). gingivitis when used as a mouth rinse, or in
0.02% Chlorhexidine. A classic study con- an oral irrigator.67
ducted by Lang and Ramseier-Grossman66 There appears to be some advantage in us-
determined the optimal dosage of Chlorhex- ing frequent professional application of hy-
idine digluconate for chemical plaque con- drogen peroxide in patients infected with
trol when applied by a fractionated jet oral Actinobacillus actinomycetemcomitans. Wi-
irrigator. They tested daily applications of kesjö et al.68 reported the effects of subgin-
numerous concentrations and volumes of ir- gival irrigation with hydrogen peroxide bi-
rigants and concluded that one daily appli- weekly until A. actinomycetemcomitans was
cation of 400 ml of a 0.02% Chlorhexidine no longer detected by selective culture at 6
solution was the minimal optimal concentra- months. They found that the irrigation regi-
tion for complete inhibition of dental plaque. men tested has some potential to suppress

Summary. The literature seems to support A. actinomycetemcomitans for up to 5 months.

a range from 0.02% to 0.2% Chlorhexidine as The reduction rate to below detectable levels
an efficacious dosage for use in an oral irri- seems related to initial numbers of cultiva-

gator as a means of reducing gingival inflam- ble bacteria from the periodontal pockets;
mation in specific clinical situations.18 Early the higher the numbers of A. actinomycetem-
evidence suggests that daily irrigation can comitans, the longer it took to eradicate
be effective in treating gingivitis and early them from the pocket.
Periodontitis with these lower concentra- Fluorides. It has been established that
tions of CHX. Rams et al. have shown that a subgingival irrigation with 1.64% stannous
5-minute subgingival irrigation per pocket in fluoride (SnF2) was more effective than 0.4%
conjunction with periodontal debridement stannous fluoride or saline in decreasing
was successful in improving clinical param- motile bacteria and spirochetes for several
eters and in eliminating Campylobacter rec- weeks in advanced Periodontitis patients,69
tus64 but not P. micros.63 Only one recent but that a single subgingival irrigation with
study supports any significant additional SnF2 may only transiently reduce the mean
benefits from using multiple irrigations of number of black-pigmented Bacteroides
higher concentrations; e.g., 2% CHX, (—20 (BPB) while not affecting the total anaerobic
times stronger than is currently available in bacterial counts.70 More recently, it has been
the United States) to enhance the effects of shown that amine fluoride-stannous fluo-
SRP.57 Dally home irrigation with water or ride gel irrigation of deep periodontal pock-
diluted Chlorhexidine appears to be benefi- ets in conjunction with conventional treat-
cial to maintenance patients. Optimal con- ment, can prevent the repopulation of the
centration and application methods are not pockets by BPB.71
firmly established for the treatment of Per- Krust et al. reported that 4 weekly profes-
iodontitis, but it would appear that higher sional irrigations with 1.64% stannous flu-
concentrations of CHX and prolonged expo- oride, saline, or 0.12% Chlorhexidine did not
sure times may be needed in order for sub- enhance the beneficial effects of SRP.43
gingival irrigation to have a significant effect The data suggest that the benefits of a sin-
on subgingival microflora associated with gle professional application of SnF2 or 0.12%
Periodontitis. CHX immediately following SRP is limited,
Peroxides. Earlier reports by Wennstrom unless reinforced with other medicaments
et al. showed that professionally performed such as povidone-iodine.
periodic subgingival irrigation with hydrogen Iodine. Wolff et al. found that a single pro-
peroxide used alone, or in combination with fessional subgingival irrigation with 1.64%
thorough mechanical debridement, has a stannous fluoride immediately following
significant therapeutic effect on clinical or SRP, when combined with dally home sub-
microbial parameters.41-59 More recently, one gingival therapy with a 3.75% iodine solu-

Annals of Periodontology
Review: Non-Surgicäl Pocket Therapy: Pharmacotherapeutics 503

tion (3.75mg/ml), was effective in gingivitis Phenolics. Ciancio et al.22 reported that the
and early Periodontitis patients.24 use of a phenolic mouthrinse in an oral irri-
Iodine has been combined with other in- gating device could result in significant re-
gredients for subgingival irrigation. Clark et ductions in plaque, bacterial cell counts, and
al.72 reported on the effect of a commercially gingival bleeding, and is an effective adjunct
prepared solution of povidone iodine and hy- to normal oral hygiene. Significant short-
drogen peroxide as the subgingival irrigant term microbiological clinical effects of sub-
on established gingivitis (Table 1). They de- gingival irrigation with phenolic mouthrin-
termined it to be a beneficial adjunctive ses have been reported by Fine et al., along
treatment for the prevention and control of with reduction of supragingival plaque and
gingivitis when used with routine oral hy- gingivitis (Table l).34
giene procedures.
Nakagawa et al.49 compared the bacteri- Irrigation With Antibiotics
cidal effects of three different concentrations
of the povidone-iodine solution delivered sub- Root substantivity. Stabholz et al.56 inves-
gingivally. Undiluted solution resulted in a tigated the substantivity and antimicrobial
significant reduction in colony forming units activity of tetracycline-HCl (TCN-HC1) after a
(CFU), but the 10% and 20% dilutions did single subgingival irrigation prior to tooth
not produce the same reductions. Total CFU extraction. They concluded that 5% tetracy-
were reduced to less than 1% in several cline (50 mg/ml) exhibited significantly
sites, which was not true for sites irrigated greater antimicrobial activity than either
with biological saline. 0.12% CHX digluconate for 12 days or saline
Iodine in combination with other agents for 16 days. The 1% tetracycline-HCl (10
has been investigated previously by Rosling mg/ml) exhibited significantly greater anti-
et al.73 74 A mixture of H2Oa-NaCl and microbial activity than 0.12% CHX diglucon-
NaHC03 was applied professionally in the ate and saline for 4 days. Thus, the amount
pocket every 14 days for 3 months. The pa- of antimicrobial activity retained is propor-
tients then used the mixture twice a day in- tional to the concentration of the TCN used
stead of dentrifice, in addition to daily for irrigation.
subgingival irrigation with 1.0% povidone io- 5% tetracycline-HCl. Given the substan-
dine. Results showed the treatment regimen tivity of TCN, it is surprising to find the effect
significantly enhanced the effect of subgin- of tetracycline-HCl irrigation after scaling
gival debridement and further reduced sub- has had mixed results. In one report subgin-
gingival spirochetes and motile rods. gival irrigation with 2 cc of 5% tetracycline-
Advantages of iodine alone or in combi- HCl (50 mg/ml) immediately following scal-
nation with other over-the-counter agents ing and root planing did not significantly
include low cost to the patient and a very low augment reduction of A. actinomycetemcom-
probability of bacterial resistance. Since itans, P. gingivalis, or P. intermedia beyond
povidone iodine is a topical antiseptic and that seen with SRP alone.48 Nylund and
kills bacteria on contact, rather than effect- Egelberg50 are in agreement that there is no
ing cell wall synthesis and other mecha- additional benefit achieved beyond SRP by
nisms that might adversely alter the ecosys- treating furcation lesions with subgingival
tem, opportunistic or resistant organisms irrigation of 5.0% tetracycline-HCl (Table 1).
are unlikely to develop in response to short- The magnitude of change seen in the sub-
term use of the antimicrobial. Disadvan- gingival microflora from one associated with
tages include sensitivity (allergy) to iodine disease to one associated with health was
which may be rather common, and the po- not apparently influenced significantly by
tential for staining teeth and restorations the addition of a 5.0% TCN irrigation.52
with prolonged use. Staining may be avoided 10% tetracycline-HCl. Using a higher con-
by swabbing the teeth with hydrogen per- centration of TCN over a longer period of
oxide or brushing with a dentifrice immedi- time has shown some interesting results in
ately after povidone-iodine use. one recent study. Christersson et al.53 con-

Vol. 1, No. 1, November 1996

504 Drisko

ducted a classic 6-month study to determine determined that topically-applied NSAIDS

the substantMty of tetracycline-HCl and the may be of benefit in the management of peri-
effects of irrigation with tetracycline-HCl or odontal inflammation, as the study reported
saline following a single session of scaling that the systemic absorption of flurbiprofen
and root planing (Table 1). They reported may have reduced the severity of the devel-
that 10% tetracycline-HCl irrigation of root oping inflammatory lesions. Other new ap-
surfaces for long periods of time (5 minutes) plications of NSAIDS are being investigated77
results in a subsequent release of active an- and are discussed below. Altering the etiol-
tibiotic into the gingival fluid at therapeutic ogy from the host response aspect by topical
levels for at least 1 week. They also reported non-steroidal anti-inflammatory medication
that the irrigation resulted in significantly is intriguing, and deserves further investi-
greater attachment gain as compared to SRP gation.
alone over at least a 6-month period of heal-
ing. The substantive properties of tetracy- Other Agents
cline-HCl, in addition to its antimicrobial
and anticollagenase activities, make it prom- Zinc sulfate. Newman et al.17 reported that
ising as an adjunct to mechanical therapy water irrigation was superior anti-plaque
through local application. 0.57% zinc sulfate when looking at the GI,
0.5% metronidazole. Linden and Newman BOP, and PD, although this difference had
found a simplified daily oral hygiene regimen no clinical relevance or probing depth
combined with daily subgingival irrigation changes. Plaque reduction was not observed
with 0.5% metronidazole or placebo was ef- with this agent when used as an irrigant.
fective in reducing Periodontitis for an ad- Most surprising was the fact that zinc sul-
ditional 8 weeks, and that proportionately fate as an irrigant did not demonstrate a
more sites improved in the metronidazole benefit in reducing gingivitis over normal
group (Table l).40 However, Macaulay and oral hygiene since water irrigation by itself
Newman19 reported that subgingival irriga- was beneficial (Table 1).
tion as part of a simplified oral hygiene reg- Chloramine-T. Herzog and Hodges78 com-
imen, with or without 0.05% metronidazole, pared the effects of subgingival irrigation
is effective in reducing the motile and spi- with and without chloramine-T. They con-
rochete portions of the subgingival flora. cluded there were no differences in any of
the clinical parameters measured when
With Non-Steroidal chloramine-T was used as an adjunct to
Topical Irrigation scaling and root planing in periodontal ther-
Acetylsalicylic acid (ASA). Flemmig et al.75 Parodontax. Itic and Serfaty investigated
investigated adjunctive supragingival irriga- the effects of parodontax subgingival irriga-
tion with 0.3% acetylsalicylic acid in pa- tion following non-surgical therapy.79 They
tients with moderate to severe Periodontitis concluded that parodontax (active ingredi-
(Table 1). They concluded that either 0.3% ent not given) is effective in the control of
ASA or water irrigation in addition to regular gingivitis and subgingival flora and appeared
oral hygiene can be a beneficial adjunct to to be effective in detoxifying the cementum
periodontal supportive therapy in patients surface. A majority of the parameters ex-
over a 6-month period. However, the use of amined at 90 days showed the test agent to
buffered 0.3% ASA as an irrigant was not su- exceed results obtained from non-irrigated
perior to water and does not appear to en- quadrants.
hance the clinical efficacy of supragingival Tetrapotassium peroxydiphosphate. Listgar-
irrigation on periodontal health. ten et al.80 followed the effect of subgingival
Flurbiprofen, meclofenamic acid, and Ibupro- irrigation with tetrapotassium peroxydi-
fen. Non-steroidal anti-inflammatory drugs phosphate on scaled and untreated perio-
(NSAIDS) have recently been investigated for dontal pockets (Table 1). They found scaling
use in subgingival irrigation. Haesman et al.76 and irrigation produced significant de-

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 505

creasesfrom the initial PI and GI scores and temic antimicrobials, particularly for refrac-
PD and attachment loss (AL) measurements tory and recurrent immunocompromised
and that coccoid cells increased while motile groups, appear to hold great promise, and
bacteria and spirochetes decreased, but should be explored further.
there were no differences for the therapeutic Povidone iodine. An older split-mouth
effect of the test solution. study by Rosling et al.84 showed remarkable
Oxygen. Schlagenhauf et al.81 used a unique results were obtained with non-surgical per-
technique consisting of repeated subgingival iodontal debridement using 0.05% povidone
applications of oxygen in untreated perio- iodine in an ultrasonic device compared to
dontal patients. They concluded that flush- modified Widman flap surgery. Resultant
ing the pocket with oxygen once a week for healing was significantly better, and attach-
8 weeks significantly improved clinical at- ment gains were significantly greater, with
tachment levels, bleeding on probing, and the ultrasonic debridement compared to
the presence of disease-associated microor- surgery.
ganisms relative to the control. Penetration. Nosal et al.85 showed that
0.12% Chlorhexidine around implants. erythrocin dye delivered as a lavage solution
Lavigne et al.45 found no significant differ- through a hollow probe-like ultrasonic tip
ences when they evaluated the effects of may achieve complete penetration in 86% of
subgingival irrigation with 0.12% Chlorhexi- the pockets 3 to 9 mm deep. The depth of
dine, sterile saline, or no irrigation in pa- penetration of the dye was localized to the
tients with hydroxyapatite-coated dental area of the ultrasonic tip with very little lat-
implants. There were no differences between eral dispersion,therefore those areas that
treatment modalities at any time interval. were inaccessible to the tip were also inac-
Decreased probing depths were obtained cessible to the dye solution.
with Chlorhexidine irrigation as well as in
the no treatment groups at all time intervals.
Safety is a concern when discussing sub-
Ultrasonics and Antimicrobials gingival irrigation. Subgingival lavage can be
Chlorhexidine. The use of ultrasonic seal-
reliably accomplished using various modes
of application. Most studies evaluated self-
ers for delivery of concentrations of 0.06%
and 0.12% Chlorhexidine as the irrigant has
irrigation by patients used a blunted irrigat-
had mixed results. Slight adjunctive effect to
ing syringe,39'40'58'86 pulsed jet irrigation,20 2338
or some other method.19-24'87 These investi-
differential clinical benefits that are site-de- have not reported iatrogenic wounds
pendent have been reported by Reynolds et or other untoward sequellae to be a problem,
al.82 and Chappie et al.35 (Table 1). More re-
although sometimes technique reinstruction
cently Taggart et al.36 discovered a slight ad- was required.
junctive effect in the reduction of PD when Cobb et al.88 reported a lack of deleterious
0.02% Chlorhexidine was used as a coolant effects when saline was delivered supragin-
during ultrasonic root planing for the treat- givally at 60 psi by a pulsating jet irrigator
ment of chronic Periodontitis.
with the tip placed at a right angle to the
Recently, Skrepinski et al.83 evaluated ul- tooth. There was no observable difference
trasonic debridement with 0.05% povidone when the tip was place 1 or 3 mm away from
iodine or 0.12% Chlorhexidine irrigating so- the tooth in regards to the control and irri-
lutions along with systemic doxycycline
gated specimens. Epithelial topography was
(DOX) therapy in adult Native American di- not affected and cavitations and microulcer-
abetics. Significant reductions in clinical ations were absent. Individual spatial rela-
and microbial parameters occured in the
DOX plus povidone iodine and CHX groups
tionships and cell appearances were normal
for both treated and untreated groups in
compared to placebo controls. These tar- these 1 to 6 mm probing depth sites.
geted therapies combining local and sys-

Vol. 1, No. 1, November 1996

506 Drisko

Dunkln et al.89 reported the possibility of support recommendation of irrigation for pa-
delivering normal saline solution to the bot- tients at risk for infective endocarditis.
tom of the pocket without causing tissue in-
jury or discomfort with an air-driven subgin-
gival delivery kit. They advised that with low Summary of Irrigation
viscosity liquid, the 28-gauge tip is tip of
choice, because it is easy to use without in- Local chemotherapy offers some advan-
flicting trauma to the area. tages over systemic applications, however
topical agents delivered in an irrigating so-
lutions may fail to affect the periodontal
Bacteremia Associated With pathogens at the base of the pocket, in fur-
cations, and in other inaccessible areas. In
Irrigation addition, most agents available for home ir-
Allison et al.90 concluded that the inci- rigation do not sustain a long term effect due
dence of bacteremia following subgingival to the rapid decline in the concentration of
ultrasonic scaling and root planing can be the agent and the high turnover rate of the
reduced using an irrigating solution of 0.12% sulcular fluid. Local application of solutions
Chlorhexidine. In direct contrast, Lx)fthus et by irrigation or mouthrinse depends on
al., reported that a single subgingival irri- "first-order kinetics" (high initial concentra-
tions and multiple applications) in order to
gation with 0.12% CHX or sterile water can
result in a similar incidence of bacteremia as provide sustained effectiveness. Modification
with other dental manipulations.37 Also, ir- of the microflora present in the periodontal
rigation of periodontal pockets with either pocket may be appropriately treated with
0.12% CHX or sterile water did not alter the irrigation or a sustained delivery device,
incidence of bacteremia after scaling and where infection within the tissue will most
root planing when compared to non-irri- likely require systemic antibiotics.
In general, it has been shown by numer-
gated controls. Waki et al.91 are in agreement ous studies presented in this review and in
with the previous results. They reported on
the effect of a single professional subgingival Table 1, that water irrigation at the gingival
irrigation with 0.12% CHX plus subsequent margin reduces gingivitis, and that the ad-
home marginal irrigation with a 0.04% CHX dition of antimicrobial agents has some ad-
solution for 3 months following SRP during ditional clinical efficacy over water irrigation
maintenance visits. The extensive regimen alone. However, subgingival irrigation as an
did not reduce the incidence of bacteremia. adjunct to conventional therapy in Periodon-
Rahn tested povidone iodine (PVP-I) in a titis sites has had mixed results. With the
10% solution rinse compared to CHX and exception of high concentrations of Chlor-
water, and found PVP-I capable of reducing hexidine57 (2%) or tetracycline53 (10%), the
the intraoral bacteria by 2 to 3 logs with a addition of other antimicrobials have re-
30-second rinse.92 Based on these findings, sulted in rather unremarkable additional
he suggests using a 30-second rinse or oral benefits beyond water or saline alone.
antisepsis to support the antibiotic regimen
given to patients requiring prophylaxis. NON-STEROIDAL ANTI-
However, in clinical trial, Witzenberger et
al.93 reported that rinsing for 1 minute with
PVP-I and then receiving subgingival irriga- It has been known for some time that bac-
tion for 3 minutes with 10% povidone-iodine teria are the essential causative agents of
solution did not have any effect on either periodontal disease. However, only within
increasing or decreasing the incidence of the last 20 years has research shown the
bacteremia following thorough subgingival pathogenesis of periodontal diseases to in-
scaling. volve the host's inflammatory response. Bac-
It would appear that irrigation may cause teria and bacterial byproducts can cause
bacteremia; therefore the evidence does not tissue damage and evoke an inflammatory

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 507

response producing metabolites from the other metabolites of arachidonic acid break-
breakdown of arachidonic acid by the cycloox- down. This was borne out by additional
ygenase pathway. This gives rise to prosta- studies.108"114 These studies confirm that the
cyclin, thromboxane, and Prostaglandins. metabolites of arachidonic acid breakdown
These metabolites have been implicated in a are potent stimulators of bone resorption
number of diseases, but in periodontal dis- and are likely to be mediators in diseases of
ease, they have been closely associated with bone loss.
gingivitis and alveolar bone resorption.94-97 Other work in the 1970s and 1980s
During the 1970s, the Prostaglandins were clearly showed the Prostaglandins and the
implicated in the pathogenesis of periodon- other metabolites of arachidonic acid break-
tal disease in a number of studies.98"101 down to be causative agents in the patho-
genesis of periodontal disease. When meas-
The History of Prostaglandins: uring crevicular fluids and gingival tissue
Implications in Periodontal Disease samples of subjects with periodontal disease
and healthy tissue there were significantly
Prostaglandins and the metabolites asso- elevated levels of Prostaglandins and other
ciated with the breakdown of arachidonic metabolites in the diseased tissues com-
acid were discovered in the 1930s, leading pared to health.99 101 109 115 122 With these
to tremendous amounts of research of the studies as a base, Offenbacher et al.123-125
molecules and their role in the human body. compared either gingival attachment levels
In the 1960s, several reports102-104 impli- or radiographic bone loss with the levels of
cated Prostaglandins as mediators of the Prostaglandins found at the tested sites. In-
cardinal signs of inflammation: redness, creased levels of Prostaglandins were seen in
edema, pain, heat, and loss of function. Re- the sites where there was loss of attachment
searchers of periodontal disease examined and/or radiographic bone loss indicative of
the contribution of Prostaglandins to gingi- periodontal disease, and that the levels of
vitis and the resorption of alveolar bone; i.e., Prostaglandins in healthy tissue were signif-
Periodontitis. icantly lower.
In the late 1960s and the early 1970s, A 1992 study by Abramson et al.126 of hu-
studies98 100 105 106 demonstrated that gingival man gingival crevicular fluid showed that
tissue cultures were capable of inducing the levels of Prostaglandin E2 and thrombox-
bone resorption. Vane107 showed that aspirin ane B2 remained constant for the duration of
and aspirin-like drugs (NSAIDS) inhibited flurbiprofen treatment in patients with early
the production of Prostaglandins. Goldhaber adult Periodontitis. It was not known if the
et al.98 later linked the inhibition of Prosta- metabolites of arachidonic acid metabolism
glandin synthesis to a marked reduction in would remain at lower levels once the flur-
the amount of bone resorption. Goldhaber et biprofen was removed, or if the severity of
al.98 hypothesized that, if Prostaglandins the Periodontitis would have any effect on
were responsible for the bone loss associated the levels in the crevicular fluids. More lon-
with Periodontitis and if NSAIDS were ca- gitudinal studies are needed to determine
pable of inhibiting Prostaglandin synthesis, the effects of NSAIDS on the metabolite lev-
then the use of NSAIDS and other inhibitors els found in the crevicular fluids. In a related
of Prostaglandins might have an effect on project, Offenbacher et al.127 evaluated the
the reduction of bone loss of periodontal dis- effects of systemic ibuprofen, systemic na-
ease. proxen, and topical flurbiprofen on beagle
In the late 1970s and the early 1980s dogs. All three NSAIDS reduced the cycloox-
multiple studies108111 found that in addition ygenase metabolites and periodontal bone
to Prostaglandins, the prostacyclines and loss between 21% and 37% compared to the
phospholipases also caused bone resorp- control bone loss rate (Table 2). It was also
tion. However, Prostaglandins—specifically determined that topical flurbiprofen was as
those of the E series—were far more potent effective in depressing the crevicular fluid
in their ability to resorb bone than were the levels of Prostaglandin E2 and thromboxane

Vol. 1, No. 1, November 1996

508 Drisko

Table 2. Non-steroidal anti-inflammatory drugs (NSAIDs)

Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =
Williams et al.156 Randomized, double-blind, pla- Twice daily systemic flurbi- Well-designed study had Relevant; 10
1989 cebo controlled profen significantly reduced run-in period of 6 months to
44/56 completed the rate of alveolar bone loss determine average rate of
Length 28 months
compared to placebo at 12 bone loss prior to initiating
and 18 months but not at 24 the experimental protocol.
months. The results suggest that in
the future, blocking the host
response with NSAIDS may
be adjunctive to antimicro-
bial therapy in the treat-
ment of Periodontitis.

