J Periodontol January 2000

Academy Report
125
A
dvances in understanding the etiology and
pathogenesis of periodontitis have led to
increasingly effective pharmacological inter-
ventions. In this regard, safe and intrinsically efca-
cious medications can be delivered into periodontal
pockets to suppress or eradicate the pathogenic
microbiota or modulate the inammatory response,
thereby limiting tissue destruction. In order to accom-
plish this, local application of pharmacological agents
must fulll 3 criteria: the medication must reach the
intended site of action; remain at an adequate con-
centration; and last for a sufcient duration of time.
1
This position paper will review pharmacologic prin-
ciples which provide the basis for effective local drug
delivery in the treatment of periodontitis. In addition,
different classes of local delivery systems and impor-
tant factors in designing a strategy for their use in
clinical practice will be discussed.
PHARMACOKINETIC PARAMETERS IN THE
PERIODONTAL POCKET
Pharmacological agents applied locally for the treat-
ment of periodontitis are targeted to several areas.
These include bacteria residing in the periodontal
pocket, soft tissue walls of the pocket, and the
exposed cementum or radicular dentin.
2-4
Experi-
mental evidence suggests that many forms of local
delivery are not able to deliver medicaments to all
these locations. For example, agents in mouthrinses
and those used during supragingival irrigation do not
predictably reach beyond 5 mm into the periodontal
pocket.
5,6
However, irrigating solutions delivered
intracrevicularly, via a cannula or other device, can
predictably be projected into deep periodontal pock-
ets.
5
On the other hand, gaining access to the
anatomical boundaries of the pocket does not nec-
essarily mean penetration to the target bacteria,
because highly organized aggregates of adherent bac-
teria (biofilms) may impair diffusion or inactivate
pharmacologic agents.
7-10
Therefore, antimicrobial
action on biolm bacteria may require higher con-
centrations of the active agent.
7-10
Once a drug reaches the site of action at an effec-
tive concentration, it must remain at the site long
enough for the pharmacological effect(s) to occur.
The duration of exposure required is dependent upon
the mechanism by which the antimicrobial agent
inhibits or destroys target bacteria. For example,
chlorhexidine, a bactericidal agent, kills microorgan-
isms by compromising the integrity of the cell mem-
brane and requires a shorter exposure time than a
bacteriostatic agent, such as tetracycline, which
inhibits protein synthesis. Accordingly, to achieve
pharmacological objectives of a locally applied
antimicrobial agent, all 3 pharmacokinetic parame-
ters: delivery to the site, maintenance of concentra-
tion, and sufciency of time must be satised.
PERIODONTAL CLEARANCE
Gingival crevicular uid is an altered serum transu-
date found in the gingival sulcus. It has been esti-
mated that the uid present in a 5 mm periodontal
pocket is replaced about 40 times an hour.
1
Thus, if
an antimicrobial agent is placed subgingivally, its
local concentration is rapidly reduced.
11
The expected half-life of a pharmacological agent
in the gingival crevice (i.e., the time necessary for
the concentration to become half the original) is about
1 minute.
1
This high rate of clearance represents the
major obstacle to maintaining effective concentrations
of an antimicrobial agent within the pocket. Longer
therapeutic duration requires the use of a subgingival
drug reservoir that can release medication to coun-
teract its continuous loss due to crevicular uid ow.
Substantivity
Substantivity refers to the property of a substance to
bind to the soft and/or hard tissue walls of the pocket,
thereby establishing a drug reservoir. An equilibrium
Position Paper
The Role of Controlled Drug Delivery for Periodontitis*
* This paper was developed under the direction of the Committee on
Research, Science and Therapy and approved by the Board of Trustees
of the American Academy of Periodontology in August 1999. It replaces
the version published in 1994.
This position paper was prepared by the Research, Science and Therapy Committee of the American Acad-
emy of Periodontology and is intended to provide the dental profession with an overview of the evidence regard-
ing the adjunctive use of locally delivered antimicrobials in the management of patients with periodontitis. J Peri-
odontol 2000;71:125-140.
2002_IPC_AAP_553060 2/15/00 9:19 AM Page 125
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between the bound and the free drug in the pocket is
established and, as the concentration of free antimi-
crobial agent decreases through crevicular uid clear-
ance, the bound medicament is gradually released in
a biologically active form. Drug half-life is thereby pro-
longed and treatment duration becomes a function of
how much drug is stored in the reservoir. In dentistry,
this property was rst described for chlorhexidine, for
which it was established that the drug reservoir offset
salivary clearance.
12-17
In the subgingival environ-
ment, tetracyclines and clindamycin have demon-
strated substantivity,
18-23
and it has been noted that
high concentrations are necessary to increase the dura-
tion of antibacterial activity.
21
The size of the drug
reservoir that can be established following irrigation
of a periodontal pocket represents the major limitation
to prolonging the half-life of a substantive drug and
thus the duration of the desired antibacterial effect.
Local Drug Delivery Devices
A local delivery device consists of a drug reservoir
and a limiting element that controls the rate of
medicament release. The goal is to maintain effec-
tive concentrations of chemotherapeutic agents at
the site of action for long periods, despite drug loss
from crevicular uid clearance. Local delivery devices
can be divided into 2 classes according to the dura-
tion of medicament release: sustained release devices
and controlled delivery devices. Sustained release
formulations are designed to provide drug delivery
for less than 24 hours.
24,25
On the other hand, con-
trolled delivery systems should have a duration of
drug release that exceeds 1 day.
24,25
Intracrevicular delivery devices should have a drug
reservoir of sufcient size to satisfy concentration and
time objectives. In order to t drug reservoirs into the
physical space of periodontal pockets, the delivery
device should be able to expand the volume of the
periodontal pocket and remain dimensionally stable.
This will avoid premature ejection from the pocket
due to the elastic memory of the soft tissue walls.
Chlorhexidine, tetracyclines, metronidazole, clin-
damycin, and ofloxacin are among the antimicro-
bials that have been used in the formulation of local