Heasman et al. Randomized, double-blind, pla- 1% flurbiprofen toothpaste Flurbiprofen toothpaste was Relevant; 9
1993 cebo controlled did not reduce bone loss but generally no more effective
UK N =
46/49 completed did show a small but signifi- in controlling Periodontitis
USA Length 12 months
cant bone gain compared to except for its minimal affect
placebo. There were no sig- on bone gain.
nificant differences in plaque,
Gl scores, PD, or attachment
Heasman et al.162 Randomized, double-blind, pla- Experimental gingivitis model Flurbiprofen controlled gin- Relevant; 9
1993 cebo controlled using 50 mg bid of flurbipro- gival bleeding by inhibiting
UK N =
21 fen significantly reduced the cyclooxygenase me-
Length 28 days
BOP but not gingival redness tabolite, and indirectly, the
compared to placebo. Con- levels of GCF-LTB,.
trols had increased GCF,
BOP, increased GCF-PG E2
and GCF-LTB4.
Heasman & Seymour16 Randomized, single-blind, par- Experimental gingivitis was Longer trial with larger Relevant; 9
1989 allel arm treated with flurbiprofen with study populations are
UK N =
25 and without toothbrushing needed to determine the
Length =
27 days and placebo plus toothbrush- efficacy of the therapy with
ing for 6 days. All treatment systemic or topically-ap-
resulted in reduced Gl be- plied flurbiprofen.
tween 21 and 27 days. Flur-
biprofen showed small but
significant differences when
used alone or in conjunction
with toothbrushing.
Heasman & Seymour13 Matched control, cross-sec- Age, plaque, and number of The authors suggest that Relevant; 8
1990 tional, study (test group teeth were no different at
case the vascularity and perme-
UK was retrospective analysis baseline between patients ability of small blood ves-
from private practice patient taking long-term NSAIDs sels may be affected by
population) and those who had no his- long-term NSAIDs, but
N =
92 tory of NSAID use. Results may have no affect on al-
Length 9 years (average) showed that there were no
veolar bone loss. The his-
significant differences in Gl, tory of type and dosage of
PD, attachment gain, or re- medications taken in the
cession. There were highly test group were not com-
significant differences in plete or always clear from
GCF flow. these private practice re-
cords which may have af-
fected the results.
gingival crevicular fluid.
Gl =
gingival index.
PD =
probing depth.

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 509

Table 2. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =

Offenbacher et al.127 Beagle dogs Systemic ibuprofen, na- Since activation of cycloox- Relevant; 9
1992 N =
30 proxen, or topical flurbipro- ygenase plays a major role
USA Length =
6 months fen retarded bone loss rate in the regulation of bone
by 21 to 36.9% compared to destruction, the authors
placebo. Topical application point out this may be a ma-
of flurbiprofen was as effec- jor site for pharmacological
tive as the systemic drugs, in modulation and may be a
reducing crevicular fluid lev- very useful tool in treating
els of PGEP. periodontal disease in hu-

Howell et al.163 Beagle dogs Experimental gingivitis treated The authors point out the Relevant; 9
1991 N =
12 with topical Piroxicam was significant role NSAIDs
USA Length =
22 weeks found to significantly de- may have in the reduction
crease BOP compared to of gingival inflammation. It
control. should be noted that Pirox-
icam is one of the most fre-
quently used anti-inflam-
matory drugs, which has
the capability of penetrat-
ing inflamed tissue easily
Kornman et al.152 Monkeys Topical application of meclo- The authors point out that Relevant; 9
1990 N =
18 fenamic acid (MEC) or ibu- the PMN response medi-
USA Length =
20 weeks profen (IBU) significantly ated by MEC may be re-
reduced radiographic bone lated to the indirect effect
loss by 67% and 44% re- on the arachidonic acid
spectively. Placebo treated pathway, which may help
animals showed a significant attract PMNs to the local
loss in bone density com- tissue. Topical application
pared to test. MEC animals of MEC should be tested in
had significant increases in humans to evaluate the ef-
bone density where IBU did ficacy of this product in the
not. topical treatment of Perio-
Johnson et al.165 Randomized, double-blind, Gingivitis patients responded This therapy may enhance Relevant; 8
1990 placebo controlled to naproxen 500 mg bid for the recovery of inflamed
102/114 completed 30 days. Statistically signifi- tissue after plaque re-
Length 30 days
cant resolution of Gl was the moval; however, the mag-
result in the test groups com- nitude of enhancement
pared to placebo. When the was very small.
drug was given following
plaque removal with a pro-
phy, Gi resolution was fur-
ther enhanced.

B2,as were the systemic formulations of the tium associated with periodontal disease.
other NSAIDS. However, interesting research by Nagai et
Previously mentioned research has shown al.128 has shown that Prostaglandin E2 stim-
considerable evidence that the Prostaglan- ulates not only bone resorption but also col-
dins, especially Prostaglandin E, is a major lagen synthesis and subsequent calcification
player in the destruction of the periodon- in vitro. These data suggest both resorption

Vol. 1, No. 1, November 1996

510 Drisko

Table 2. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =
Jeffcoat et al. Randomized, double-blind, Ketorolac tromethamine oral This proof-of-principle trial Relevant; 8
1995 placebo and positive con- rinse or systemic flurbiprofen should be tested in a larger
USA trolled significantly reduced bone population over an ex-
N =
55 loss compared to placebo. tended period of time to de-
Length =
6 months Significant bone loss oc- termine the long-term
curred in the placebo group effects of the ketoprofen
(-6.3 ± 0.11 mm; P0.001), rinse therapy. The authors
but not in the systemic flur- did not address the poten-
biprofen (-0.10 ± 0.12 mm) tial effect that the signifi-
or ketorolac rinse (+0.02 ± cant differences in baseline
0.11 mm) groups. PD between groups may
have had on results
Jeffcoat et al.166 Randomized, double-blind, Root planing plus 500 mg The authors suggest that Possibly
1991 placebo controlled daily systemic dose of na- this NSAID may be useful relevant; 7
15 proxen bid in a group of rap- as an adjunct to scaling
Length =
3 months idly progressive Periodontitis and root planing in the
patients resulted in signifi- treatment of rapidly pro-
cantly less bone loss than gressive Periodontitis pa-
placebo. Significant propor- tients.
tions of teeth showed bone
gain in the test group but not
placebo groups.
gingival crevicular fluid.
Gl =
gingival index.
PD =
probing depth.

and formation of bone in vitro by Prostaglan- Further evidence in support of the lipoxy-
din E2; however, resorption far exceeded for- genase pathway contributing to bone resorp-
mation in the cultures. tion was found in a study by Gallwitz et al.132
Although most of the research of the In studying giant cell tumors of bone, Gall-
pathogenesis of periodontal disease has witz and coworkers found that mononuclear
been centered around the cyclooxygenase cells produce an activity which stimulates
pathway, specifically the Prostaglandins, both giant cells from giant cell tumors and
there may be a need to look down other av- rodent osteoclasts to resorb bone in vitro.
enues. Several studies120 129
show that the The activity was identified and was found to
non-prostaglandin metabolites of the break- be representing several products of the li-
down of arachidonic acid by the lipoxygen- poxygenase pathway of arachidonic acid me-
ase pathway, mainly hydroxyeicosatetrae- tabolism, mainly 5-hydroxyeicosatetraenoic
noic acid (HETE), specifically 12-HETE and acid and the leukotrienes. These data indi-
15-HETE, are important mediators of in- cate that 5-lipoxygenase metabolites stimu-
flammation in the tissues of patients with late isolated osteoclasts to resorb bone in
diseased gingiva and advanced periodontal vitro.
disease, respectively. One study131 showed With this further research, there is a sub-
that both leukotrienes and HETEs were po- stantial amount of evidence which impli-
tent stimulators of bone resorption and may cates the byproducts of arachidonic acid
play an important role in the localized bone metabolism, whether they are products of
loss associated with inflammatory lesions. the cyclooxygenase or the lipoxygenase

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 511

pathways, in the pathogenesis of gingivitis did not affect the rate of attachment loss,
and Periodontitis. plaque index, gingival index, probing depth,
or bone loss (Table 2). Though not generally

The Role of NSAIDS in the Control of considered as antibacterial agents, there is

some evidence to suggest that certain
Periodontal Disease Progression
NSAIDS may indeed inhibit bacterial growth,
Soon after the discovery of Prostaglandins but it may be necessary to use a local deliv-
and their association with inflammation, re- ery system in order to achieve a sufficient
searchers began to look for ways to inhibit concentration of the drug.138 While the stud-
the effects of Prostaglandins and other prod- ies are not in total agreement, NSAIDS re-
ucts of arachidonic acid metabolism. In search shows great promise in the treatment
1971, Vane107 discovered that aspirin and of periodontal disease.
other aspirin like drugs (NSAIDS) inhibited Much of the research of NSAIDS has con-
the products of arachidonic acid metabo- centrated on three major groups. They are:
lism. It was then thought that, since NSAIDS
1) pyrazolone compounds (indomethacin,
played an important role in disease progres- Phenylbutazone, and tolmetin); 2) the phen-
sion, eventually they might be used effec-
ylproprionic acid derivatives (ibuprofen, fen-
tively in the treatment of disease itself. In the oprofen, ketoprofen, naproxen); and 3)
late 1970s, researchers began to experiment
with non-steroidal anti-inflammatory drugs
flurbiprofen and the oxicams specifically
Piroxicam. Most of the earliest work study-

and their association with periodontal dis-

ease. Retrospective human studies of pa-
ing the inhibition of periodontal bone loss
was with indomethacin. It was found to be a
tients with rheumatoid arthritis and anky-
significant inhibitor of bone resorption in
losing Spondylitis have shown that NSAIDS both tissue cultures and animal studies. In
are effective in relieving the symptoms as-
an early report of indomethacin and its ef-
sociated with these diseases. Although ret- fects on bone loss, Torbinejad et al.139 ad-
rospective studies are difficult to assess ministered indomethacin to cats that had
because of the diversity of the medications, been given an injection of simulated immune
at least they show that patients taking
NSAIDS have demonstrated lower amounts
complexes. The induced bone loss in the
of bone loss. Three distinct studies in the periapical regions was inhibited by the ad-
ministration of indomethacin.
1980s have shown that arthritis and anky-
losing Spondylitis patients had fewer sites of Indomethacin has been tested extensively
periodontal disease. Waite et al.133 showed in animal studies with ligature-induced Per-
that patients taking NSAIDS for arthritis and iodontitis. One report140 showed that bone
ankylosing Spondylitis had fewer and shal- resorption was inhibited in rats that were
lower periodontal pockets and had a lower given indomethacin, as opposed to the un-
gingival index. In 1983, Feldman et al.134 treated group. Nyman et al.141 reported that
studied the effects of NSAIDS on alveolar in beagle dogs with ligature-induced Perio-
bone loss. This study showed that arthritic dontitis the inflammatory response and,
patients who were taking aspirin or aspirin subsequently, the alveolar bone resorption
plus indomethacin had fewer sites of 10% or was suppressed by the daily administration

greater bone loss and the overall bone loss of indomethacin. It could be hypothesized
in the dentition was lower. Similar results from this study that indomethacin, if given
were reported by Sjöstrom et al.,135 but here at the early onset of periodontal disease,
the question was raised as to whether or not could lessen the progression of the disease
the test group had better periodontal care. and result in less overall bone loss.
Del Puente et al.136 also showed that adult Lasfargues and Saffar142 induced Perio-
patients taking NSAIDS suffered less attach- dontitis in hamsters, and showed that daily
ment loss associated with periodontal dis- doses of indomethacin (2.0 mg/kg) reduced
ease. However, a more recent study by Heas- bone loss by 28%. Another study143 reported
man and Seymour137 reported that NSAIDS that the administration of indomethacin

Vol. 1, No. 1, November 1996

512 Drisko

prior to the placement of ligatures and dur- tion could be due to their inhibitory effect on
ing the ligature-induced disease in the excessive Prostaglandin formation as well as
squirrel monkeys significantly inhibited al- their destructive effect on periodontal patho-
veolar bone loss. In 1986, Vogel et al.144 genic microorganisms.
studied the effect of topical indomethacin The proprionic acid derivatives recently
on ligature-induced periodontal disease in have been given specific attention with re-
squirrel monkeys. Both the systemic and gards to periodontal disease treatment. Spe-
topical administrations of the NSAIDS inhib- cifically, numerous studies have been done
ited the resorption of interproximal alveolar on ibuprofen, naproxen, and flurbiprofen.
bone, with the additional inhibition of gin- The first of many studies to examine the ef-
gival inflammation by the administration of fects of NSAIDS on naturally occurring bone
the tested substituted oxazolopyridine deriv- loss was Williams et al.10 in 1984. The bone
ative (SOPD). A more recent study145 further loss associated with naturally occurring Per-
supports the role that indomethacin inhibits iodontitis in the beagle dog model was tested
bone resorption. The second part to the by the use of flurbiprofen. With doses that
study145 it was noticed that during the were l/50th the standard doses used to
course of the treatment, although the bone treat humans for arthritic pain, the authors
resorption was inhibited, there was a wid- reported that the rate of bone loss in the
ening of the periodontal ligament space. It group treated with flurbiprofen was 66% less
was determined that root resorption was go- than expected when compared to pre-treat-
ing on while the bone resorption was halted. ment rates of bone loss. Jeffcoat et al.11 con-
This suggested that odontoclast differentia- firmed these results. A study by Offenbacher
tion and activation are not regulated by et al.149 showed that treatment with flurbi-
Prostanoids, while osteoclastic differentia- profen in naturally occurring and ligature-
tion and activation are so regulated. In 1993, induced periodontal disease in the primate
Leroux and Saffar146 confirmed that indo- model gave statistically significant results
methacin was capable of inhibiting the cy- that flurbiprofen inhibited attachment loss,
clooxygenase metabolites that cause bone gingival inflammation, and bleeding on
resorption in continuous treatment, but probing after 6 months of treatment. In a re-
when the indomethacin was removed for a lated study,150 it was found that thrombox-
one-day "free" period, the bone resorption ane B2 was inhibited sooner and at a lower
rate was distinctly higher than the continu- dosing level than Prostaglandin E2.
ous treatment group. This indicated that an- A 1987 comparative study95 of indometh-
other metabolic pathway began resorption acin and flurbiprofen in the beagle dog
despite the inhibition of the cyclooxygenase showed that the dogs that received the flur-
pathway. The group of studies suggests that biprofen and the indomethacin had de-
indomethacin is able to reduce bone loss of creased rates of bone loss of 62.8% and
periodontal disease. 23.8%, respectively. The discrepancy of the
A pilot study by Reiff et al.,147 followed by amounts of bone loss in the NSAIDS is most
a complete study,148 compared the effects of likely due to the different pharmaceutical
aspirin, buffered aspirin, and effervescent properties of the drugs. However, it was
buffer rinses in reducing gingival inflam- found that these drugs were able to keep
mation in patients with gingivitis and early sites which had been determined to be "in-
Periodontitis. The results showed that after active" from becoming "active," and that
4 days of rinsing with the agents there were they could also decrease the number of "ac-
no statistically significant differences in re- tive" sites. In a joint study with Offenbacher,
duction of gingival inflammation as meas- Williams et al.121 attempted to determine the
ured by the sulcus bleeding index. After 21 relationship between the levels of arachi-
days, however, there were statistically sig- donic acid metabolites in the crevicular fluid
nificant differences among the three groups. and the amount of bone loss. The results
As the authors note, the effectiveness of showed that there were increased levels of
these agents in reducing gingival inflamma- Prostaglandins, thromboxane, and prosta-

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 513

cyclin in the crevicular fluids of the control series of related studies, Williams et al.155157
animals, whereas the group treated with examined the effect of fiurbiprofen on the
fiurbiprofen showed reduced levels of me- progression of alveolar bone loss in human
tabolites. This research further shows the periodontal disease. It was noted that at 6,
significance of these drugs as cyclooxygen- 12, and 18 months of the treatment period
ase metabolite inhibitors. the placebo group had a rate of bone loss
In another study, Williams et al.151 at- above that seen at baseline, whereas the
tempted to evaluate the effect of topical fiur- fiurbiprofen group showed decreased rates
biprofen in comparison to systemically ad- of bone loss at these same times (Table 2).156
ministered ibuprofen. The fiurbiprofen was However, at 24 months there was a reduction
formulated to be equivalent to the systemic in the inhibition of bone loss by fiurbiprofen.
doses as reported in previous studies by Wil- This was attributed to a lack of patient com-
liams et al.10 95 The ibuprofen was adminis- pliance. In the patients who completed the
tered in slow release and standard formula- study, there was a significant inhibition of al-
tions. The results of the study showed that veolar bone loss with fiurbiprofen.
the control group of dogs continued to lose Other studies of human bone loss have
significant amounts of bone while the topical shown similar results with fiurbiprofen. Jeff-
flurbiprofen-treated group's bone loss de- coat et al.138 used subtraction radiography in
creased by 71%. This rate of decrease of 1988 to show that fiurbiprofen significantly
bone loss was equivalent to both formula- slowed the progression of human periodon-
tions of ibuprofen. It has been hypothesized tal disease. Soon after, Heasman et al. per-
that, due to the rapid absorption of topical formed a series of human studies.159 163 They
fiurbiprofen by the mucosa, locally delivered examined the topical effect of a fiurbiprofen
fiurbiprofen may be better at controlling the dentifrice and showed that there was no sig-
rate of disease than systemic administra- nificant difference between the treatment
tions. A study by Kornman et al.152 on the and sections of the test mouths, but the au-
effects of topical application of an anthran- thors attributes this to the rapid systemic
ilic acid derivative (meclofenamic acid) and absorption of fiurbiprofen (Table 2).161 In an-
ibuprofen on bone loss, subgingival micro- other report,159 it was shown that the sys-
biota, and gingival PMN response in the pri- temic administration of fiurbiprofen pro-
mate model, Macaca fascicularis, confirmed duced a decrease in gingival inflammation
the results of Williams et al.153 that ibupro- and crevicular fluid flow. A subsequent
fen or meclofenamic acid could significantly study160 showed that during systemic ad-
inhibit bone loss (Table 2). Also, an increase ministration, the serum drug levels were
in bone density was observed in the test higher than crevicular fluid levels. This is
group administered meclofenamic acid. A pi- significant in that it demonstrated the pres-
lot report on the efficacy of meclofenamate ence of the drug in crevicular fluid. The
sodium by Reddy et al.154 showed that me- fourth study examined the effect of 1% w/w
clofenamate sodium may be a useful adjunct fiurbiprofen toothpaste on bone metabo-
in the treatment of rapidly progressive Per- lism.161 It was shown that the flurbiprofen-
iodontitis due to the significant dose re- treated group had a small, yet significant,
sponse of bone gain by the treatment groups effect of the amount of bone gain when com-
as compared to the placebo group. Addi- pared to the placebo group. The fifth study162
tional studies are needed to confirm these showed that fiurbiprofen was effective in the
early results, and to establish whether the treatment of experimental gingivitis by
drug will be a useful adjunct to treating showing that systemic administration sig-
other forms of Periodontitis. nificantly inhibited the development of red-
The evidence that NSAIDS are effective in ness and bleeding associated with develop-

reducing the progression of periodontal dis- ing gingivitis, and that it inhibited bleeding
ease has been well established in animal in established gingivitis. The final related
studies. Until the present decade, there have study163 examined the effect of systemically-
only been a few human investigations. In a administered fiurbiprofen as an adjunct to

Vol. 1, No. 1, November 1996

514 Drisko

toothbrushing on the resolution of experi- cumulation was equivalent among the three
mental gingivitis. It was concluded that the test groups, but there was a significant re-
serum concentrations of flurbiprofen were duction in the gingival index and the num-
sufficient to produce significant anti-inflam- ber of bleeding points for the piroxicam-
matory effects in the gingival tissues. A treated group. An unrelated study by Her-
somewhat related clinical trial by Taiyeb and man et al.169 showed the effects of piroxicam
Waite164 investigated the influence of short- in an in vitro test of prosthesis pseudomem-
term ibuprofen therapy on the early phase of brane-induced bone resorption associated
the treatment of adult chronic Periodontitis. with aseptic cemented (total hip joint) pros-
The results showed that at the 2-week as- thesis failure. It was shown that the prophy-
sessment following the drug regimen signif- lactic administration of piroxicam, in
icantly greater reduction in gingival bleed- contrast to indomethacin and sodium salic-
ing, color, and probing depths were detected ylate, significantly decreased membrane-as-
in the test group as compared to the placebo sociated bone resorption. Further work
group. These further studies confirmed the needs to be performed to determine the role
effectiveness of NSAIDS in the treatment of of piroxicam.
periodontal disease and showed that flurbi- There is ample evidence presented here
profen, specifically, was a proven inhibitor of supporting the role of non-steroidal anti-in-
bone loss. flammatory drugs in the treatment of perio-
It has been shown that several of the pre- dontal disease. It appears that these drugs
viously mentioned NSAIDS are effective as may serve as potential adjunctive treat-
adjunctive treatments in slowing the pro- ments.
gression of periodontal disease. Several
other NSAIDS have also been examined for
their effect on the disease. Naproxen, a very Risks Versus Benefits of NSAIDS for
potent NSAID, was first looked at by John- Periodontal Disease Treatment
son et al.165 in 1990 for its role in reducing
bone loss (Table 2). It was found that na- NSAIDS may produce harmful side ef-
proxen was not statistically different than fects, such asgastrointestinal upset and
the placebo in the amount of plaque devel- hemorrhage,170171 renal172 and hepatic im-
oped, gingival inflammation, or the amount pairment,173 and induction of an aseptic
of gingival bleeding; but after professional meningitis in previously healthy patients.174
cleaning following abstention from oral hy- It is the gastrointestinal side effects of
giene for 30 days, the naproxen enhanced NSAIDS which are most common and seri-
the recovery of the gingival tissues. A study ous and make NSAIDS the most frequent
by Jeffcoat et al.166 using digital subtraction cause of drug side effects reported each
radiography showed that the naproxen- year.175 In a review by Roda176 of the phar-
treated group showed less bone loss, and ac- macology and dental therapeutics of na-
tually increased bone gained as compared to proxen, a similarity of the adverse effects of
the placebo group (Table 2). A study by How- almost all of NSAIDS can be seen. There are
ell et al.167 reported that naproxen signifi- potentials for adverse effects in many body
cantly lessened the amount of bone loss in systems and the severity of these effects vary
the treated group of naturally occurring Per- between drugs. For example, in the central
iodontitis in beagle dogs. nervous system (CNS), the side effects can
Another compound of interest has been include headache, drowsiness, and dizzi-
Piroxicam. It is known that piroxicam is ef- ness. HypersensitivLty reactions can encom-
fective in penetrating inflamed tissue easily, pass a wide range including urticaria,
which makes it a good choice for topical ap- angioneurotic edema, anaphylactoid reac-
plications of NSAIDS. In another study by tions, exfoliative dermatitis, and even Ste-
Howell et al.168 the topical application of pi- vens-Johnson syndrome. Roda also reports
roxicam was tested on the development of that naproxen can inhibit platelet aggrega-
gingivitis in beagle dogs (Table 2). Plaque ac- tion and may prolong bleeding time, al-

Annals of Periodontology
Review: Non-Surgiccd Pocket Therapy: Pharmacotherapeutics 515

though the effect is much less than that of et al.,183 Jeffcoat et al.,184 and Reddy et al.185
acetylsalicylic acid. have shown that the bone resorbing effects
Although one of the main pharmacologic of peri-implantitis, the resorption of the sup-
activities of NSAIDS is to inhibit inflamma- porting bone surrounding implants, are most
tion, it has been reported that ibuprofen in likely caused by the same mechanisms as per-
high doses impairs wound healing.177 Fur- iodontal disease. These studies have shown,
thermore, it is not clear whether NSAIDS thus far, positive results with NSAIDS in slow-
promote or hinder the overall mineralization ing the rate of resorption of bone supporting
process in contemporary periodontal regen- the implants. With the popularity of implants
erative therapy.178 increasing dramatically, future studies need
Other adverse effects of NSAIDS are aller- to assess the role of NSAIDS in the mainte-
gic reactions, blood and bone marrow dam- nance of dental implants.

age, CNS disturbances, and potential risks Future research needs to keep searching
to the unborn fetus, such as malforma- for different approaches to the problems of
tions.179 human health. New drugs need to be re-
searched for their potential roles in not only
The Role of NSAIDS in the Future periodontal health, but all disease-related
problems. For example, Relafen (nabume-
The data clearly show the abilities of the tone) has an advantage over other NSAIDS
NSAIDS to inhibit arachidonic acid metabo- in that there is a decreased possibility of
lite breakdown and to slow the progression stomach and intestinal irritation.186 Re-
of periodontal disease, either by topical or search into pharmacologic techniques to
minimize gastric irritation include new drug
systemic applications. However, there is still
much research needed to clarify the specific classes, enteric coatings, non-acidic drugs,
role of NSAIDS in the treatment of periodon- and the development of prodrugs, which are
tal disease. Although initial studies of hu- newly developed drugs that lack many of the
man models by Johnson et al.,165 Jeffcoat et properties often associated with gastrointes-
al.,166 and Ruttimann et al.180 are very en- tinal damage.187
A 1987 study by Saxton et al.188 reported
couraging, well-controlled longitudinal stud-
ies in humans on the effect of NSAIDS in that triclosan added to toothpaste improved
periodontal therapy, either as adjunctive gingival health. This is usually explained in
treatment or primary treatment, are needed. terms of antibacterial and anti-plaque ef-
With a study by Yewey et al.181 showing fects. The available literature indicates that
the effectiveness of a locally delivered NSAID the anti-inflammatory effect of triclosan may
into affected sites, it will be important to de- also be involved. Recent studies by Barkvoll
termine if there are other routes of delivery and Rolla189 190 with triclosan have shown
of NSAIDS that will be as efficacious as pre- that it possesses an anti-inflammatory effect
in the oral cavity. Furthermore, Gaffar et
viously discovered, in preventing or slowing
periodontal disease progression. al.191 have recently shown that this agent in-
To date, there has not been much study hibits the cyclooxygenase and lipoxygenase
on the effective dosages of NSAIDS in the pathways with similar efficacy.
treatment of periodontal disease. As stated A 1995 study by Jeffcoat et al.192 com-
by Howell and Williams,182 "It is not clear pared the inhibitory effect of topical ketoro-
that we can rely on NSAID dosages used in lac, systemic flurbiprofen, and placebo on
rheumatology in the treatment of pain to the bone loss associated with adult Perio-
maximally slow the alveolar bone loss of Per- dontitis. In the study period, it was noticed
iodontitis. Lower doses of NSAIDS could be that there was a significant loss of bone
efficacious in slowing bone loss, and this height in the placebo group but not in the
needs to be examined." ketorolac or flurbiprofen groups (Table 2).
A current problem and definitely one of Statistical tests revealed that the ketorolac
future concern is bone resorption around and flurbiprofen groups had less bone loss
dental implants. Separate studies by Weber and reduced levels of Prostaglandin E2 in the

Vol. 1, No. 1, November 1996

516 Drisko

crevicular fluid compared to the placebo and these relationships should be ex-
group. Statistical tests also revealed that the plored.151 NSAIDS research in the treatment
ketorolac rinse preserved more alveolar bone of periodontal disease could be just the be-
than systemic flurbiprofen at the test doses. ginning of a whole new line of preventive and
These data indicate that ketorolac rinse may treatment modalities for periodontal disease.
be beneficial in the treatment of adult Per-
iodontitis and suggest that further clinical
investigations of ketorolac are warranted, TOPICAL AND SUSTAINED
along with testing of other NSAIDS, in the RELEASE ANTIMICROBIALS
treatment of periodontal disease.
Along with increased NSAIDS testing, fu- Selection of an appropriate delivery sys-
ture clinical trials are needed to assess the tem to control plaque and oral infection
role of initial disease status in the outcome should take into consideration several char-
of periodontal treatments. In recent longi- acteristics of a pharmacologic agents and
tudinal studies, it was indicated that initial types of delivery systems. These character-
disease status correlates with future disease istics include toxicity, potency, permeability,
progression. Recent work by Williams et intrinsic efficacy, and substantivity.196
al.193 showed that prognostic factors such as Tetracycline and most other antibiotics, for
initial alveolar bone height can influence the example, are low on the toxicity scale where
treatment response in Periodontitis patients. fluorides are high. Potency is important in de-
The authors reported that flurbiprofen de- termining drug dose, frequency, route of ad-
creased the rate of alveolar bone loss in sites ministration, and the formulation of the agent.
that specifically excluded those that did not For example, some drugs penetrate well into
initially show established bone loss, thus periodontal abscesses, where others are effec-
eliminating the dilution effect of non-dis- tive in the treatment of some forms of perio-
eased sites. Further testing needs to estab- dontal disease because of their high degree of
lish the ideal interceptive periods for absorption. Intrinsic ability can refer to the
optimum treatment outcomes. ability of an antibacterial agent to completely
It is also not clear which NSAIDS are the inhibit bacterial growth. Substantivity is an
most efficacious inhibitors of arachidonic acid important characteristic of a chemotherapeu-
metabolism. Some may inhibit cyclooxygenase tic agent. A typical example would be the con-
better in gingiva and others in bone. 194 Like- trol of plaque by the prolonged contact of an
wise, various agents may affect one pathway agent such as Chlorhexidine with the hard
more than the other. The questions needing and soft tissue of the oral cavity.
answers are: 1) which pathway is primarily re- The benefits of using controlled delivery
sponsible for the metabolites associated with devices include: 1) better patient compli-
periodontal disease progression, the cycloox- ance; 2) enhanced or improved pharmaco-
ygenase, the lipoxygenase, or the combination kinetic response; 3) greater access and
of the two pathways causing the most de- ability to position the drug adjacent to the
struction and 2) which specific NSAID or com- disease; and 4) the ability to deliver a lower
bination thereof is the most efficacious in total dosage of the drug at a more controlled
halting periodontal disease? concentration.196
Although it seems that the Prostaglandins The following discussion will encompass
are the opponents in the fight against peri- supra- and subgingival topical agents and
odontal disease, this could be only one of sustained release devices. A variety of new
many possible mediators of periodontal de- supragingival antimicrobials aimed at con-
struction. Recent research using various fla- trol of plaque and gingivitis are included: a
vonoids has shown differing effects upon broad spectrum adhesive antibiotic; sus-
some inflammatory mediators including in- tained-release Chlorhexidine and arginin
terleukin-lß, prostaglandin-E2, and leuko- varnishes; Chlorhexidine polymeric coating;
triene-B4.19S The effects of NSAIDS are not and cetylpyridinium chloride methacrylic
strictly upon arachidonic acid metabolism acid copolymer. Recently developed subgin-

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 517

gival topical and sustained release agents for control among patients with mental retar-
treating or maintaining Periodontitis sites dation; however, more studies are needed to
include: gels containing Chlorhexidine, me- determine the exact effects.
tronidazole, Clindamycin, tetracycline, and Chlorhexidine polymeric coating. A single
flurbiprofen; acrylic strips with Chlorhexidine, supragingival application of ethylcellulose
metronidazole, or tetracycline; antimicrobial with or without Chlorhexidine resulted in a
ointments with minocycline; controlled re- significantly lower plaque index for 3 days
lease devices and bioresorbable materials and gingival index for 4 days compared to
containing Ofloxacin, doxycycline, tetracy- baseline.199 The coating prevented plaque
cline, and methylene blue; tetracycline- accumulation but did not reduce the total
loaded ethylene vinyl acetate fibers; and salivary flora during this 6-day pilot study.
finally locally delivered antimicrobial mi- Of particular interest in this study was the
croencapsulated minocycline polymer. absence of tooth staining despite this rela-
tively high concentration (3% w/v) of Chlor-
hexidine. However, the study was too short
Supragingival Sustained-Release to truly evaluate this effect. The authors
Coatings for Plaque and Gingivitis point out the potential usefulness of this
Various supragingival applications of slow type of product is in preventive therapy, par-
release devices that last about 3 days are be- ticularly for disadvantaged patients who
cannot practice adequate oral hygiene.
ing explored for their potential role in con-
trolling plaque accumulation and gingivitis. Cetylpyridinium chloride (CPC) methacrylic
These systems are briefly discussed below. acid copolymer. An active film-forming prep-
TA antibiotic adhesive. TA is a broad- aration containing 11% CPC was compared
spectrum, macrocyclic, bactericidal antibi- with a placebo for the effects on plaque ac-
otic produced by the M. xanthus strain. One cumulation and gingivitis on anterior teeth
study showed some clinical improvement in over 4 weeks following daily application by the

gingivitis and plaque accumulation following patient.200 The CPC group showed a signifi-
4 applications of the adhesive antibiotic cant 58% inhibition of plaque accumulation at
compared to placebo.197 test sites compared to placebo, but the treat-
Sustained-released varnishes of Chlorhexi- ment had no effect on gingivitis. However the
dine and arginin. Chlorhexidine is effective as authors point out that initial gingivitis scores
an oral rinse, but many disabled individuals were low leaving little room for improvement,
are unable to use this protocol and require and suggested the study be repeated with
alternative methods to facilitate compliance. more severe gingivitis baseline scores.

Shapira et al. studied the effects of sus-

tained-release of Chlorhexidine and arginin SUBGINGIVAL SUSTAINED-
varnishes in a controlled pilot study of 34 RELEASE CHEMOTHERAPEUTIC
mentally retarded patients.198 The partici- DEVICES FOR THE TREATMENT OF
pants received professional scaling followed PERIODONTITIS
by one month of professional toothbrushing
and were then assigned to either the Chlor-
hexidine group, the arginine group, or the Historical
placebo group. The varnishes were applied
daily to the buccal and lingual surfaces of all Agents used for therapy in oral infections
teeth for 8 weeks. No significant differences have diverse pharmacokinetic characteris-
were found among the three groups in gin- tics: potency, permeability, intrinsic efficacy,
gival index scores at either 4 or 6 weeks. The and substantivity.196 Previous studies have
Chlorhexidine and arginine groups showed demonstrated that antimicrobial agents re-
significant reductions in the number of S. leased from sustained release delivery de-
sanguis. The results of this study suggest vices produced clinical and antibacterial
that topically applied Chlorhexidine and ar- effects of variable magnitude and dura-
ginine may have some relevance to plaque tion.201 Reports of local delivery methods and

Vol. 1, No. 1, November 1996

518 Drisko

antimicrobials have included metronidazole, to 40% tetracycline paste, with and without
Chlorhexidine, and tetracycline by dialysis SRP, and have shown no significant differ-
tubing,202"205 acrylic strips,201204 ences between treatment groups in clinical
or irriga-
tion.2648'52 Tetracycline (TCN) wasfirst and microbial parameters in adult Periodon-
studied in sustained release devices such as titis (Table 3).227 Similarly, when 26 juvenile
hollow or monolithic fibers.201211 215 Investi- Periodontitis subjects randomly received 1%
gations of other slow release devices have in- CHX gel, 40% TCN paste, or no treatment,
cluded collagen films with immobilized the least effect was seen in the CHX groups,
tetracycline,216 Chlorhexidine gel,217 219 Chlor- with the untreated group showing the
hexidine films,220221 and others. Since the greatest probing depth reduction (Table
1989 Workshop, the first sustained antimi- 3) 228 Negative results might be explained as
crobial delivery device, an ethyl vinyl acetate the mechanical interference of the antimi-
fiber loaded with 25% tetracycline hydro- crobials with early stages of healing as pre-
chloride, was approved for use by the United viously described by Goodson et al.222
States Food and Drug Administration and Additionally, A. actinomycetemcomitans-as-
countries outside the TJS.212222 Other local sociated juvenile Periodontitis is not usually
delivery antimicrobial products including treated successfully by scaling and polishing
2% minocycline gels and a 25% metronida- alone and frequently requires surgical de-
zole gel are now available outside the United bridement with or without systemic antibi-
States and are included in the following dis- otics to eradicate the disease.228 230
cussion. Metronidazole gels. Metronidazole (MET)
is particularly attractive as an antimicrobial
Antimicrobial Gels because of its selective efficacy against ob-
Locally Applied ligate anaerobes. A large multi-center study
Chlorhexidine gels. Oosterwaal et al. com- of 206 subjects investigated 2 applications of
pared the clinical and microbiological effects MET gel in 2 randomly selected quadrants
of locally-applied 2% Chlorhexidine (CHX) gel versus 2 quadrants of scaling (Table 3).231
to 1.25% amine fluoride gel, 4% stannous Bleeding on probing (BOP) was reduced by
fluoride, or placebo. The gels were applied 88% for both treatment groups. Probing
subgingivally, immediately following me- depths (PD) were reduced by 1.3 mm in the
chanical debridement. Results showed no gel and 1.5 mm in the scaling group. At 6
significant differences between groups (Ta- months, the difference between treatments
ble 3).223 Later they reported short-term bac- was statistically, but not clinically, signifi-
tericidal effects that lasted for 30 minutes cant. In another study, two topical subgin-
after 2% CHX and stannous fluoride gel ir- gival applications of 25% metronidazole
rigation with significant short-term reduc- dental gel, one week apart, were compared
tions of bacterial counts and black-pig- to SRP in the treatment of adult Periodonti-
mented Bacteroides compared to placebo.224 tis. At 6 months, no significant differences
When they used a fluorescein gel model to between treatments were found except that
study pocket clearance of the gel, 50% of the A. actinomycetemcomitans repopulation was
irrigated gel left the pocket immediately and non-detectable following metronidazole ther-
the remaining gel dissipated within about apy and scaling, while root planing resulted
12.5 minutes.225 This relatively short wash- in a statistically significant increase in A. ac-
out time may explain the limited short-term tinomycetemcomitans.232 A. actinomycetem-
effect of local irrigation of CHX gel on comitans is usually considered resistant to
subgingival microorganisms in these stud- metronidazole, however, during the initial 8
ies. hours after application of the gel, metroni-
Kalaitzakis et al. irrigated subgingivally dazole concentration in periodontal pockets
with 1% CHX gel on 2 consecutive days but exceeded 128 Lig/ml, which is about lOOx
failed to show any significant effect on the MIC of most anaerobic bacteria.233 234 The
plaque composition and gingival indices (Ta- observed significant increase in proportions
ble 3).226 Others have compared 1% CHX gel of streptococci and the decrease in propor-

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 519

Table 3. Antimicrobial gels, ointments, and polymers

Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =
Garrett et al.256 Randomized, double-blind, 10% doxycycline hyclate This is the largest multi-cen- Relevant; 10
1996 vehicle controlled, parallel (DH) in a biodegradable drug ter randomized controlled
USA design multi-center study. delivery system was com- double-blinded parallel arm
N =
163/180 completed pared to 5% sanguinarium trial to date in the literature
Length =
9 months chloride (SC) or vehicle con- using a locally delivered sus-
trol and found to significantly tained-release system. Treat-
reduce PD at all time per- ment outcomes would indi-
iods, with the maximum re- cate that 2 applications (1
duction of 1.9 mm at 6 each 4 months) of DH in a
months. Attachment gains biodegradable drug delivery
(AG) were significantly greater system, used as a monoth-
than vehicle or SC at all time erapy, was effective in re-
periods with 1.2 mm maxi- ducing PD and promoting
mum at 6 months. Maximum AG in maintenance patients
AG (1.7 mm) and PD reduc- with recurrent Periodontitis.
tion (2.9 mm) occurred in > 7
mm pockets in the DH group.
Moderate 5 to 6 mm sites
showed AG of 0.8 mm and
PD reductions of 1.6 mm.
Van Steenberghe Randomized, double-blind, MIN HCl ointment applied Patient analysis was simi- Relevant; 8
et al.249 vehicle controlled, parallel every 2 weeks for 6 weeks lar to site-specific analysis
1993 design multi-center study. (total 4 applications) signifi- but there were no signifi-
Belgium N 103
cantly reduced PD by 1.7 cant differences between
Length 12 weeks mm compared to vehicle groups. Attachment level
control of 1.4 mm. Attach- gains of 1 mm by site anal-
ment gains were greater in ysis were statistically and
the > 7 mm groups, with test clinically significant where
significantly better (3.1 mm) 0.3 mm average PD reduc-
than control (2.1 mm). tions were statistically, but
perhaps not clinically signif-
icant. Therapeutic changes
were primarily due to at-
tachment gains rather than
recession and PD reduc-
tion. Treatment efficacy
may be dependent on pa-
tient compliance to return
for multiple visits.
Ainamo et al.231 Randomized, multi-center, 25% MET gel in 2 applica- No attachment level meas- Possibly
1992 quadrant split mouth tions or SRP resulted in sig- urements were recorded in relevant; 6
Scandinavia N 199/206
completed nificant (P > 0.01) this study. Examiner repro-
24 weeks reductions of PD, and bleed- ducibility and blinding not
ing on probing. Differences reported. Two applications
between treatments were of the MET gel was statis-
significant in favor of SRP. tically inferior to SRP; how-
ever, the differences were
very small and considered
clinically insignificant. There
were significant differences
in results between centers,
likely due to the type of
pre-study therapy and inci-
dence of smoking among
study populations.
Chlorhexidine. PD =
probing depth.
metronidazole. SRP =
scaling and root planing.
minocycline. TCN =

Vol. 1, No. 1, November 1996

520 Drisko

Table 3. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =
Stezel & Flores-de- Randomized, split mouth 2 applications of 25% MET MET gel effective in
was as Possibly
Jacoby235 N =
30 dental gel was not signifi- improving clinical and mi- relevant; 6
1996 Length = 24 weeks cantly superior to SRP in re- crobial parameters as SRP
Germany ducing PD bleeding on in this group of moderate to
probing or darkfield micros- severe adult Periodontitis
copy. maintenance patients. It is
not clear whether the ex-
aminer was calibrated for
measurement reproducibil-
ity or blinded to the treat-

Unsal et al.228 Randomized controlled, sin- 1% CHX gel and 40% TCN The authors suggest that Possibly
1995 gle-blind, parallel arm paste were adjunctive to the antimicrobials may relevant; 7
Turkey N =
26 SRP. Control scaled only have interfered with wound
Length 12 weeks
sites had more recession healing in this group of pa-
(localized juvenile Periodon- and greater PD reduction tients.
titis) than treated interdental sites.
Controls gained more attach-
ment but were not signifi-
cantly different than test
Oosterwaal et al.223 Randomized double-blind, pla- 3 irrigations over 10 minutes Earlier studies by the au- Possibly
1991 cebo controlled 4 quadrant with either a 2% CHX gel, or thors had established that relevant; 7
Netherlands split mouth design. a 4% stannous fluoride gel 10-minute contact was
N =
10 resulted in significant reduc- necessary for a bactericidal
Length 12 weeks
tions of cultivable black pig- effect. A placebo gel was
mented Bacteroides com- included to evaluate the
pared to placebo gel. Amine non-specific effect of the
fluoride gel did not differ sig- mechanical action of irri-
nificantly from placebo. gation.
Kalaitzakis et al.226 Randomized controlled, dou- 2 applications of a 1 % CHX Irrigation without subgingi- Possibly
1993 ble-blind, split mouth gel and placebo showed no val debridement did not relevant; 6
Sweden N =
11/16 completed difference in plaque and gin- have an effect on clinical or
Length 28 days
gival indices or subgingival microbial parameters.
microflora at the end of this
short study.
Unsal et al.227 Randomized, controlled par- A single application of a 1% One time application of an Possibly
1994 allel arm CHX gel or a 40% paste of antimicrobial appears to be relevant; 6
Turkey N =
22 TCN in conjunction with SRP of no benefit in addition to
Length =
3 months showed no different clinical SRP. Saline irrigation prior
effects than scaling alone. All to placement of the antimi-
treatments produced pro- crobials may have had an
nounced clinical effects, but effect which masked the ef-
the addition of subgingival fects of the test products,
antimicrobials had no addi- since saline irrigation has
tional benefit. been shown to have posi-
tive therapeutic effects. It is
not clear whether there
was one or multiple exam-
iners who were blinded to
treatments or calibrated for
measurement reproducibil-

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 521

Table 3. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =
Eckles et al.247 Randomized, 4 quadrant, split 40% TCN ointment, applied TCN ointment was nearly Possibly
1990 mouth once, was effective in reduc- as effective as SRP in un- relevant; 6
USA N = 9 ing PD, bleeding on probing, sealed sites in moderate to
Length =
12 weeks and % motile rods and spi- severe adult Periodontitis
rochetes for 8 to 12 weeks. subjects. The antibiotic
The effect of SRP was simi- therapy may be useful in
lar but lasted a longer period conjunction to SRP or as
of time. monotherapy, but was not
tested in this protocol. It
was not clear whether the
single examiner was blinded
to therapy or calibrated for
measurement reproducibil-
Nakagawa et al.! Randomized controlled, par- 4 weekly applications of 2% Multiple subgingival appli- Possibly
1991 allel arm MIN-HCI ointment combined cations of MIN-HCI oint- relevant; 6
Japan N =
11 with SRP in recurrent Perio- ment in recurrent Periodon-
Length 12 weeks
dontitis patients significantly titis patients was successful
reduced PD (P < 0.05) by in improving clinical and
1.8 mm compared to 0.7 mm microbial parameters in
with a saline irrigation con- this short-term study. The
trol. Attachment gains of 1.5 effect of therapy may be in-
mm were significantly better fluenced by patient compli-
with the test (P < 0.01) than ance to return for multiple
0.0 mm with control. Bleed- visits. It was not clear
ing on probing was signifi- whether there was one or
cantly reduced by 72.8% in more examiners or if they
test compared to 27.3% in were blinded or precali-
control. Motile bacteria and brated for measurement re-
P. gingivalis were signifi- producibility.
cantly reduced (P < 0.01)
compared to control.
Jones et al.280 Randomized controlled, MIN-HCI microencapsulated Presence of at least 2 > 7 Possibly
1994 single-blind, parallel arm polymer powder alone com- mm pockets and at least relevant; 7
39/51 completed pared to MIN plus scaling or one periodontal pathogen
Length 6 months
SRP alone showed no differ- (P. gingivalis, P. interme-
ences in PD reduction among dia, and A. actinomycetem-
groups at 6 months. SRP comitans) was confirmed
had significantly greater at- by culture prior to study en-
tachment gains than MIN try. There was a drop out
alone or no treatment. P. gin- rate of about 20% in this
givalis was significantly re- study. MIN polymer pow-
duced at 1 month only in the der was generally inferior
MIN and MIN + SRP groups. to SRP in this study.
Chlorhexidine. PD =
probing depth.
metronidazole. SRP scaling and root planing.

minocycline. TCN tetracycline.

tions of black pigmented Bacteroides (BPB) ble with health. In addition, there were no
species and spirochetes were most likely due apparent changes in antibiotic susceptibility
to the shift in the composition of the subgin- of selected plaque bacteria or overgrowth of
gival microflora towards one more compati- Enterobacteriaceae or yeasts. Comparative

Vol. 1, No. 1, November 1996

522 Drisko

studies are needed to determine if the MET moval or translocation of dentin, plaque, cal-
gel will enhance the effects of SRP. culus and cementum following root
A recent randomized 6-month study of 30 planing."240 241 Surface demineralization may
patients from a recall program were treated occur and could enhance new attachment by
twice, one week apart with 25% metronida- "detoxifying" the root, making it more bio-
zole dental gel in two quadrants and scaling logically acceptable for mammalian cells.242
and root planing in the remaining quadrants Demirel and Gwinette have shown in vitro
(Table 3).235 Results showed no difference in application of a doxycycline solution for 3
treatments relative to PD and BOP. Dark- minutes on periodontally diseased root
field microscopy showed a more healthy planed teeth yielded root surfaces devoid of
flora in both groups which persisted for 6 a smear layer.243 Non-root planed surfaces
months. This study is further evidence that showed altered morphology, indicating po-
locally delivered antimicrobials are capable tential chemical dissolution of the surface
of maintaining clinical and microbial para- integument and demineralization. Biologic
meters similar to scaling and root planing on principles would support the rationale for
a periodic basis for at least 6 months. this product; however, further evidence re-
Clindamycin-HCI gel. Use of a small garding patient safety in using a product
amount of Clindamycin hydrochloride in- with sucha low pH is needed.
serted into periodontal pockets once a week
for 2 weeks enhanced the effect of scaling Locally Applied Anti-Inflammatory
and root planing on the subgingival micro- Gels
flora of adult Periodontitis subjects.236 At 1
month, motile rods and spirochetes were not Flurbiprofen. Earlier studies have sup-
detected, and at 3 months, they remained 3- ported the positive role of anti-inflammato-
fold lower than pretherapy levels. In addi- ries in the treatment of periodontal disease.
tion, Eikenella corrodens, usually resistant Williams and co-workers have investigated
to Clindamycin, was not detectable after Clin- the effect of topical application of a non-ster-
damycin gel therapy at any time during the oidal anti-inflammatory drug flurbiprofen,
3-month study. on periodontal disease progression in beagle
Root conditioning gels. Tetracycline or a dogs.151 Dogs treated dally with 0.3 mg flur-
mixture of tetracycline and citric acid gels biprofen applied to the gingival margin
have been explored in a non-surgical study showed considerably less tooth loss than
in moderate pockets, using a 5-minute bur- untreated control dogs over the 7-month
nishing technique to burnish the gel into the study. Further research into the effect of
roots subgingivally, with and without root topical and local delivery of cyclooxygenase
planing.237 Clinical and microbial parame- inhibitor in animals and in humans is ex-
ters were significantly reduced following gel panding and is discussed in detail below.
placement for up to 12 weeks in all groups.
TCN plus citric acid showed slightly better Sustained Release of Antimicrobials
attachment gains at the 12-week exam com- With Dialysis Tubing or Acrylic
pared to TCN. Previous studies have shown Strips
that tetracycline is adsorbed to, and subse-
quently released from dentin, while still Chlorhexidine, metronidazole, and tetracy-
maintaining its antimicrobial activity which cline-HCI. Previous reports using dialysis
may be beneficial to decontamination of the tubing as the delivery device have shown
root surface and subgingival environ- Chlorhexidine in concentrations ranging
ment.56238 However, some adverse effects from 0.2% to 40% to have positive effects on
caused by the low pH of citric acid have been the subgingival microbes and clinical para-
reported, which may delay wound healing.239 meters. However, the device usually releases
Beneficial effects of the acidic gels may in- the drug within the first 24 hours.202203 De-
clude "elimination or diminution of a surface velopment of dmg-containing acrylic strips
smear layer resulting from incomplete re- were developed for sustained delivery of an-

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 523

timicrobial agents and have also been re- petrolatum carrier, or placebo (Table 3).247
ported earlier in a series of collaborative TCN was released from the periodontal pock-
studies.202-205-207209244 In vitro evidence ets in a biologically effective state in the gin-
confirmed the acrylic strips were capable of gival crevicular fluid (GCF) for at least 3 days
sustained release of CHX as well as tetracy- (mean concentration of 115.8 ± 43.1 ug/
cline and metronidazole over a period of days, ml).Both SRP and the TCN gel decreased
at levels exceeding the minimum inhibitory probing depth, but the result was main-
concentration for many oral bacteria.202 tained longer (12 weeks) with SRP than with
Comparisons between 0.5% metronidazole TCN (8 weeks). Similarly to all locally deliv-
in dialysis tubings, 40% metronidazole in ered antibiotics, the total cumulative dose
acrylic strips applied weekly for 4 weeks, or was reduced (70 mg here) from that normally

daily 0.2% CHX irrigations for 28 days given systemically (1,000 mg/day for 14
showed beneficial changes in the microbial days or 14,000 total mg if using TCN). When
flora for up to 3 months compared to root these moderate to severe Periodontitis sites
planing alone.244 Both the dialysis tube and were treated with a single application of 40%

acrylic strip methods of delivering metroni- tetracycline-HCl, reductions in motile rods,

dazole showed reductions of plaque and per- spirochetes, BOP, and PD occurred, however
iodontal inflammation.207 A similar study in all parameters, the effect of scaling and
comparing 0.2% CHX daily irrigation to 4 root planing was superior to the ointment
weekly insertions of 40% metronidazole and lasted longer.
strips showed metronidazole superior in re- Minocycline-HCI ointment. Clinical and
ducing the sulcular bleeding, but equal in microbial conditions were monitored follow-
other parameters to 0.2% daily CHX irriga- ing SRP plus 4 weekly irrigations with saline
tion.205 (control) versus 4 weekly placements of a 2%
When 40% CHX, MET, and TCN acrylic minocycline-HCl ointment. Culture studies
strips were compared after only 2 to 3 days of specific target organisms showed the test
in vivo, motile organisms were almost com- group significantly sustained repression or
pletely eliminated from some sites treated elimination of A. actinomycetemcomitans, P.
with metronidazole and tetracycline. MET gingivalis, and P. intermedia for up to 12
was significantly more effective in reducing weeks (Table 3).248 Dark field microscopic
spirochetes than TCN or CHX.206 Addy et al. counts were significantly reduced in the test
have confirmed the usefulness of MET in the group. Attachment level gain, reductions in
management of chronic Periodontitis in a 3- PD, and BOP were also significantly better in
month trial. MET compared favorably to SRP the test group. Minocycline-HCl ointment
in reduction of probing and in attachment appeared to enhance the effect of scaling
gain (Table 4).210 A similar study using these and root planing in this 3-month study.
devices has shown TCN to be more effective van Steenberghe et al.249 conducted a large
when applied 4 times over 16 days.245 Treat- multi-center randomized, double-blind, vehi-
ment effects were not sustained after the de- cle-controlled trial of 103 adult Periodontitis
vices were removed. patients (Table 3). Patients were treated with
The in vitro release profile of Chlorhexidine either 2% mmocycline ointment or vehicle
in a local degradable delivery system com- control and followed at 2,4,6 and 12 weeks.
posed of cross-linked protein has been ex- Probing depths were significantly reduced in
plored for development of yet another both groups, but to a greater extent in the
sustained-release device.246 rninocycline gel group. Attachment levels and
gingival indices were reduced at 12 weeks, but
no significant differences were found between
Locally Delivered Antimicrobial test and control except in deeper sites with >7
Ointments mm probing depths and a bleeding index of >
Moderate to severe Periodontitis patients 2 [P < 0.0001). DNA probes showed statisti-
were randomly assigned to receive SRP, no cally significantly greater reduction of P. gin-
treatment, 40% tetracycline HCl in a white givalis, P. intermedia and A. actinomyce-

Vol. 1, No. 1, November 1996

524 Drisko

Table 4. Antimicrobial films, strips, and chips

Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =
Addy et al.210 Randomized controlled, CHX, MET, and TCN applied This short-term study Possibly
1988 single-blind, parallel arm twice within 2 weeks with showed clinically, but not relevant; 7
UK N =
75 acrylic resin strips, produced statistically, significant re-
Length =
3 months significant reductions in clin- sults in both the MET and
ical parameters. MET and SRP group, and suggests
SRP had the most profound that MET therapy was at
effects, with 2.7 mm and 1.8 least as effective as SRP.
mm PD reductions respec- Only 1 site per patient and
tively. Attachment gains single-rooted teeth were
were 2.6 mm for MET and evaluated in this study. Ex-
1.2 mm for SRP. aminer reproducibility not
Wade et al.281 Randomized, controlled MET, TCN strips, root plan- Site selection was based Possibly
1992 N =
73 ing, or root planing then MET on PD of 6 mm, but no relevant; 7
UK Length =
12 weeks strips resulted more pro- BOP or gingival inflamma-
nounced short-term microbial tion or other indications of
changes following treatment disease activity. Only sin-
than CHX strips. Microflora gle-rooted teeth were stud-
showed a marked shift in ied. The authors suggest
TCN resistant organisms in that emergence of micro-
one pocket in particular. At bial resistance was a prob-
12 weeks, microbial counts lem in this group of TCN
were significantly lower in treated patients and did not
root planing, TCN, and MET recommend local drug de-
than CHX and control. livery as a preferred route
of TCN administration.
Stabholz et al.220 Randomized controlled, split Multiple applications of CHX The therapy consisted of 3 Possibly
1991 mouth in an ethyl cellulose-based applications q 3 days then relevant; 6
Israel N =
10 device resulted in reduced 2 applications q 3 days
Length 24 months
PD and attachment gains of every 3 months totaling 57
3 mm in at least 1 pocket in applications during the 24-
8/10 subjects compared to month period in a small
only 1 or 2 of 10 subjects in group of subjects. Clinically
the maintenance only sites. and statistically significant
results would have to be
weighed against the poten-
tial compliance of the pa-
tient to return for repeated
Gibson et al.261 Randomized controlled, MB gel irrigation, and slow The MB treatment had less Possibly
1994 single-blind,
4 quadrant split release device with MB, sa- side effects and was better relevant; 7
UK mouth line irrigation and SRP re- tolerated than SRP. The
N 24
sulted in PD reductions of redox potential of the MB
Length 12 weeks
about 1.2 mm for all treat- has a positive effect on
ments. Only MB in the slow subgingival microflora. MB
release device or by irriga- as a monotherapy was as
tion significantly reduced effective as SRP in this
black pigmented Bacteroides group of adult Periodontitis
(BPB). A subgingival micro- patients. Examiner repro-
flora similar to health was es- ducibility was k> 0.9 for all
tablished by the subgingival measurements.
debridement as well as by 3
applications of MB in a slow
release device or by irriga-
tion. MB was significantly
better than SRP or saline ir-
rigation in controlling BPB.

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 525

Table 4. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =
Taner et al.254 Randomized, controlled, par- DOX in 2 slow release films SRP showed slightly better Possibly
1994 allel arm compared to SRP or no results than DOX. During relevant; 5
Turkey N 11
treatment showed that test the course of the study, the
Length =
10 weeks groups resulted in significant test drugs were applied 12
improvements in clinical par- times (twice a week for 6
ameters. weeks). The treatment out-
comes were not signifi-
cantly better than SRP but
required significantly more
frequent participation by
the patient. Groups were
extremely small with 2 to 3
subjects per treatment.
Ower et al.262 Randomized controlled MB redox agent in a slow re- Some soft tissue staining Possibly
1995 N 18
lease device showed after 2 was observed for 30 relevant; 6
UK Length 3 months
applications that PD and minutes following therapy.
BOP were significantly im-
proved by subject analysis
but not by site analysis.

Yamagami et al.'' Randomized placebo Water soluble, controlled re- Ofloxacin was significantly Possibly
1992 trolled, single-blind lease insert containing Oflox- effective in reducing gingi- relevant; 5
Japan N =
40/46 completed acin, applied 4 times over 4 val index, BOP, and PD in
Length =
4 weeks weeks resulted in significant a group of adult Periodon-
reductions in PD (1.53 mm) titis patients. Attachment
compared to control (0.63 levels and examiner repro-
mm). Gingival bleeding was ducibility not reported.
also significantly reduced in
the test, but not the control.

Minabe et al.258 Randomized controlled, split Class II furcations treated 4 weekly applications of Possibly
1988 mouth with a TCN-immobilized cross- the drug delivery device relevant; 6
Japan N 16
linked collagen film plus SRP with TCN was adjunctive to
Length 8 weeks
reduced PD by 2.80 mm SRP in reducing PD and
compared to 1.88 mm in gaining attachment in fur-
SRP alone. Attachment gain cation sites in adult Perio-
was 2.0 mm for TCN + SRP dontitis cases. Examiner
and 0.81 mm for SRP, 0.80 blinding and reproducibility
for control. were not reported.
bleeding on probing. MB=
methylene blue. SRP =
scaling and root planing.
Chlorhexidine. MET =
metronidazole. TCN =
doxycycline. PD=
probing depth.

temcomitans for up to 12 weeks compared to Controlled Release Devices: Films,

control. Minocycline ointment was recently
used to condition the highly inflammed tissue
Inserts, Membranes and
and control infection prior to guided tissue re-
Bioresorbable Polymers
generation on an LJP patient.250 Further re-
search is needed to explore the role of locally Ofloxacin. A newly developed quinolone,
delivered antimicrobials in conjunction with Ofloxacin (OFLX), is effective against anaer-
regenerative procedures. obes nearly equivalent in antibacterial activ-

Vol. 1, No. 1, November 1996

526 Drisko

ity in vitro to Ciprofloxacin, erythromycin, these carriers in clinical practice. These and
and tetracycline.251 A new soluble insert, other studies suggest that use of sustained-
with both fast and sustained-release parts release antimicrobials, with or without scal-
containing 10% w/w Ofloxacin, showed that ing, may have positive effects on clinical
a constant level of above 2 ug/ml, (minimum parameters, and may be alternative thera-
antibacterial concentration for most patho- pies for recurrent disease in supportive per-
genic microorganisms) could be sustained iodontal therapy.
for up to 7 days. Four weekly applications of Tetracycline. Atelocollagen films with im-
the insert resulted in significant resolution mobilized tetracycline (TNC) have been
of periodontal inflammation, PD reduction, found to produce an effective MIC dose in
and inhibition of supragingival plaque ac- the gingival crevicular fluid for up to 10
cumulation, compared to control (Table days.258 When the TNC film was compared to
4) 252 Further investigation failed, however, non-immobilized placebo film, bleeding and
to show any additional effect on the subgin- spirochetes were significantly reduced at 4
gival microflora beyond SRP alone.253 and 7 weeks in the test groups. (See Table 4)
Doxcycline. Two different resorbable mem- In a similar study, comparing the TCN film
branes were tested, hydroxypropylmethylcel- to root planing or to a combination of scaling
lulose and methylcellulose containing 40% and root planing plus TCN in furcations,
doxycycline (Table 4).254 Treatment consisted Minabe et al.259 found marked decreases in
of twice weekly application of the strips for 6 rate of bleeding on probing and increases in
weeks compared to SRP or no treatment in attachment gain in the combined therapy
moderate Periodontitis subjects. At the end of group. Maze et al. recently conducted a pilot
10 weeks, significant improvements in clini- study to evaluate a 25% intracrevicular con-
cal and microbial parameters were seen for trolled release poly(lactide/glycolide) film
both doxycycline inserts and scaling and root strip in 10 adult Periodontitis subjects.260
planing compared to control. Others have Compared to baseline, the antibiotic strips
shown Chlorhexidine or tetracycline delivered significantly reduced PD for 26 weeks, in-
by a similar resorbable base material was creased attachment, and decreased motile
successful in producing marked changes in rods for 3 months. Control and placebo
the subgingival microbial composition of per- showed isolated effects on clinical and mi-
iodontal pockets.255 crobial parameters, but not to the extent of
Garrett et al.256 have recently tested a bio- the test article.
resorbable polymer containing 10% doxycy- Chlorhexidine. Sustained release of CHX
cline hyclate as a monotherapy compared to delivered in an ethyl cellulose-based form
a vehicle control in maintenance patients has been shown to be effective in reducing
with recurrent Periodontitis. Results from subgingival flora as well as probing depths.
this large multicenter randomized controlled Recently, a small clinical trial showed 2-year
trial showed that doxycycline reduced prob- effects of multiple applications of this CHX
ing depths and bleeding scores significantly delivery device (Table 4).220 Results are
better than the vehicle control (Table 3). promising, but larger controlled trials are
Similarly, the attachment levels were signif- needed to establish the clinical and micro-
icantly improved after two applications of bial benefits of this therapeutic modality.
the polymer, once each 4 months, compared The significant numbers of required appli-
to controls. cations of the product may detract from its
Recently other bioabsorbable materials usefulness in periodontal therapy.
and acrylic strips have been tested for their Methylene blue. A redox dye, methylene
ability to release doxycycline into liquids and blue (MB), was compared with subgingival
for their residual antibacterial activity.257 root surface debridement and sterile water
Both a hemostatic gauze and a fibrin sealant in a 4 quadrant design in Periodontitis pa-
were capable of prolonged release of doxy- tients (Table 4).261 One quadrant was irri-
cycline in vitro, however no in vivo data are gated with 0.1% methylene blue gel or a slow
available to determine the potential use of release device (MB-SRD) of 33% w/w of

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 527

methylene blue in a biodegradable collagen and cultural analyses showed that TNC fiber
alginate vicryl composite. Test and control and SRP significantly reduced the number of
sites were treated at baseline and all but the detectable species from baseline.264
SRP were treated again at 1 and 4 weeks. All Heijl used a 4-quadrant design in 10 sub-
sites showed improvements in clinical and jects to study fiber therapy with or without
microbiological parameters, but there were scaling. Fiber and scaling plus fiber both sig-
no statistically significant differences be- nificantly reduced bacterial counts for 2
tween treatment types for clinical measures months compared to baseline. Microbial reduc-
at the end of 12 weeks. SRP, MB irrigation, tions were significantly different at fiber sites
and MB-SRD significantly reduced spiro- than untreated sites (Table 5}.265 In the fiber
chetes at different time points in the study. plus scaling groups, complete elimination of
The culture data showed that MB was su- BPB was seen at 62 days but no significant
perior to subgingival debridement in reduc- microbial or clinical changes were seen in the
ing proportions of black-pigmented anaer- untreated group. Fiber therapy and SRP were
obes. This treatment modality is intriguing, not statistically different, and resulted in nearly
since methylene blue has been shown to equivalent microbial and clinical changes in
raise the redox potential of an anaerobic en- this short-term clinical trial.
vironment to a more positive value, one that A large 60-day multi-center trial of 107
is lethal to obligate anaerobes such as P. gin- subjects by Goodson et al. demonstrated
givalis. Mild side effects included transient that in the absence of SRP, fiber therapy
localized staining of the tissues for 30 alone showed mean clinical probing depth
minutes or so. reduction of 1.02 mm compared to 0.67 mm
Other work by Ower et al. has shown po- for SRP, a gain in attachment of 0.56 mm
tential adjunctive affects on the subgingival compared to 0.04 mm for SRP, and a 50%
microbiota after two applications one month reduction in bleeding points (Table 5).266 The
apart262 (See Table 4). magnitude of the clinical response to SRP
has been questioned compared to results of
other studies. One explanation for this find-
Non-Resorbable Release Devices
ing is that supragingival scaling and oral hy-
Tetracycline-loaded ethylene vinyl acetate giene instruction were performed prior to
fibers. Goodson and coworkers have re- evaluating the efficacy of the subgingival
ported a series of studies, beginning with therapies. Both TNC fiber and scaling de-
tetracycline hollow fibers then later ethylene creased the number of sites infected with all
vinyl acetate fibers (TNC), showing the abil- of the monitored species, (A. actinomycetem-
ity of the fibers to reduce bleeding on prob- comitans, E. corrodens, F. nucleatum, P. gin-
ing and probing depths, and to increase givalis, P. intermedia, and C. rectus). Bacte-
attachment levels.201-212213 Tetracycline fi- rial composition at untreated and control
bers maintain a constant average concentra- fiber sites was relatively unchanged. Signif-
tion of 1,590 ug/ml in periodontal pockets icant reducions of probing depths were only
for over a 10-day period.263 Tissue collage- found at sites initially infected with P. gin-
nase activity was shown to be inhibited in givalis.
rat's polymorphoneuclear leukocyte collage- Kerry267 reported on 60 maintenance pa-
nase activity and bacterial collagenase activ- tients with recurrent Periodontitis who were
ity in vitro.215 After removal, the tetracycline treated with TCN fiber plus SRP (Table 5). Re-
concentration decreases exponentially with sults of this 6-month, non-controlled case
a half-time of 4.5 hours. DNA probe and se- study showed dramatic improvements in both
lective cultural methods were studied to ex- moderate and deep probing depths and bleed-
amine the effects of the fibers on 6 putative ing on probing. Tonetti et al.268 have reported
periodontal pathogens. The microbiota in similar results in a series of case reports.
this 4 quadrant study at untreated sites and A 6-month multi-center study of 106 re-
control fiber sites did not appear to be sig- current maintenance patients by Newman et
nificantly altered from baseline. Both DNA al. found scaling plus fiber (SF) reduced

Vol. 1, No. 1, November 1996

528 Drisko

Table 5. Sustained-release tetracycline fibers

Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =

Drisko et al.270 Randomized, single-blind, 4 Clinical changes following a The clinical response was Relevant; 8
(Clinical Response) quadrant split mouth, con- single or 2 consecutive ap- essentially maintained for 1
1995 trolled plications of TCN fiber were year following treatment
116/122 completed no different than scaling without benefit of mainte-
Length 12 months
alone, or fiber plus scaling. nance therapy. There may
All treatments showed signif- have been some crossover
icant attachment gains (0.96 effect due to the large num-
to 1.18 mm), and reduction ber of fibers used per pa-
of BOP and PD (1.18 to 1.43 tient.
Lowenguth et al.272 Randomized, single-blind, 4 Six periodontal putative The numbers and propor- Relevant; 8
(Subset of above270: quadrant split mouth, con- pathogens monitored with tions of detectable patho-
microbial response) trolled DNA probes showed fiber gens (except P. gingivalis)
1995 N =
31 plus scaling produced lower showed a precipitous initial
USA Length 12 months
percentage of sites, but not decrease immediately fol-
statistically significantly dif- lowing therapy; a rise in the
ferent levels of detectable F. proportions of pathogens in
nucleatum, P. gingivalis, P. the first 1-3 months follow-
intermedia, or C. rectus. ing therapy; and finally a
spontaneous decline in the
absence of therapy from 3-
12 months.

Michalowicz et al.271 Randomized, single blind, 4 Sites treated with scaling Scaling plus fiber therapy Relevant; 8
(Subset of above270: quadrant split mouth, con- plus fiber had significantly for 10 days can signifi-
maintenance response) trolled less (P < 0.05) disease re- cantly reduce disease re-
1995 N =
116/122 completed currence than scaling (9%), currence (Periodontitis) 3-
USA Length 12 months
fiber alone (10%), or 2 serial 12 months following treat-
applications of fiber (12%). ment in the absence of
maintenance therapy.

Goodson et al.266 Randomized, single-blind, 4 TCN fiber significantly in- PD were reduced by 1.2 Relevant; 8
1991 quadrant split mouth, pla- creased attachment by 0.67 mm between screening
USA cebo control mm (P < 0.0002) and re- and baseline following a
N =
107 duced PD by 1.02 mm (P < supragingival prophy. This
Length 60 =
days 0.0002) and BOP (P < may account for the small
0.0001) compared to pla- but statistically significant
cebo, no treatment, and scal- clinical changes between
ing. baseline and the end of the
Newman et al.269 Randomized, parallel arm, Scaling plus TCN fiber ther- Scaling plus TCN fiber Relevant; 8
1994 single-blind, controlled field apy resulted in significantly therapy in localized recur-
USA trial from multiple private higher attachment gains rent Periodontitis in main-
practices. (1.56 mm) than scaling alone tenance patients was more
N =
113 (1.08 mm). PD were also sig- effective than scaling and
Length =
6 months nificantly reduced with scal- root planing.
ing plus fiber (1.81 mm)
compared to scaling alone
(1.08 mm).

mean by 1.81 mm versus 1.08 mm for

PD A more recent 1-year multi-center trial of
scalingalone. Attachment gains were 0.65 116 subjects found all treatments, fiber (F),
mm for SF and 0.40 mm for SRP alone, with two serial fiber applications (FF), SRP alone
a 35% reduction in SF (Table 5).269 (S), or SRP plus TCN fiber (SF) reduced PD

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 529

Table 5. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =

Heijlet al.265 Randomized, single blind, 4 Scaling, scaling plus fiber, Although the differences Possibly
1991 quadrant split mouth, con- and fiber therapy alone re- between treatments were relevant; 7
Sweden/USA trolled sulted in reductions of PD, not significantly different,
N 10
BOP, and black-pigmented scaling plus fibers pro-
Length 60 days =
Bacteroides (BPB). No sig- duced a greater effect than
nificant differences were either scaling or fiber ther-
found between treatments. apy alone. With the com-
bined therapy, BPB were
completely eliminated, as
was the BOP.

Kerry267 Longitudinal study PD were significantly re- The combination of fiber Possibly
1994 N =
60 duced following scaling plus plus scaling was effective relevant; 7
USA Length =
6 months TCN fibers in all sites by 2.8 in providing significant clin-
mm, in deep sites by 3.1 ical improvements which
mm, and in moderate sites lasted up to 6 months in a
by 1.5 mm on average. BOP group of private practice
was reduced from 97% to maintenance patients with
27%. recurrent localized Perio-

bleeding on probing.
PD =
probing depth.

and BOP and increased attachment levels. Collaborative studies by Morrison274 et al.
There were no significant differences be- and Kazakos et al.27B looked at the root sur-
tween treatments over 1 year without benefit faces and soft tissue lining the pocket after
of maintenance therapy (Table 5).270 Inter- 10-day in vivo exposure to TCN fibers. Soft
estingly, SF sites had significantly less dis- tissue pocket walls, examined by scanning
ease recurrence than any other treatment electronic microscopy (SEM), energy disper-
groups (Table 5).271 It would appear that the sive spectroscopy, and light microscopy
combination of TCN fiber and SRP may be showed no adverse effects in the epithelial
useful in maintaining attachment gain and lining or inflammatory response in the ad-
preventing disease recurrence. jacent soft tissue. The SRP plus fiber sec-
Microbial data showed that, when com- tions showed incomplete removal of adsorbed
pared with SRP, the adjunctive use of TCN root surface pellicle and demineralization of
fiber consistently resulted in a lower per- the subsequently exposed root surface.
centage of sites with detectable levels of F. Specimens treated with fiber alone or in
nucleatum, P. gingivalis, P. intermedia, and combination with root planing showed a su-
C. rectus (Table 5).272 An early study by Man- perficial penetration of tetracycline into the
dell et al. reported that fibers did not elimi- root surface of about 10 microns. Areas of
nate A. actinomycetemcomitans in patients demineralized root showed slight tetracy-
with juvenile Periodontitis.273 The lack of ef- cline penetration into exposed dentinal tu-
fect may have been due to the possibility bules. The relative importance of TCN pen-
that tetracycline-resistant bacteria were etration is not known, but Adriaens et al.
harbored in the pocket from previous TCN observed microbial invasion of root struc-
therapy. It is also conceivable that A. acti- tures in 87% of the teeth they looked at
nomycetemcomitans, which is known to in- SEM.276 These authors also reported that
vade tissue beyond the pocket epithelium, they believed the root to be a potential res-
was simply out of reach of the fiber therapy. ervoir for microbial re-colonization of the

Vol. 1, No. 1, November 1996

530 Drisko

pocket from within the root. They estimate ent from no treatment. Like many other
that SRP may, at best reduce the incidence studies oflocally delivered antimicrobials,
of viable intra-dentinal bacteria to about probing depths were further reduced at 1
74%, making the application of an antimi- and 3 months in favor of the antimicrobial
crobial capable of absorbing into the root an but failed to maintain that difference at 6
attractive therapeutic option. months.
Ciancio et al. have reported that TCN pen-
etrated the soft tissue wall of fiber treated Resistance to Locally
sites, ranging in depth from 1 to 20 mi-
crons.277 They reported no significant ad-
verse effects on healing and probing depth Acrylic strips with either Chlorhexidine,
reductions, indicating the TCN fiber does not tetracycline, or metronidazole and polyme-
appear to interfere with postsurgical heal- thyl methacrylate (50% acrylic w/w) were
ing. tested for their effects on the composition
Serum concentrations of TCN following and antimicrobial susceptibility of the sub-
TCN fiber therapy for 10 days ± 2 days gingival flora in chronic Periodontitis sub-
showed that a transient and insignificant jects. Tetracycline appeared to effect major
level of no greater that 0.1 Lig/ml of TCN was shifts in the composition of the microflora of
available systemically shortly after the treated pockets but caused a marked selec-
placement of multiple fibers in four adult se- tion of tetracycline-resistant organisms.281
vere Periodontitis subjects.278 In contrast, amoxicillin with clavulanic acid
Locally delivered antimicrobial microen- has been tested in one study by incorporat-
capsulated polymer. The effect of a minocyc- ing the antibiotic in acrylic strips at varying
line HCl microencapsulated in a biodegrad- concentrations of 30/40/50 w/w. Short-
able polymer (polyglycolide-co-dl-lactide) term results show that at 40% concentra-
was tested on subgingival microflora in a tion, the sensitivity of P. gingivalis and P.
group of severe Periodontitis patients over 6 intermedia isolated before and after treat-
months. Significant decreases in propor- ment with amoxicillin and clavulanic acid
tions of spirochetes and motile rods were remained unchanged.282 Further evidence
seen at 1 and 3 months in the minocycline for concern resulted from a study by Wade
group but at 6 months the opposite was et al.,281 where acrylic strips containing
true, with the placebo group having signifi- CHX, MET, or TCN were tested to determine
cantly less spirochetes.279 Dark-pigmented their effect on the composition and antimi-
Bacteroides spp. and P. intermedia were sig- crobial susceptibility of the subgingival flora
nificantly lower at 3 months compared to in chronic Periodontitis (Table 4). CHX
placebo, but were not different at 6 months. caused no detectable changes in the com-
The clinical efficacy of this same product position of the subgingival microflora, while
was tested with and without SRP in adult MET had a variable effect. Tetracycline af-
patients with moderate to severe Periodon- fected major shifts in the composition of the
titis. A standard volume of powder (4 mg, flora but also caused marked selection of tet-
equivalent to 1 g of minocycline base in each racycline-resistant organisms.281 One 6-
syringe) was delivered (Table 3).280 At 6 month pilot study of three patients investi-
months, gains in clinical attachment level gated the emergence of resistant bacterial
were significantly greater for SRP than for ei- strains following TCN fiber therapy.283 The
ther the no treatment groups or the MIN findings showed a transient selection of re-
plus SRP or MIN alone. Test sites showed sistant strains, but the flora returned to nor-
short-term significant reductions of P. gin- mal in a few weeks. In another study, sites
givalis and P. intermedia. All treatment were treated with a hemostatic gauze of ox-

groups resulted in significant mean de- idized regenerated cellulose were impreg-
creases in gingival index, but by 3 months, nated with a 2% solution of doxycycline.284
the minocycline groups had rebounded, and Doxycycline resistence was increased from
only the SRP group was significantly differ- less than 1% prior to treatment, to 22% at

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 531

the tongue site and 35% from the tonsils. marketing approval, and do not provide suf-
Gram-positive cocci made up most of the re- ficient evidence of clinical efficacy.
sistant bacteria, but decreased again by Very little evidence exists to date to an-
week 13. swer the question of potential side effects
It is not known whether intraoral sites, and adverse reactions similar to those found
other than those containing the fibers or the with systemic antibiotics. Overgrowth of op-
doxycycline/gauze, develop resistant bacte- portunistic organisms and bacterial resis-
ria. Since there is a justifiable concern over tance need to be explored further. There is
the emergence of resistant bacteria due to ample evidence to show that locally delivered
systemic antibiotic therapy, investigations of antimicrobials can reduce clinical and mi-
the effect of local antibiotic therapy with all crobial parameters to a level comparable to
sustained-release devices should be ex- scaling and root planing. Mechanical instru-
plored further. mentation, whether in an open or closed en-
vironment, can be extremely technically
SUMMARY demanding, time consuming, and, in some
periodontal defects, ineffective or incom-
Locally administered antibiotics as a plete. Local drug delivery systems on the
monotherapy have been shown in some other hand, generally appear to be simple to
studies to have a similar therapeutic effect use and may conceivably, in the future, be
to root planing. The monotherapy approach delivered by the patients themselves. It is
is questionable since most evidence sup- apparent that local drug delivery systems
ports the use of pharmacotherapeutics in re- can be useful adjuncts to routine methods
current or refractory cases which are for the management of chronic periodontal
preceded by mechanical therapy or are ap- disease in maintenance patients, and in
plied in conjunction with SRP, however sites with recurrent or refractory disease.
monotherapy may help extend maintenance Regardless of the agent used however, the
visits. The evidence supports the fact that mode of administration, salivary flow, and
when traditional therapies fail to arrest the crevicular fluid flow, significantly affect the
disease, topical or locally delivered sus- ultimate efficacy of pharmacotherapeutic
tained-release antimicrobial therapy gener- agents used in treating intraoral infec-
ally has some effect, at least over a short tions.197
period of time. Due to a small number of Future therapeutic considerations might
long-term studies (> 1 year) to support their include alternating drugs, using different
use as a monotherapy, locally applied anti- antimicrobials from one treatment time to
microbials should be regarded as an ad- the next, as more drugs and delivery sys-
juncts to mechanical periodontal therapy in tems become available. Targeted therapy
the treatment of recurrent and refractory pa- based on rapid chair-side assays of bacterial
tients. susceptibility would also be desirable to en-
The results of short-term studies suggest hance the ability of the operator to select ap-
that most local drug delivery systems appear propriate antimicrobials. Timed-release, se-
to be fairly equivalent. Questions concerning rially-delivered, or combination local delivery
how long the effects of therapy will exist re- drugs, such as metronidazole plus amoxicil-
main to be answered. How these new prod- lin and ketoprofen, may be beneficial for cer-
ucts will compare to SRP or surgery over a tain refractory subjects. Incorporation of
2- to 3-year maintenance period is yet to be anti-infectives with anti-inflammatory prod-
determined. Clearly, further investigations ucts, as well as growth factors to enhance
are required. Study lengths and sample sizes cell attachment, would, of course, be ideal.
must be increased before any concrete con- Future products should consider incorpo-
clusions can be drawn regarding the short- ration of antimicrobials and other agents
or long-term benefit of local drug delivery into the membranes and guided tissue de-
systems, since most of the small short-term vices that can enhance regenerative out-
trials are proof of principle studies for pre- comes. Regardless of new developments and

Vol. 1, No. 1, November 1996

532 Drisko

products, excessive use of locally delivered Periodontitis in this review section will be
pharmacotherapeutics should be avoided, based on that described by van Winkelhoff as
and careful clinical monitoring, and per- attachment loss despite optimal subgingival
haps, diagnostic tests, as they become avail- debridement and performance of excellent
able, should accompany the use of locally oral hygiene by the patient.304 Recurrent dis-
applied agents. ease is not identified as a separate category of
periodontal disease, and is found in the tables
SYSTEMIC ANTIBIOTICS and text under adult Periodontitis.
Slots and van Winkelhoff 305 have sug-
Historical Perspective gested that antimicrobial activity in the per-
iodontal pocket is influenced by a variety of
In addition to locally delivered anti-inflam- factors including: 1) the total bacterial mass;
matory and anti-microbials agents, many 2) microbial invasion into root surfaces and
studies prior to the 1989 World Workshop the periodontal tissues; 3) microorganisms
have reported the effects of treating periodon- in biofilms; 4) subgingival recolonization of
tal diseases with systemic antibiotics. Among the pocket from sugragingival plaque; 5)
earlier studies are those using systemic anti- binding of the drug to other non-target mi-
biotics as a monotherapy, including tetracy- croorganisms and tissues; and 6) presence
cline hydrochloride,229'285286 mmocycline,215 of beta-lactamase producing microorgan-
metronidazole,7 doxycycline,287"291 spiramy- isms. While the evidence presented in the
cin,292293 and erythromycin.292 Scaling and following section does not address all of
root planing (SRP) in conjunction with a vari- these factors, it will reflect the progress to
ety of antibiotics such as metronidazole (Ta- date that researchers have made towards
bles 6, 7, and 8),294 296 tetracycline hydrochlo- the efficacy of certain antibiotics either in
ride (TCN),6297298 a composite drug containing single or combination drug therapy.

spiramycin and metronidazole,299 rninocyc- Antibiotics are currently of great interest

line,300 and Clindamycin have been explored to the periodontal community, as evidenced
previously.301 The review below encompasses by the extensive list of publications since
only those studies published since 1988 ex- 1989. In order to present the most relevant
cept for earlier studies that were included for antibiotic data from recent studies, both by
clarification or comparison. specific antibiotic therapy, as well as by dis-
The criteria used in the 1989 World Work- ease type, the review has been organized so
shop defined a subject as having refractory that each new study is discussed under the
Periodontitis if multiple sites continued to name(s) of the specific antibiotic(s). The evi-
lose attachment despite appropriate perio- dence tables are organized by disease pattern
dontal management.302 The Glossary of Per- with the various representative antibiotic
iodontal Terms specifically defines refractory protocols listed for each disease. Preference
disease as, "a heterogenous group of condi- was given in the evidence tables to those
tions including those which do not respond studies that were blinded, had a positive and
to treatment and others in which recur- negative control, were of at least 6-months
rences appear at a few or many sites."303 It duration, and included > 10 patients per
is difficult, if not impossible, to judge treatment group.
whether "appropriate care" was given in the
studies viewed in this section. Differences of
opinion by various authors were obvious rel- Tetracyclines
ative to the heterogeneity of the terms "re- The tetracyclines are broad-spectrum anti-
fractory" and "recurrent." Frequently, the biotics that are effective against a wide range
description of the patient population was of microorganisms. They are the most com-
consistent with recurrent disease, yet the title monly prescribed antibiotic used in periodon-
of the paper used to describe the study pop- tics.306 Tetracyclines include tetracyclrne-HCl,
ulation contained the term refractory. In order rriinocycline, and doxycycline, all of which in-
to avoid more confusion, the term refractory hibit most putative periodontal pathogens.

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 533

Table 6. Systemic antibiotics plus periodontal debridement: adult Periodontitis

Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =

Loesche et al.373 Randomized, double-blind, pla- MET 250 mg tid for 7 days The effect of the antibiotic Relevant; 9
1991 cebo controlled plus debridement signifi- was maintained for the 2 to
33/39 completed cantly reduced the need for 3 year recall period. MET
Length up to 44 months
surgery by about 5 teeth per can significantly reduce the
patient compared to control need for periodontal sur-
(P =
0.0007). Spirochetes gery compared to debride-
were significantly reduced (P ment alone.
< 0.05) by 90% at MET sites
versus 64% in control.

Al-Joburi et al.319 Randomized, double-blind, pla- The results showed SPIR, 6 hours of SRP were per- Relevant; 9
1989 cebo controlled TCN, or placebo, plus de- formed on all patients in
Nova Scotia N =
79/96 completed bridement resulted in im- the study. The addition of
Length 24 weeks
proved plaque, crevicular antibiotics had no signifi-
fluid measurements, BOP, cant adjunctive effect on
PD, and attachment levels. clinical parameters, but did
Only SPIR maintained signif- significantly reduce spiro-
icant post-treatment reduc- chetes for the duration of
tions of spirochetes at 24 the study.

Söder et al.395 Randomized, double-blind, pla- Debridement plus 400 mg tid The addition of MET to per- Relevant; 8
1990 cebo controlled of MET for 7 days or placebo iodontal debridement had
Sweden N =
98 resulted in statistically signif- an adjunctive effect in re-
Length 6 months
icant improvements in the ducing the number of in-
number of sites > 5 mm in flamed pockets > 5 mm.
both test and control groups. The entry criteria included
Complete healing was de- only those patients who
fined as no pockets > 5 mm had not responded to non-
occurred in 30% of test and surgical debridement; there-
9% of the controls. fore the study population
may be better defined as
refractory patients rather
than adult Periodontitis.

Loesche et al.374 Randomized, double blind, Patients selected with > 20% Significant PD reductions Possibly
1992 placebo controlled spirochetes or had plaques and attachment level gains relevant; 7
33/46 completed which hydrolyzed benzoyl- (P < 0.01) were associated
Length 4-6 weeks
DL-arginine-naphthylamide with significant reduction in
responded significantly bet- the number of teeth per pa-
ter to MET, 250 mg for 7 tient needing surgery in the
days than the placebo MET group (8.4) compared
treated group. Significantly to control (2.6). MET had a
lower proportions of spiro- significant adjunctive effect
chetes, selenomonads, mo- in addition to debridement
tile rods, and P. intermedia in this short-term study.
were associated with the Antibiotic therapy given af-
MET group. ter debridement appeared
to have positive results.

AL attachment level.
AMOX amoxicillin.
PD =
probing depth.
DOX doxycycline.
scaling and root planing.
LJP localized juvenile
Periodontitis. TCN =

Vol. 1, No. 1, November 1996

534 Drisko

Table 6. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =
Bain et al.392 Multi-center randomized, dou- SPIR, 1,500,000 units bid for No intra- or inter-examiner Possibly
1994 ble-blind, placebo controlled 14 days resulted in signifi- reproducibility data re- relevant; 7
Nova Scotia N 189/193 completed
cantly better (P 0.0075)
ported for this multiple op-
Length 24 weeks=
probing depth reductions (2.97 erator, 7 center study. SRP
mm) versus placebo (2.40 averaged 3-5 hours per pa-
mm). Attachment gains were tient. Differences were sta-
significantly better for SPIR tistically different but clini-
(1.87 mm) versus control cally insignificant averaging
(1.58 mm) at 12 weeks only. about 0.57 mm in PD
changes and about 0.29
mm in attachment gain.

van Winkelhoff et al.393 Longitudinal MET plus amoxicillin tid for 7 Patients still positive for Aa Possibly
1992 N =
50 days resulted in significant and Pg had higher bleeding relevant; 7
The Netherlands Length =
4 to 9 months reductions in probing depths tendencies after therapy
(2.5 mm) and attachment than those where the bac-
gains (1.2 mm). A. actino- teria were no longer detect-
mycetemcomitans {Aa) and able. MET plus amoxicillin
P. gingivalis {Pg) were al- and subgingival debride-
most completely eliminated. ment is effective in reduc-
ing Aa in severe adult Per-
iodontitis subjects.

Müller et al.364 Longitudinal Minocycline 200 mg/day for Aa was persistent in the Possibly
1993 N =
15 3 weeks was used in gener- generalized Periodontitis relevant; 7
Germany Length =
24 months alized mild and severe Perio- groups, and treatment re-
dontitis patients. Elimination sponse was different when
of Aa was significantly as- comprehensive treatment
sociated with mean attach- (some went on to surgery)
ment gain of > 2 mm only failed to eliminate the or-
after scaling. Aa was still ganism. In another subset
present in about 50% of sub- of the study including lo-
jects, where it was generally calized juvenile Periodonti-
eliminated in a subset of lo- tis cases, clinical results
calized juvenile Periodontitis were significantly better
patients. than in the generalized
adult Periodontitis group.

Freeman et al.361 Longitudinal Short-term changes in clini- Bacteriostatic concentra- Possibly

1992 N =
30 cal parameters were no dif- tions of gingival crevicular relevant; 5
Ontario Length =
15 days ferent between 100 mg or fluid were achieved with a
200 mg/day of minocycline single 100 mg dose per
therapy. At 8 days, Pg and Pi day of minocycline.
were reduced but not elimi-
bleeding on probing. SPIR =
metronidazole. SRP =
scaling and root planing.
PD =
probing depth. TCN =

Pharmacology. The first TCN were isolated static in nature, and are generally more
from a Streptomyces strain in 1948. Since effectiveagainst Gram-positive bacteria than
then newer versions have been produced or Gram-negative bacteria. TCN concentration
derived semi-synthetically and include dox- in the gingival crevice is 2 to 10 times that
ycyline and minocycline. They are bacterio- in serum which allows a high drug concen-

Annals of Periodontology
Review: Non-Swgical Pocket Therapy: Pharmacotherapeutics 535

Table 7. Systemic antibiotics plus periodontal debridement: juvenile Periodontitis

Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =

Saxen & Asikainen376 Randomized, controlled MET 200 mg tid for 10 days Due to the small sample Possibly
1993 N =
27 suppressed A. actinomyce- size, no statistical compar- relevant; 7
Finland Length 18 months
temcomitans to below detec- isons were made; however,
(enrollment over 3 years) tion levels at all test sites MET appeared to result in
compared to 17/26 TCN 250 slightly better clinical and
mg qid for 12 days or 19/26 microbial changes than the
(no medication) control sites. other groups.
All groups showed clinical
Christersson et al.230 Longitudinal TCN-HCI 250 mg qid for up There was a strong asso- Possibly
1993 N =
6 to 8 weeks (1 week after no ciation between mean relevant; 7
USA Length =
24 months detectable Aa) resulted in numbers of Aa and
significant PD reductions of 2 changes in PD and AL. 9/
mm (P =
0.02) and attach- 13 negative sites had no
ment level gains of 1.4 mm change in AL where 8/9
for up to 12 months. positive sites had AL.
van Winkelhoff et al.393 Longitudinal MET + AMOX tid for 7 days Patients with detectable Aa Possibly
1992 N =
28 resulted in 2.2 mm of PD re- had higher bleeding scores. relevant; 7
The Netherlands Length =
4.9 months duction and 1.3 mm of at- MET + AMOX is effective
tachment gain. Aa was vir- in eliminating Aa from sub-
tually eliminated from most gingival plaques in LJP pa-
sites. tients.

Asikainen et al.289 Randomized double-blind, pla- DOX 100 mg/day for 2 study showed Possibly
This short-term
1990 cebo controlled weeks reduced PD by 1.6 no advantage of systemic relevant; 7
Finland N =
16 mm compared to 1.4 mm for DOX for 2 weeks above
Length 8 weeks
placebo which were not sig- that of SRP plus placebo in
nificantly different. Bleeding LJP patients.
on probing, suppuration, and
gingival fluid flow measure-
ments were not different be-
tween test and control.

Saxen et al.288 Randomized double-blind, pla- Clinical condition improved The DOX may have had a Possibly
1990 cebo controlled in both test and control transient effect on the Aa. relevant; 7
Finland N =
14/16 completed groups, but the DOX group DOX therapy had no clini-
Length 20 months
showed a significantly greater cal benefit in addition to
(20 month results of Asikai- reduction in the prevalence SRP in this group of LJP
nen269) of Aa (P < 0.001) at 8 patients.
months following therapy
compared with the control

tration to be delivered into periodontal pock- ful drugs in the treatment of A. actinomyce-
ets (4 to 8 ug/ml).307308 Gingival crevicular temcomitans infections.312
fluid levels of this magnitude have been Animal studies. Systemic administration
shown to be very effective against many per- of tetracyclines reduces plaque, gingival in-
iodontal pathogens.309 311 In vitro antimicro- flammation, and bone loss in rats313 and
bial susceptibility tests have indicated dogs314315 lasting approximately 2 years.
tetracycline and minocycline to be very use- However, a study in dogs reported that after

Vol. 1, No. 1, November 1996

536 Drisko

Table 8. Systemic antibiotics plus periodontal debridement: refractory Periodontitis

Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =

McCulloch et al.290 Randomized, placebo con- Statistically significant reduc- Outcome measurement Relevant; 9
1990 trolled, double-blind tion of relative risk (43%) in was a periodontal abscess
Canada N =
55 subjects treated for 3 weeks or significant (> 2 mm) at-
Length =
7 months with DOX compared to pla- tachment loss which oc-
cebo. curred in 13/29 DOX and
15/19 placebo subjects.
Kulkarni et al.346 Randomized, placebo con- Results showed a 40% re- Long term clinical improve- Relevant; 9
1991 trolled, double-blind duction in 6 pathogens com- ments observed in the
N =
27 pared to placebo at 1 week DOX groups may be due to
Length 7 months
and no difference at 7 the anti-collagenase activ-
(Subset of McCulloch 1990290) months. ity rather than antimicrobial
Aitken et al.345 Longitudinal MET given for 10 days Serial DOX then MET ap- Possibly
1992 N = 23 to not responding to pears to be useful for pa- relevant;
patients 7
Length 7 months
DOX. Results showed dis- tients who are at particu-
(Subset of McCulloch 1990290) ease recurrence (abscesses larly high risk for recurrent
or > 2 mm attachment loss) disease.
at 9% of sites (1/11) treated
with DOX then MET com-
pared to 42% (5/12) of sites
previously treated with pla-
cebo then MET.

Magnusson et al.387 Randomized, placebo con- AC and control groups CLIN had increased % at- Relevant; 9
1994 trolled showed about 1 mm of at- tachment from an annual
21 tachment gain compared to rate of 0.9% to 5.1%. Pla-
Length =
24 months CLIN which was significantly cebo was no different in %
worse than control. sites gaining or losing. By
12 to 15 months, attach-
ment loss was retarded but
not arrested.

Golub et al.348 Rat; randomized, placebo Treatment of Pg infected rats These results confirm that Relevant; 9
1994 controlled with DOX, or a chemically TCN can inhibit host-de-
USA N 22
modified TCN (eliminates the rived MMPs by mecha-
Length =
7 weeks drug's antimicrobial activity) nisms that are unrelated to
showed both drugs reduced the antimicrobial activity of
gingival matrix metalloprotei- the drugs.
nase activity to a level com-
parable to non-infected
control rats. Pg and alveolar
bone loss were reduced to
normal levels.

Golub et al.287 Randomized, placebo con- 30 mg/b.i.d. low dose TCN A regimen of low-dose Relevant; 8
1990 trolled given for 2 weeks prior to DOX may not induce tet-
8 surgical excision showed racycline resistance and
Length =
2 weeks mammalian collagenase ac- may serve as a useful ad-
tivity was reduced by ap- junct to the management of
proximately 60 to 80% destructive collagenolysis
compared to placebo. in periodontal patients.

Pavicic et al.396 Multi-center longitudinal MET ± AMOX for 7 days re- Only one patient showed a Possibly
1994 N 48
sulted in suppressing Aa be- slight increase in probing relevant; 7
Netherlands Length 24 months
low detectable levels at 47/ depth and 3 showed some
48 subgingival sites and in loss in mean clinical at-
the saliva, tonsillar areas, tachment level between
and cheeks. baseline and 24 months.

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 537

Table 8. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =

Collins et al.381 Longitudinal, retrospective days qid plus 6 26/30 patients had im- Possibly
AC for 14
1993 N =
30 subgingival irrigations with proved clinical parameters relevant; 7
USA Length =
34.3 months (mean) 10% povidone iodine the first for a success rate of
2 weeks resulted in > 1 mm 86.6%.
of attachment gain in 41.2%
of sites. If P. gingivalis was
eliminated, 55.2% gained > 1
mm attachment, if black-pig-
mented Bacteroides was
eliminated, 50.2% gained > 1
mm of attachment.

Gordon et al.382 Longitudinal Prior to treatment, there was Annual rate of active dis- Possibly
1990 N =
24 an average of 3.1 mm of at- ease (3 mm attachment relevant; 7
USA Length = 24 months tachment loss. Following 7 loss or abscess) was re-
days of 150 mg of CLIN qid, duced from 8.0% to 0.5%
there was attachment gain of (P < 0.001). There was
2 mm at 6 months and 1.5 0.3% attachment loss (AL)
mm at 24 months. BOP was at year 1, and 1.0% AL at
significantly reduced. Sur- the second year. 20 pa-
vival data showed likelihood tients remained in the
of no disease 0.65 for year 1, study at 12 months and 13
and 0.16 for year 2. at 24 months. One patient
experienced pseudomem-
branous colitis.
van Winkelhoff et al.393 Longitudinal MET + AMOX for 7 days tid The combination of MET + Possibly
1992 N =
40 resulted in a significant 2.0 AMOX may improve the ef- relevant; 7
The Netherlands Length =
4.9 months (mean) mm PD reduction and 1.4 ficacy of the drugs against
mm of attachment gain (P < Aa and may be synergis-
0.001). BOP was also signif- tic since over 96.6% of
icantly reduced. sites showed non-detecta-
ble Aa in severe Periodon-
titis cases.

Papliet al.331 Longitudinal TCN HCl 250 mg qid for 6 The number of sites in the Possibly
1989 N =
16 days resulted in significant 4 to 6 mm range and the 7 relevant; 7
Australia Length =
6 to 24 months PD reductions in most teeth to 10 mm range were re-
and sites that lasted for up to duced with correspondingly
2 years. increasing numbers of 1 to
3 mm sites. In patients fol-
lowed for 6 months to 7
years prior to antibiotic
therapy, 27 teeth were lost,
where after therapy, at 6
months to 2 years following
therapy only 3 teeth were

van Winkelhoff et al.394 Longitudinal MET + AMOX for 7 days Possibly

1989 N 11 refractory
significantlyreduced PD by relevant; 7
The Netherlands N =
11 localized juvenile 1.9 mm and BOP from 98%
Periodontitis of sites to 48%. Overall,
Length 9 to =
11 months 98.6% of sites previously in-
fected with Aa were elimi-
nated at 3 to 9 months.

Vol. 1, No. 1, November 1996

538 Drisko

Table 8. Continued
Author Type of Study Rank
Date of Publication Number 10 =
Country Length of Study Results Comments 1 =
Magnusson et al.385 Longitudinal AC given tid for 14 days re- The frequency of the Possibly
1989 N =
10 sulted in 2.5 mm PD reduc- bleeding and suppuration relevant; 7
USA Length =12 months tions and 2.2 mm of attach- was low initially and did not
ment gain. change significantly over
the study. The use of ad-
junctive antibiotic may have
reduced the incidence of
attachment loss in sites re-
sistant to tetracycline for at
least 12 months. Prior to
therapy, sites were losing
2.2 mm of attachment
where 3 months following
therapy these sites had re-
gained 2 mm.
Walker & Gordon3' Longitudinal CLIN 150 mg qid for 7 days No significant increases Possibly
1990 N =
9 resulted in the Gram-nega- were seen post-therapy in relevant; 7
USA Length =
12 months tive components of the sub- 6 bacteria resistant to
gingival microbiota being CLIN. No obvious resis-
either eliminated or severely tance developed following
suppressed. antibiotic therapy.
Mombelli et al.404 Longitudinal Ornidazole compound 500 The effect of the ornidazole Possibly
1989 N =
10 mg bid for 10 days resulted compound is similar to relevant; 7
Switzerland Length =
11 months in 2.43 mm of PD reduction MET in that it is used for
and 1.84 mm of attachment Gram-negative infections.
gain. Results are comparable to
other studies using MET.
Matisko et al.399 Longitudinal DOX for 5 days followed by Patients were defined as 9 Possibly
1993 N =
11 AC for 5 days resulted in sig- recurrent/refractory, 1 rap- relevant; 7
USA Length =
24 months nificant gain of 0.8 mm in at- idly progressive and 1 lo-
tachment at 4 and 12 weeks. calized juvenile Periodonti-
DOX alone significantly re- tis. Sequential DOX then
duced PD only at 4 and 12 AC plus scaling and root
weeks. Without root planing, planing gave the best over-
changes with either antibiotic all results with attachment
regimen were clinically insig- gains of 0.5 mm and PD re-
nificant. ductions of 1.4 mm that
were maintained at 24
Gusberti et al.294 Longitudinal 10 days of 250 mg of MET At > 7 mm sites that were Possibly
1988 N = 5 tid resulted in significant PD treated with antibiotics, the relevant; 6
Switzerland Length =
9 months reduction (1.33 mm) and at- clinical and microbial ef-
tachment gain (1.19 mm) in fects were greatest imme-
sites > 7 mm. Spirochetes diately following therapy;
were significantly reduced however, significant reduc-
and non-motiles significantly tions of Fusobacteria and
increased. P. gingivalis lasted for over
6 months.

AC amoxicillin/clavulanate.
Clindamycin, PD =
probing depth.
AMOX amoxicillin.
DOX doxycycline. TCN =
BOP bleeding on probing.

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 539

2 years of continuous systemic administra- sence of SRP or surgery. Results over the 1-4
tion of tetracycline, the beneficial effect of re- year follow-up available on 4 of the 6 pa-
ducing the rate of bone loss may no longer tients showed long-term stability of the clin-
exist,316 which could be due to an increase ical and radiographic improvement, with
in the frequency of resistant organisms. significant, marked resolution of the defects.
Problems with resident organisms that are Mattout et al.327 have confirmed the rather
resistant to tetracyline are addressed later in remarkable regeneration and repair poten-
the review. tial of a LJP patient in their case report,
Clinical use in adult Periodontitis. An early where the treatment consisted of tetracy-
study by Listgarten et al. failed to demon- cline therapy in addition to SRP and tooth
strate any adjunctive benefit of using sys- bud transplantation. Results of this well
temic TCN in conjunction with scaling and documented case, show nearly complete ra-
root planing.317 Due to the lack of heteroge- diographic bone fill and successful trans-
neity of sample size, study designs, and out- plantation of the tooth bud in a 12 year-old
come measures a recent attempt to combine patient. Tetracycline therapy included an in-
other TCN studies for meta-analysis was lim- itial 10-day regimen of 500 mg per day, fol-
ited to 2 of 30 trials.318 Based on the evidence lowed by 3 more 5-day, 500 mg doses, (once
available for critical analysis, it appears that a month) over a 3 month postsurgery period.
use of tetracyclines in adult Periodontitis is Prues et al.328 have treated two siblings with
generally not warranted. Al-Joburi et al.319 rapidly destructive Periodontitis in Papillon-
have confirmed this lack of support for using Lefevre syndrome with 15 mg/kg/day for 6
tetracyline when they compared spiramycin, months followed by extraction of remaining
tetracycline, and placebo in a randomized infected deciduous teeth and 1 g a day of tet-
controlled trial in adult Periodontitis patients racycline for 10 days. The family dog was
and found tetracycline to be no different than also treated with antibiotics to reduce the
placebo relative to changes in probing depths risk of possible reinfection of the children
and attachment levels and percent spiro- with A. actinomycetemcomitans, since it was
chetes (Table 6). determined that these strains had most
Clinical use in localized juvenile Periodon- likely been transmitted to the children from
titis. Tetracycline has been widely used in the family pet dog. This and other evidence
the treatment of both generalized and local- reported in Section IB, Periodontal Dis-
ized juvenile Periodontitis.273 320 323 In a re- eases, Microbiology, indicates a need to con-
cent 2-year study, 6 localized juvenile sider eradication of pathogenic bacteria from
Periodontitis (LJP) subjects who were A. ac- siblings, other family members, and pets in
tinomycetemcomitans positive were moni- close contact with the person infected with
tored by clinical and cultural methods.324 A. actinomycetemcomitans to prevent trans-
The subjects were given 250 mg of tetracy- mission or recolonization of the organism.
cline-HCl 4 times a day until one week after Suppression of A. actinomycetemcomitans
any A. actinomycetemcomitans could be de- with a 2-week dose of TCN prior to the stan-
tected, for a total of 8 weeks maximum. Prior dard prophylaxis for infective endocarditis
to treatment probing depths had remained (amoxicillin) has been recommended for LJP
the same for 3 months, but at 12 months patients at risk for infections.329
probing depths were significantly reduced Clinical use in refractory Periodontitis. A
from 7.1 mm to 5.1 mm, for an average of classic study by Lundstrom et al.330 followed
1.4 mm. The relationships were significant 9 subjects with refractory periodontal dis-
between levels of A. actinomycetemcomitans ease for 18 months following scaling and
in the pocket, and probing attachment lev- root planing plus either 100 mg/day doxy-
els, van Winkelhoff et al.325 recommend us- cycline for 2 weeks or 600 mg/day metroni-
ing 500 mg tid for 21 days to treat most dazole for 1 week. The adjunctive benefit of
juvenile Periodontitis. In a case report of 6 antibiotic therapy was evident by significant
patients, Novak et al.326 used 250 mg of tet- reduction of spirochetes, motile rods, prob-
racycline q 6 hours for 6 weeks in the ab- ing depths, and suppuration. Papli and

Vol. 1, No. 1, November 1996

540 Drisko

Lewis331 conducted a longitudinal study us- Long-Term Low-Dose Tetracycline

ing 250 mg of tetracycline for 6 days and re-
ported significant probing depth reductions Kornman and Karl340 reported on 12 re-
in most teeth and sites that lasted up to 2 fractory Periodontitis patients treated with
years (Table 8). regular long-term low-dose (LTLD) tetracy-
cline compared to patients not exposed to
Moskow and Tannenbaum have shown the same therapy. Results showed LTLD
case reports suggesting that TCN-HC1 can
enhance a dramatic repair and regeneration
subjects had healthy clinical conditions and
diverse tetracycline-resistant microflora.
of lost periodontal tissues following systemic When the tetracycline was discontinued, the
administration of tetracycline either alone or clinical and bacterial signs characteristic of
in combination with other forms of periodon-
tal therapy in severe adult Periodontitis.332
Periodontitis were evident. Golub et al.215
have recently observed the therapeutic po-
Shapiro has confirmed this finding in case tential of specially formulated low-dose dox-
reports of osseous defect fill following sys- ycycline (LDD) capsules containing 20 to 30
temic TCN and scaling and root planing.333
mg instead of the usual 50 to 100 mg avail-
Indications. TCN is indicated for patients able commercially. Preliminary results indi-
at high risk for periodontal breakdown in- cate that LDD can inhibit elevated colla-
cluding early-onset Periodontitis (localized genase activity in the gingival crevicular
juvenile Periodontitis, generalized juvenile fluid of adult Periodontitis patients. Further,
Periodontitis, rapidly progressive Periodon- LDD does not cause gastrointestinal distur-
titis) and refractory cases.334 Debridement bances or emergence of resistant organisms,
and even surgery have failed to eliminate A. due to the superior absorption of about 90%
actinomycetemcomitans from the LJP infec- of the drug. Several double-blind, placebo-
tion, indicating that chemotherapy may be controlled longitudinal studies have been
necessary in some cases to irradicate A. ac- conducted resulting in the conclusion that
tinomycetemcomitans completely from the the main therapeutic mechanism of action
subgingival area.335 There are, however, no seems to be a direct block of active collage-
current data to justify the use of tetracycline nase in the periodontal pocket and gingival
in conjunction with non-surgical therapy in tissues by the LDD.215287 Future research in
adult Periodontitis. this area, based on these results and current
Contraindications. Tooth staining is possi- on-going studies, is aimed at use of sensi-
ble if TCN is used in children less than 8 years tive, reliable diagnostic tests for disease ac-
old. There is also the potential that TCN may tivity and intermittent use of LDD when the
tests show disease activity is present.
effect the efficacy of low dose birth control
pills.336'337 Subjects with renal or hepatic dis-
ease are at risk for significant side effects.
Adverse effects. Adverse effects can in-
clude enamel hypoplasia, tooth discolora- Pharmacology. Doxycycline (DOX) is closely
related to tetracycline and concentrates in
tion, lichenoid drug reaction erythema the gingival crevicular fluid (GCF) at com-
multiforme, and angioedema.338 A case of
parable levels to tetracycline ranging be-
Pseudotumor cerebri, a rare adverse reac- tween 1.2 pig/ml and 8.1 Lig/ml.341 Unlike
tion to tetracycline, was reported by Minu-
tello et al., following administration of 250 tetracycline HCl, doxycline may be given
concomitant with food or dairy products
mg qid of tetracycline HCl for 2 weeks.339 since the decrease in absortpion is only
Symptoms included severe headaches, mild about 20% versus 50% with TCN. Both dox-
vertigo, pulsing sensations in the ear, and ycycline and minocycline may be given safely
visual disturbances. Following a neuro-oph-
to patients with renal dysfunction, unlike
thalmic evaluation, a carbonic anhydrase in-
hibitor rapidly relieved the symptoms. tetracycline, which is eliminated essentially
unchanged by glomerular filtration.338 Spi-
rochetes and motile rods have been shown

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 541

to decrease significantly following adminis- 100 mg per day for 3 weeks), or a placebo
tration of DOX.342 Low dose DOX has been taken on the same schedule. Doxycycline
shown in a controlled clinical trial to be ef- therapy proved to reduce the risk of disease
fective in significantly reducing collagenase recurrence for 7 months by 43% compared
activity in the GCF and gingival inflamma- to placebo. However, 45% of test and 79% of
tion (Table 8).287 Several benefits with this control had to be exited and entered into an-
drug over TCN include better patient com- other open-design study to receive metroni-
pliance since it is usually given only once a dazole.345 After receiving metronidazole, 250
day. In addition, the absorption from the mg tid for 10 days, only 9% of MET sites had
gastrointestinal tract is not altered by cal- recurrence during the 7-month follow-up ver-
cium, metal ions, or antacids, so the patient sus 42% of placebo. The frequency of 5 com-
is not likely to intake substances that will
as mon pathogens, A. actirwmycetemcomitans,
interfere with the absorption. P. gingivalis, P. intermedia, E. corrodens, and
Animal Studies. Golub et al. have shown F. nucleatum was significantly reduced in the
an anti-collagenase effect on collagen dede- serial DOX then MET group. At 7 months, the
gradation with chemically modified tetracy- healthy control sites were compared to the
cline in the rat (Table 8).348 serial DOX then MET group and no differ-
Clinical use in adult Periodontitis. No stud- ences were found. This serial DOX-then-MET
ies have been reported since 1988 that in- protocol may be useful for patients who are
dicate any benefit of using doxycycline in at particularly high risk for recurrent disease.
adult Periodontitis, except for host modula- When collagenase activities were assayed at
tion by low-dose doxycycline.287 To the con- sites exhibiting attachment loss or abscesses,
trary, the temporary subgingival over- 15/19 subjects on placebo had recurrent dis-
growths of enteric rods, yeasts, and staphy- ease compared to 13/29 on doxycycline (Ta-
locci has been reported by Rams et al.344 fol- ble 8).345 The presence of collagenase activity
lowing a 20-day regimen of doxycycline. was 20% higher at active disease sites than
These findings were especially true if the in other sites in the mouth and was 60%
person already harbored these organisms higher than healthy controls.
prior to DOX therapy. The authors specu- Kulkarni et al.346 took a subset of 27 of the
late that in some patients previously nega- original290 study patients and looked at the
tive for these organisms DOX may have effect of doxycycline on the microflora of ac-
suppressed the periodontal pocket micro- tive and inactive sites(Table 8). At one week,
flora and enabled species from other sites 6 putative pathogens were unchanged in the
in the mouth, such as the tongue, to colo- placebo groups versus significantly reduced
nize subgingivally. in the DOX group (P 0.0002). The authors

Clinical use in refractory Periodontitis. A point out, however, that by 7 months, mi-
research group at the University of Toronto crobial levels were no different between test
has conducted a series of studies supporting and control, and speculate that the anti-col-
the use of doxycycline followed by metroni- lagenase effect of DOX may have a more pro-
dazole for treating refractory Periodontitis in longed effect than the antimicrobial activity
patients not responding to doxycycline (Table of the drug.
7).280.345.346 McCulloch et al.290 have reported a Clinical use in juvenile Periodontitis. Two
well designed double-blind, randomized, studies compared DOX to placebo in juvenile
placebo-controlled trial of 82 patients iden- Periodontitis, and found no significant ben-
tified as having refractory Periodontitis efit of the antibiotic over SRP (Table ?).2ss,289
based on a recent history of attachment loss Indications. DOX has the same spectrum
or of periodontal abscesses despite regular of activity as TCN.
periodontal care. During a 12-month pre- Contraindications. Hypersensitivity to DOX;
trial monitoring period, any patient who lost hepatic disease; and increased rate of me-
> 2 mm or developed a periodontal abscess tabolism of barbiturates, carbamamepine,
was placed in the treatment group and given and hydantoins are contradindications for
either doxycycline (200 mg loading dose then the use of DOX. Subgingival enteric rods,

Vol. 1, No. 1, November 1996

542 Drisko

yeasts,and staphylococci may be increased and epithelial cells or macrophages/mono-

by as much as 10-fold following a 2 to 4 cytes. They conclude that the tissue-degrad-
week antibiotic regimen of 200 mg loading ing activities of the PMNs can directly be
dose and 100 mg per day of DOX. inhibited by pharmacologic levels of doxy-
cycline.353 Others358 360 have described col-
lagenolytic activity from selected bacterial
strains of Bacteroides gingivalis as well as
Chemically Modified Tetracyclines other mechanisms of tissue.
Perhaps the most innovative and promis-
ing new drugs to be under investigation to- Minocycline
day are the chemically modified doxycy-
clines (CMT-1) that have been pioneered by Pharmacology. Minocycline (MIN) has the
Golub and coworkers347-353 and recentiy con- same spectrum of activity as TCN. No differ-
firmed by others354"357 within the last decade. ence was found between the GCF concentra-
In a large series of studies, they have dis- tion of 100 mg/day and 200 mg/day,
covered that certain host-derived enzymes therefore the lower dose is recommended to
called matrix metalloproteinases (MMPs) can reduce side effects of vertigo and stomach
be inhibited by tetracyclines. Work towards upset.361 Some organisms exhibit a low sus-
characterizing and further defining the non- ceptibility to minocycline while some may
antimicrobial action of chemically modified become less susceptible after exposure to
tetracycline and a vehicle control, was tested low concentrations of minocycline for several
in rats innoculated with P. gingivalis follow- weeks according to one in vitro study.362 It
ing antibiotic therapy. Tetracyclines inhib- has been shown in vitro to be effective
ited in vivo alveolar bone loss by a against anaerobic subgingival purified
mechanism other than that of antibiotic ac- strains of bacteria.363 Minocycyline is capa-
tivity, namely an anticollagenase activity ble of inhibiting most periodontitis-associ-
ranging from experimental cancer to corneal ated organisms and can kill them in a
ulcers.247248 Although CMT-1 did not sup- relatively short period of exposure time.
press P. gingivalis, it did inhibit bone loss Clinical use in adult Periodontitis. Moder-
and gingival collagenolytic activity as effec- ate to severe adult Periodontitis treated with
tively as doxycycline, suggesting that the an- a 7-day course of minocycline with and with-
timicrobial property of tetracycline is not out SRP was compared to placebo with and
necessary for blocking bone cell collagenase without SRP in a 1982 double-blind split-
activity. Many other aspects of mechanisms mouth study by Ciancio et al. Results
of therapeutically modulating the host re- showed the greatest effect was with the com-
sponse are under investigation in their labs. bination of minocycline and SRP, but even
The authors point out that the therapy may minocycline without SRP caused short-term
have a significant impact on the medical, as shifts in the subgingival microflora.
well as the dental, community since the Clinical use in juvenile Periodontitis. Müller
anti-inflammatory properties of the agent et al.384 have shown that successive periods
are capable of treating serious skin disor- of systemic minocycline plus mechanical de-
ders such as bullous pemphygoid, gangren- bridement and minocycline plus modified
osum, epidemolysis bullosa, and others.291 Widman flap were successful in maintaining
Recently, they have also found that the dox- reduced probing depths in LJP subjects, but
ycyclines can prevent osteoporosis in the not in generalized juvenile Periodontitis sub-
uncontrolled diabetic rat through a mecha- jects (Table 6). Multiple regression analysis
nism that enhances Osteoblast activity and showed a significant influence of log-trans-
stimulates bone formation.291 Golub et al. re- formed numbers of A. actinomycetemcomi-
cently reported matrix metalloproteinases in tans in cheek and saliva samples, and a
inflamed gingival tissue are most likely orig- cluster on the percent residual number of
inating primarily from infiltrating PMNs in- sites with periodontal probing depth of > 7
stead of from the local gingival fibroblasts mm (P < 0.001). They concluded that the an-

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 543

tibiotic regimen was not appropriate for use beagle dog and found the antimicrobial to be
in more severe and generalized forms of A. effective against periodontal organisms.371
actinomycetemcomitans associated Perio- Clinical use in adult Periodontitis. Loesche
dontitis, since it did not reduce the A. acti- et al. have shown MET has short-term ef-
nomycetemcomitans to acceptable levels. fects on periodontal infections due to anaer-
Indications. A single daily dose of 100 mg obic bacteria based on probing depths of <
or 200 mg of minocycline has been shown to 5 mm.372 373 Loesche et al. have shown a re-
achieve equal antibiotic concentration in the duced need for surgery following a 1 week
GCF, when tested in a longitudinal trial to regimen of 250 mg tid of metronidazole and
determine therapeutic dose regimens.361 periodontal debridement (Table 6).373374After
Fewer side effects and better compliance following the patients for 4 to 6 weeks374 and
were suggested as benefits of this lower dose up to 44 week, the authors reported approx-
for managing Periodontitis. imately 8 less teeth in the SRP plus MET
Contraindications. Two-year results from groups needed surgery verus only 2.9 in the
a comprehensive treatment which combined SRP plus placebo groups. Recently, Söder et
mechanical/surgical and adjunctive mino- al. examined 98 subjects aged 31 to 40 for
cycline (200 mg/day for 3 weeks then an ad- the effect of 400 mg/day metronidazole for 1
ditional 2 weeks) showed a significant week versus a placebo control (Table 6).295
asssociation between A. actinomycetemcom- Healing was complete at 6 months after
itans in buccal mucosa and saliva samples therapy in 30% of test patients and 9% of
and numbers of residual pockets.365 Results controls. The authors suggest this regimen
indicated that even this rather prolonged ad- may be useful particularly when conven-
ministration of adjunctive minocycline did tional non-surgery has been unsuccessful,
not completely eliminate oral A. actinomy- and rapid elimination of inflammation is de-
cetemcomitans, making MIN a questionable sirable. A study by Loesche and Giordano
choice of antibiotics for A. actinomycetem- shows there was a significant additional im-
comitans infections. Vertigo is a common provement in deep pockets if metronidazole
side effect and, rarely, increased pigmenta- was administered 1 week following comple-
tion of the soft tissue or bone which can take tion of the subgingival debridement instead
months to years to resolve.366 368 of during the time of initial debridement.372
Another study compared patients with in-
adequate oral hygiene on a 5-day course of
Metronidazole metronidazole in conjunction scaling on one
side of the mouth.375 Results showed only
Pharmacology. Serum and crevicular lev- modest adjunctive effects of MET, with only
els of metronidazole (MET) have been shown spirochetes being significantly reduced as a
to reach MIC levels for most periodontal result of the antibiotic alone or with scaling.
pathogens.369 In vitro studies have shown Clinical use in juvenile Periodontitis. Saxen
MET to be effective against 10 pure strains and Asikainen376 showed complete elimina-
of oral spirochetes and were found to elimi- tion of A. actinomycetemcomitans in 9 juve-
nate spirochetes from acute necrotizing ul- nile Periodontitis subjects, 6 of whom later
cerative gingivitis lesions.370 It is a direct- had surgery to correct residual defects (Ta-
acting amebicide/trichomonacide that binds ble 7). Clinical and microbiologic results
and degrades DNA in the organism. Metron- were superior to those of the other 9 tetra-
idazole is the drug of choice for subgingival cycline-treated subjects. In this study, 250
plaque consisting primarily of anaerobic mg tid of metronidazole for 10 days was
Gram-negative rods and spirochetes. It is more effective in suppressing A. actinomy-
bactericidal rather than bacteriostatic, which cetemcomitans than 250 mg qid of tetracy-
allows it to function effectively independent cline for 12 days.
of the host defense system. Clinical use in refractory/recurrent Perio-
Animal Studies. Heijl and Lindhe studied dontitis. Slots et al. have reported that the
the plaque and gingivitis development in the combination of metronidazole and ciproflox-

Vol. 1, No. 1, November 1996

544 Drisko

acin may be necessary in many refractory Indications for clinical use in refractory Per-
cases in order to eliminate the overgrowth of iodontitis. Ciprofloxacin is active against
Pseudomonas and enteric rods, leaving a most putative periodontal pathogens includ-
"beneficial" population of Streptococci in the ing Gram-negative rods.379 Because it has a
periodontal pocket that might inhibit the minimal effect on streptococcal microbes,
growth of several putative periodontal path- Ciprofloxacin therapy may, indeed, facilitate
ogens.377 Fusobacteria and P. gingivalis were the repopulation of the pocket with a micro-
reduced for a period of 6 months in sites > 7 flora more associated with periodontal
mm following a 10-day regimen of MET (Ta- health.377 Since the resistant organisms are
ble 8).294 mainly streptococci, overgrowth of subgin-
Indications. Metronidazole has been gival streptococci, which are non-periodon-
shown to be beneficial in treating severe topathic, may facilitate the longevity of the
adult Periodontitis where the desired out- therapeutic benefit of the drug and delay
come is reducing the need for surgery (Table pocket colonization of pathogens. A study of
6) 373,374 Refractory Periodontitis, with or non-oral Gram-negative facultative anaero-
without other antibiotic combinations in- bic rods in advanced adult Periodontitis
cluding Ciprofloxacin, amoxicillin or doxy- cases found that virtually all strains were
cycline, has been successfully treated for up susceptibile to Ciprofloxacin, at 500 mg bid
to 2 years following periodontal debridement for 10 days.379 As many as 5% of severe Per-
plus MET. The hydroxymetabolite of metron- iodontitis lesions may harbor these non-oral
idazole (produced in the human liver) is even pathogens.
more active against A. actinomycetemcomi- Contraindications. Ciprofloxacin may in-
tans in vitro, and has been shown to act syn- terfere with growth patterns so this drug
ergistically against A. actinomycetemcomi- should not be used in young children and
tans.378 In addition, both metronidazole and teenagers. Gastrointestinal upset, oral can-
its hydroxymetabolite act synergistically didiasis, headache, restlessness, insomnia,
with amoxicillin. Metronidazole covers most hypersensitivity, hyperpigmentation and
anaerobes, and amoxicillin most facultative photosensitivity, and a few anaphylactic re-
and aerobic bacteria, making this combina- actions have been reported.338
tion useful for many mixed periodontal in-
fections. Recommended doses of metroni-
dazole are 250 to 500 mg TID for 7 to 10
days.304 Indications. These drugs are indicated in
Contraindications. Some objections to use certain acute infections thought to be of
of metronidazole are gastric discomfort, se- Gram-positive bacterial origin. Current pro-
vere diarrhea, and bitter taste. A significant tocols for HIV infections would recommend
GI reaction may occur if metronidazole is a more narrow spectrum drug, such as me-
taken in conjunction with alcohol, since tronidazole for ANUG or ANUP type lesions.
MET has an antabuse effect. Rams et al. reported that Peptostrpetococcus
micros, a Gram-positive organism frequently
found in Periodontitis patients, is suscepti-
Ciprofloxacin ble to penicillins and Clindamycin, and may
Pharmacology. Ciprofloxacin is a broad- be useful alone or in combination with me-
spectrum bactericidal agent that inhibits en- tronidazole for mixed periodontal infections
zyme DNA gyrase needed for replication of involving P. micros.63
DNA. This fluoroquinolone anti-infective
agent is frequently used in medicine for uri- Amoxicillin
nary tract infections. Slot and Rams have
shown it to be beneficial in treating super- Amoxicillin is a close relative to penicillin,
infections of enteric rods pseudomonads or and is used for penicillinase-resistant organ-
staphylocci cultured from Periodontitis sub- isms. It achieves higher blood levels, is bet-
jects.379 ter absorbed, and not impaired by food

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 545

compared to ampicillin. It is the drug of croflora patterns), only group D responded

choice in patients not allergic to penicillin, to therapy, with the others not only failing to
and is used routinely for antibiotic prophy- improve but losing additional attachment.
laxis for those patients at risk for infective Long-term evaluation was available on 11 of
endocardititis. The recommended regimen is the 30 original subjects after 16 to 54
3 g amoxicillin 1 hour before the appoint- months (mean 34.3). Of these, there was not
ment and 1.5 g 6 hours following the first a statistically significant difference in the
dose. clinical attachment compared to the initial
Contraindications. Ten patients developed 6-week re-evaluation. Mean attachment for
clinical evidence of periodontal abscesses these subjects (included representatives
following systemic penicillin therapy.379 The from all groups A to D) was 0.53 mm at 6
prevalence of subgingival coagulase-positive weeks, and maintained at level of 0.36 mm/
staphylococci increased significantly follow- site at the 34-month average time. This
ing systemic therapy which may account for means that in this small subset of subjects,
the abscesses. the effect of the RefTx therapy appeared to
be a statistically significant long term (3
Amoxicillin/Clavulanate year) effect; 41.2% of the sites maintained 1
mm of gained attachment. This protocol
Amoxicillin combined with clavulanic acid should now be tested against a placebo
inhibits ß-lactamases produced by certain group in a randomized controlled clinical
bacteria, protecting the amoxicillin from en- trial to see if, in fact, the response to therapy
zymatic deactivation. It is usually given in was indeed due to the RefTx rather than
125 to 500 mg doses tid, and is suggested some other unknown effect.
for high levels of Peptostreptococcus mi-
Refractory periodontits. Collins et al.381
designed a unique treatment protocol for re- Pharmacology. The minimum inhibitory
fractory Periodontitis (RefTx) aimed at elim- concentration of Clindamycin (CLIN) in the
inating P. gingivalis from the subgingival mi- GCF can be maintained at levels in the per-
croflora of 30 refractory patients (Table 8). In iodontal pocket exceeding the MIC for most
addition to a 14-day prescription for amoxi- Gram-negative anaerobes.383
cillin/clavulanate potassium, Chlorhexidine Clinical use in refractory Periodontitis. Re-
mouthrinse was used bid. Six intrasulcular searchers at the University of Florida have
professional applications of 10% povidone conducted a series of controlled clinical
iodine were used followed by a 3% hydrogen studies that have shown both CLIN and
peroxide rinse to remove any residual iodine amoxicillin/clavulanate (AC) to be effective
to avoid tooth staining. There was a signifi- in treating refractory Periodontitis.384 Mag-
cant, rather remarkable, improvement in nussen et al. treated 10 refractory subjects
clinical parameters for 26/30 subjects, for by scaling and root planing plus amoxicillin/
an overall positive response to treatment of clavulanate (750 mg/day) for 2 weeks.385 A
86.6% up to 6 weeks. The most visible effect pre-trial run-in period to assess disease
occurred with deep pockets in the RefTx activity showed that prior to study entry and
groups showing a 56% decrease in the num- subsequent therapy, attachment loss in-
ber of pockets > 6 mm; 70% of bleeding sites creased an additional 2 mm and probing
in this group were decreased relative to bas- depths increased an additional 1.5 mm.
eline; 35.5% of sites gained 1 mm attach- Three months after therapy, 2 mm of AL was
ment, where only 7.4% lost > 1 mm. This is regained and remained stable for up to 1
similar to findings of the Florida group, on year. Probing depth reduction of 2.5 mm was
the response of refractory subjects following seen at 6 months and remained stable for
Clindamycin therapy (Table 8).382 When the the rest of the study. Number of sites with
RefTx group D was compared to other RefTx bleeding scores of 2 to 3 were reduced from
groups A, B, and C (assigned by initial mi- 13.3% to 1.9% post therapy.

Vol. 1, No. 1, November 1996

546 Drisko

The clinical, microbiological, and immu- Twenty-four of 30patients with a history

nological characteristics of patients with re- consistent with refractory periodontal dis-
fractory periodontal disease and progressive ease were followed in a longitudinal study by
attachment loss of 0.8 to 1.2 mm as meas- Gordon et al.301 After a period of 1 year of
ured by the Florida probe were described by monitoring disease activity following SRP,
Magnusson et al.386 This group of patients patients with sites that lost more than 2 mm
presented generally with shallower baseline of attachment were entered into the antibi-
PD and lower plaque scores than patient otic phase of therapy (Table 8).388 If Clinda-
populations studied by others. A bacterial mycin was indicated by culture and
sample taken from the site compared to a sensitivity testing to be the most effective
deep non-progressing site showed a lack of drug to inhibit 95% of isolates the patients
traditional pathogens associated with dis- were placed on Clindamycin hydrochloride
ease to one populated with a more Gram- (CLIN) 150 mg qid for 7 days. Microbiologic
positive flora. Serum antibody studies also data available on a subset of 9 of these re-
revealed significantly higher number of fractory cases showed they were success-
these refractory subjects had elevated serum fully treated by reducing Gram-negative
IgG antibody titer against P. gingivalis, yet microbiota for at least one year following
the organism itself was not found in any of Clindamycin HCl therapy. Gram-negative
the refractory patients. The authors suggest anaerobic rods accounted for approximately
it may have flourished following previous an- 20% of the culvitable bacteria and specifi-
tibiotic therapy, in what they termed as cally, spirochetes and motile rods were still
"therapy-resistant" subjects. They propose reduced by 3-fold compared to pre-treat-
one explanation may be the Gram-positive ment. Prevotella intermedia and Porphymor-
flora in these cases may be pathogenic, but monas gingivalis were reduced from about
since this is speculative, further research is 20% to less than 2% of the flora. No signifi-
necessary to further characterize these pa- cant increases in bacterial resistance were
tients. reported in any of the 6 bacteria tested. This
Magnusson et al. later compared the ef- treatment regimen could be beneficial for
fects of CLIN or AC therapy on a small group adult Periodontitis patients who have deep
of 21 subjects and followed them for 2 years pockets and a predominately Gram-negative
(Table 8).387 Subjects given the 2-week regi- infection that has been unsucessfully
men of AC or the 10 day CLIN regimen re- treated in the past by conventional perio-
sponded favorable to therapy following SRP. dontal therapy, including the use of other
Results show that there were no significant antibiotics such as tetracycline and penicil-
differences in the proportion of sites losing lin.
attachment at 2 years follow up. The pro- Gordon et al.382 reported the 2-year results
portion of sites gaining attachment after on 24 patients with further attachment loss
treatment increased from 0.09% to 5.1% in following treatment with scaling and root
the antibiotic groups. Of the four patients planing, periodontal surgery and tetracy-
who have completed the 2-year follow-up in cline. In addition, all had received at least
the placebo group, sites that were losing at- one other antibiotic, including penicillin V,
tachment decreased from 5.1% to 2.3%. metronidazole, ampicillin, amoxicillin plus
However the proportion of sites gaining at- clavulanate, erythromycin, or cephaflexin
tachment was not maintained and fell from within the year prior to entering the study.
2% to 1% after 2 years. The clinical signifi- The 30-patient cohort group included 13 pa-
cance of these data will become clearer as tients from a previous 1985 study301 as well
the rest of the controls complete the follow- as 17 new patients. When active disease oc-
up period Nevertheless, the authors suggest curred (24 of 30), defined as > 3 mm attach-
that selected antimicrobial therapy may be ment loss or the occurence of a periodontal
indicated and beneficial to refractory sub- abscess, patients were scaled and root
jects but may not completely arrest disease planed and then given a 7-day regimen of
progression based on their data so far. 150 mg qid of Clindamycin. Results of this

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 547

study showed that active sites lost an aver- high concentrations in saliva. It is used as
age of 3.1 mm of clinical attachment level an adjunct to periodontal treatment in Can-
(CAL). During the first 6 months the active ada and Europe but is not available in the
sites regained 2 mm CAL. This decreased to United States.
1.5 mm by 24 months. Bleeding reduced Clinical use in adult Periodontitis. Several
from 31.8% to 12.3% at 12 months and studies have shown benefits of SPIR when
17.9% or about 50% at 24 months. The au- used in advanced periodontal disease and
thors concluded that Clindamycin was effec- others have not found it to be synergistic
tive in controlling the rate of attachment loss with scaling and root planing.390 391 Mechan-
in refractory Periodontitis patients. ical debridement, with and without the ad-
This important group of studies shows junctive use of either SPIR or TCN, was
that in some cases of refractory Periodontitis studied in a controlled double-blind parallel
just maintaining the existing attachment randomized trial.319 Mechanical debridement
level could be considered highly successful, alone sucessfully reduced spirochetes to a
since sites treated with a combination of level conducive to health. Only spiramycin
scaling and root planing plus Clindamycin significantly reduced spirochetes from other
maintained attachment where the scaling groups. With, TCN, spirochetes had re-
only or placebo groups continued to lose at- bounded to 7% at 24 weeks which was no
tachment. different from the placebo.
A large multi-center clinical trial of 193
patients, investigated spiramycin as an ad-
Erythromycin junct to SRP in adult Periodontitis (Table
Pharmacology. Erythromycin (ERY) is a g) 392 statistically significant reduction of
high molecular weight macrolide and has probing depths were seen up to 24 weeks in
similar activity to penicillin against Gram- the spiramycin group, (93 subjects). Attach-
positive organisms. ERY is ineffective ment levels were also significantly reduced,
against most dental pathogens due to its but only lasted up to 12 weeks. However,
rather limited action on aerobic bacteria and this and the previous studies indicate that
few, if any, anaerobes. Allergic reactions to spiramycin may be effective against some of
erythromycin are uncommon, but a rather the periodontopathic organisms associated
common side effect is mild to severe gastro- with adult Periodontitis.
intestinal upset. Indications. SPIR appears to be a safe,
Contraindications. The clinical effects of nontoxic drug with relatively few adverse
systemic ERY and penicillin (PEN) were com- side effects found with other antibiotics.
pared in a group of 72 subjects, (24 PEN, 21 Other positive features include the fact that
ERY, and 27 control).389 Both antibiotics de- it is not in general use in medicine, making
creased plaque, and only ERY reduced gin- it more attractive as a dental antibiotic.
givitis. In the PEN group, 10 patients
developed abscesses during the study, and Combination Therapy
the clinical parameters worsened. Clinical
changes had returned to baseline level by 12 Metronidazole plus amoxicillin. van Win-
weeks after antibiotic treatment. No signifi- kelhoff et al. have treated a large group of A.
cant or lasting effect of antibiotic treatement actinomycetemcomitans-associated Periodon-
alone was seen in patients with severe Per- titissubjects, including 28 localized Perio-
iodontitis. dontitis, 50 generalized Periodontitis and 40
refractory Periodontitis subjects with a com-
bination of 250 mg metronidazole plus 375
Spiramycin mg amoxicillin tid for 7 days (Tables 6,7, and
g) patients still positive for A. actinomy-

Pharmacology. Spiramycin (SPIR) is a cetemcomitans or P. gingivalis showed a sig-

macrolide antibiotic that is active against nificantly higher bleeding tendency after
Gram-positive organisms and is excreted in therapy.392 Mechanical periodontal treat-

Vol 1, No. 1, November 1996

548 Drisko

merit in combination with the metronidazole sada (Table 8).399 Subjects with Periodontitis
plus amoxicillin therapy is effective for the and positive DNA probes findings of A. acti-
subgingival suppression of A. actinomyce- nomycetemcomitans or P. gingivalis were
temcomitans associated severe Periodonti- identified as refractory/recurrent (9),
tis.394 Case reports have supported these LJP (1) or rapidly progressing Periodontitis
findings.395 Pavicic et al. found debridement (1). Following random assignment, half were
along with this combination therapy was treated with a standard regimen of doxycy-
very effective in suppressing A. acttnomyce- cline (DOX) for 10 days. The second group
temcomitans below detectable levels and that received sequential therapy of doxycycline
recolonization was rare. Following the elim- 200 mg (loading dose) followed by 100 mg
ination of A. actinomycetemcomitans (47/48 per day for 4 days then 5 days of amoxicillin
subjects), the periodontal status improved and clavulanate (AC) 500 mg tid for an ad-
further in the 2-year evaluation period. Two ditional 5 days. Patients also received SRP
of the 18 subjects continued to harbor P. gin- on one-half of their mouth. Results favored
givalis and 29 still had P. intermedia. the sequential DOX/AC which maintained
Recommended doses of metronidazole PD reductions for 6 months where DOX
plus amoxicillin include 250 to 500 mg tid alone only maintained reductions for 3
for 7-8 days. months. Both DOX and DOX/AC had signif-
Metronidazole plus tetracycline HCl. Re- icant CAL changes up to 6 months. The side
fractory patients were given a regimen of 250 of the mouth that received SRP plus the se-
mg TCN plus 250 MET for 7 days and fol- quential DOX/AC maintained the CAL gain
lowed for 3 months in a series of case re- for 6 months, whereas the non-scaled side
ports. Nine patients showed mean PD of was only significantly different for 1 to 3
2.78 mm versus 4.93 mm for scaling months. Other studies are needed to deter-
alone.397 mine if this regimen and dosage are the most
Metronidazole plus spiramycin. Spirainy beneficial when used in conjunction with
ein and metronidazole, available as a com- SRP.
mercially prepared composite tablet, were Clinical use in refractory Periodontitis.
shown to be present in thegingival fluid at Combination therapy of 250 mg tetracycline
concentrations higher than those needed to HCl 4 times a day and 250 mg metronidazole
inhibit the growth of periodontopathic or- 3 times a day for 20 days significantly re-
ganisms.398 Spiramycin achieved levels duced PD from a mean of 4.93 mm to 2.78
nearly 8 times that of blood (1.06 to 1.8 Lig/ mm in this three month study.397
ml) and metronidazole reached (11.8 to 13.5 Contraindications. Paresthesia of the
|ig/ml) well above MIC levels. Quee et al. tongue was found in 2 study volunteers after
have reported in vitro activity against most taking TCN/MET which disappeared after
strains of periodontopathic organisms, in- 30 minutes. Three others complained of mi-
cluding Bacteroides species and anaerobic nor gastrointestinal disorders, nausea and
spirochetes.391 Synergistic effects were also tiredness.398
noted with the combination drug against
Propionibacterium and Actinomyces species. Other Antibiotics
Metronidazole plus Ciprofloxacin. This
combination of drugs has been shown to ex- Ofloxacin. A new synthetic pyridone car-
hibit synergy when tested against A. actino- boxylic acid derivative, Ofloxacin (OFLX),
mycetemcomitans.378 It is the combination of produces strong antibacterial effects on bac-
choice in Periodontitis involving anaerobes teria associated with periodontal disease by
and superinfections of yeasts and enteric inhibiting DNA gyrase.400 It shows marked
rods. It is given in doses of 500 mg bid for 8 antibacterial activity against periodonto-
days of each drug for adults. pathic organisms, and is similar in activity
Amoxicillin and clavulante plus doxycy- to ciprofloxicin, and tetracycline, but slightly
cline. Sequential use of multiple antibiotic weaker than Clindamycin.401 Higashi et al.
agents was evaluated by Matisko and Bis- showed that GCF concentrations after a sin-

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharmacotherapeutics 549

gle oral dose 200 mg of OFLX concentrated corded for 11 months and results showed
in saliva and reached a peak of 3 ug/ml that Gram-negative rods were reduced to
within an hour after administration, then less than 3% and no further attachment loss
decreased gradually to 1 ug/ml after 1 hour. occurred. Probing depths were significantly
However, the GCF concentrations were reduced as was bleeding tendency. The ther-
much higher, at 7 ug/ml, and decreased to apy was successful in this small groups of
2 ug/ml after 10 hours. The pharmacokinet- subjects in the re-treatment of their recur-
ics of Ofloxacin is similar to tetracycline.281 ring periodontal disease.
Systemic temafloxicin. Three refractory
subjects with recurring periodontal ab-
scesses were analyzed by culture and sen-
Periodontal Abscesses
sitivity following unsuccessful non-surgical
therapy. Based on the culture, the antibiotic Tetracycline. Twenty patients, in a longi-
temafloxicin was prescribed along with sev- tudinal study, who had experienced a peri-
eral sessions of scaling and root planing.402 odontal abscess were followed with clinical
While not a large clinical study, these case and microbiological monitoring. ELISA
reports support the use of culture and sen- methods were used for analysis of specific
sitivity to guide the clinician to a better antibodies.408 Treatment consisted of supra-
choice of the appropriate antibiotic, leading gingival scaling, drainage, and irrigation of
to a rather significant reversal of the disease the pocket with 0.85% sodium chloride and
progression for over 30 months in these systemic TCN, a gram a day for 14 days.
downhill cases. Sites responded favorably to therapy, and
Tinidazole. Tinidazole is a drug which is results indicated that P. gingivalis and P. in-
similar in structure to metronidazole and can termedia are associated with periodontal ab-
be used in a single oral dose as a long-acting scesses.
drug. It is secreted both in the saliva and
GCF. In a study by Abo El-Fadl, refractory
patients were scaled and root planed. Ten
subjects were treated with 2 gm tinidazole in Effect of Plaque Control on
a single dose once a week for 2 weeks and the Antibiotic Therapy
other 10 subjects were given minocycline403
100 mg bid for 2 weeks. After 4 months, clin- Kornman et al.405 have evaluated which
ical and microbial levels were significantly re- clinical and microbial parameters appears to
duced, however changes were more profound be most influenced by plaque control. Two
in the tinidazole group. Of importance in this hundred thirty-six (236) patients were seen
in private practice by periodontists and
study is the potential efficacy of a drug which
only has to be taken once a week could be treated for moderate to severe Periodontitis
effective in treating subjects with refractory with scaling and root planing and a variety
Periodontitis. A single dose per week antibi- of systemic antibiotics. Selection of the an-
otic regimen versus the normal 1 to 4 doses tibiotics was based on microbial and clinical
per day regimen could have a profound effect profiles provided for each patient. Results
on patient compliance. showed that good oral hygiene and plaque
Ornidazole. Recurrent Periodontitis pa- control are directly related to the clinical and
tients that had previously received SRP, sur- microbial response to therapy. They ob-
gery, and regular maintenance, yet had served that variability in both supragingival
recurring disease, were entered into an lon- plaque control and in specific species found
gitudinal study to determine if there was any subgingivally may account for some of the
benefit in prescribing ornidazole (an antibi- inconsistencies in the literature regarding
otic used for the treatment of anaerobic in- responses to antibiotic therapy. In this
fections) in 500 mg doses, twice a day for 10 study, greatest reductions in specific Bacter-
days in addition to SRP (Table 8).404 Micro- oides species and P. gingivalis were depend-
biologic and clinical parameters were re- ent on good supragingival plaque control.

Vol. 1, No. 1, November 1996

550 Drisko

Interference With Oral Contraception use of antibiotics in dental applications is

appropriate, especially local drug delivery
Deleterious side effects from systemic an- systems for antibiotics gain clinical accep-
tibiotics may be especially important in tance as vehicles for specific site treatment
women taking oral contraceptives. Broad- with minimal side effects.
spectrum antimicrobials including ampicil- There are two general categories of bac-
lin, Sulfonamides, and tetracyclines may terial resistance to antibiotics: intrinsic and
interfere with oral contraceptive efficacy
acquired. Intrinsic resistance implies that
through a variety of possible mechanisms. inherent features of the cell, usually ex-
The most frequently cited include: increased
pressed by chromosomal genes, are respon-
urinary or fecal excretion of the contracep- sible for preventing antibiotic action. Ac-
tive; decreased enterohepatic circulation of quired resistance occurs as previously sus-
sex steroids; increased liver degradation (as
in rifampin therapy); displacement of the
ceptible bacteria become resistant when
exposed to the antibiotic.409 Acquired resis-
contraceptive steroids from their bioreceptor tance can develop as a mutation of genetic
site reducing the amount of gut absorption; material within the cell, or by receiving new
and direct or indirect opposition of the con- DNA sequences that are coded for resistance
traceptive steroid through an unknown to the specific antibiotic.410'411 Plasmid trans-
physiologic mechanism.336 337 Although there fer is commonly acknowledged as an effi-
is some controversy, it is thought that drug cient method of exchanging genetic material
interactions are usually more common in to develop resistant strains of bacteria.407-412'413
women taking low-dose varieties of contra- Transposons, which are mobile DNA se-
ceptives. The only evidence to date to sup- quences, frequently carry resistance genes
port these concepts consists of case reports, from cell to cell, and may be primarily re-
since no large controlled clinical trials have
been published to support these hypotheses.
sponsible for the emergence of multiple drug
resistant strains of bacteria.414 Both of these
It has been suggested that patients at risk
should practice additional means of contra-
types of resistance can limit the options that
exist for treatment of infections.
ception for the duration of their menstrual In studies that address the development
cycle following broad spectrum antibiotic of bacterial resistance following antibiotic
therapy to avoid any potential adverse side
use in periodontal diseases, there is evi-
effects. dence of the presence of resistant strains of
ANTIMICROBIAL RESISTANCE bacteria after the administration of antibi-
otics.415 417 This appears to occur with both
Emergence of antibiotic resistant strains systemically and locally delivered antibiotics,
of bacteria was first reported shortly after in- and in long- and short-term therapy.418 421
troduction of clinical use of antibiotics in the However, the increases in resistant bacteria
early 1940s. The development of resistant appear to be a transient phenomenon.422 423
strains of bacteria can reduce the usefulness Further study is needed to clarify the issue
of antibiotics that are safe, inexpensive, and using well-controlled longitudinal studies.422
cost-effective treatment for infections. There Special consideration of resistant strains
are special epidemiological settings that are of bacteria may be indicated for patients at
at particularly high risk for development and risk for developing infective endocarditis.415
transmission of antibiotic resistance, in- A. actinomycetemcomitans has been identi-
cluding hospitals, developing countries, day fied as an etiologic agent of endocarditis.
care centers, and animal feed lots.407408 Al- Due to the tendency for resistance to the an-
though dental use of antibiotics is not gen- tibiotics that are used for prophylactic pre-
erally considered one of the areas where medication, a multi-stage approach to anti-
resistance is a particular epidemiological biotic prophylaxis has been recommended
problem, it cannot be ignored as a potential for patients at risk of infection with A. acti-
area of concern. Careful consideration of the nomycetemcomitans.329

Annals of Periodontology
Review: Non-Surgical Pocket Therapy: Pharrnacotherapeutics 551

As the impact of development of resistant effective in infections with large numbers of

strains of bacteria is recognized as an in- black pigmented Bacteroides and spiro-
creasing epidemiological problem in medi- a predominantly Gram-negative
chetes; e.g.,
cine, it is apparent that indiscriminate use flora.
Clindamycin is also effective in a
of antibiotics is inappropriate. In periodontal Gram-negative refractory adult Periodonti-
applications, most infections can be man- tis. When metronidazole and amoxicillin are
aged with mechanical debridement and sur- combined, a synergistic effect of the two
gical therapy. Antibiotic therapy should be drugs together is highly predicable in ridding
reserved for the situations that cannot be the subgingival flora of A. actinomycetem-
managed solely with mechanical therapy, comitans. These and others have been rec-
such as severe or acute infections, early-on- ommended by Van Winkelhoff et al. in a
set periodontal diseases, and refractory cases. recent review of systemic antibiotics in Per-
Use of culture and sensitivity testing should iodontitis.426
be considered prior to use of antibiotics, es- Most clinical studies to date do not sup-
pecially in patients with a history that in- port the use of antibiotics in adult Periodon-
creases the risk of the presence of resistant titis. The exceptions are those by Loesche et
strains of bacteria, such as frequent expo- al.,373 374 who report using metronidazole rel-
sure to antibiotic therapy.334 Use of local de- ative to reducing the need for surgery. Cer-
livery systems may prevent unnecessary tain A. actinomycetemcomitans associated
exposure of normal bacterial populations in severe adult Periodontitis cases may benefit
the body to antibiotics and reduce emer- from a combined metronidazole plus amox-
gence of resistant bacteria within these cell icillin therapy according to van Winkelhoff et
populations.420 Choosing appropriate anti- al.393 In countries where it is available, spi-
biotics and regimens of administration, com- ramycin may be the drug of choice since it
bined with careful attention to patient worked well in severe adult Periodontitis
compliance with the treatment may greatly cases and is a drug not used frequently by
increase the efficacy of the antibiotic usage the medical community.392
and may reduce the development of resis-
tant strains of bacteria.423
Ellen and McCulloch have recently com-
pleted a critical review of the evidenced 1. Irrigation, both home and professionally
based literature in the rational use of sys- applied, reduces gingivitis and in some cases
temic antimicrobials and stated that the probing depths and subgingival microflora.
strongest data supporting systemic antimi- The addition of antimicrobials to the irrigat-
crobial therapy for the treatment of Perio- ing solution does not appear to add substan-
dontitis are reports on refractory and tial benefit beyond water irrigation alone.
recurrent Periodontitis.424 Based on the Some evidence exists to support the devel-
present review, the evidence presented here opment of more potent, substantive agents
would support that conclusion. for subgingival irrigation including anti-in-
A recent review by Gordon and Walker fectives and anti-inflammatories.
stated that the tetracyclines (TCN,MINO, 2. Non-steroidal anti-inflammatory drugs
DOXY) are the most commonly used antibi- have been shown to serve as potential ad-
otics in the United States, and that TCN, junctive treatments for periodontal disease.
MINO, and DOX are capable of inhibiting in New delivery systems are being explored that
vitro most putative periodontal pathogens. may lead to agents that can be used system-
Amoxicillin clavulanate is effective in treat- ically or topically with minimal side effects
ing refractory cases with a predominant while maintaining their ability to slow peri-
Gram-positive flora, where metronidazole is odontal disease progression.

Vol. 1, No. 1, November 1996

552 Drisko

3. In general, locally delivered and systemic 6. Slots J, Mashimo P, Levine MJ, Genco RJ. Perio-
antibiotics may be recommended as ad- dontal therapy in humans. I Microbiological and
clinical effects of a single course of periodontal
juncts to conventional mechanical therapy, scaling and root planing, and of adjunctive tetra-
but strong evidence has not been provided cycline therapy. J Periodontol 1979;50:495-509.
for their use as a monotherapy. An exception 7. Loesche WJ, Syed SA, Morrison EC, Kerry GA, Hig-
might be the use of locally delivered antimi- gins T, Stoll J. Metronidazole in Periodontitis. I.
crobials to enhance or extend the benefits of Clinical and bacteriological results after 15 to 30
weeks. J Periodontol 1984;55:325-335.
supportive periodontal therapy in recurrent 8. Loesche WJ. Clinical and microbiological aspects
and refractory Periodontitis. Refractory Per- of chemotherapeutic agents used according to the
iodontitis appears to benefit the most from specific plaque hypothesis. J Dent Res 1979;58:
both site specific sustained-release antimi- 2404-2412.
crobials as well as systemic antibiotic ther- 9. Williams RC, Leone CW, Jeffcoat MK, Nitzan D,
Goldhaber P. Tetracycline treatment of periodontal
apy. Most interesting of all new anti-infective disease in the beagle dog. II. The cultivable perio-
agents are the low-dose doxycycline and dontal pocket flora. J Periodont Res 1981; 16:666-
chemically modified tetracyclines. These 674.
pharmacologic agents hold great promise in 10. Williams RC, Jeffcoat MK, Wechter WJ, Johnson
controlling the progression of periodontal HG, Kaplan ML, Goldhaber P. Non-steroidal anti-
disease by their ability to block collagenase inflammatory drug treatment of Periodontitis in
beagles. J Periodont Res 1984;19:633-637.
activity and to potentially inhibit bone loss, 11. Jeffcoat MK, Williams RC, Wechter WJ, et al. Flur-
without the side effects associated with biprofen treatment of periodontal disease in bea-
other systemic drugs. gles. J Periodont Res 1986;21:624-633.
12. Golub LM, Ramamurthy NS, McNamara TF,
Greenwald RA, Rifkin BR. Tetracyclines inhibit
Acknowledgments connective tissue breakdown: new therapeutic im-
plications for an old family of drugs. Crit Rev Oral
The assistance of Robin Henderson and BiolMed 1991;2:297-322.
Drs. Henry Greenwell, John Wittwer, Reid Irrigation Methods and Delivery Devices
Nelson, Margaret Hill, Martha Nally, Tracey
Professional Application
Vest, Jean Bichara, and John Dodge is 13. Boyd R, Holander B, Eakle W. Comparison of a su-
gratefully acknowledged in the preparation bgingivally placed cannula oral irrigator tip with a
of this manuscript. supragingivally placed standard irrigator tip. J Clin
Periodontol 1992;19:340-344.
14. Lamer JR, Greenstein G. Effect of calculus and ir-
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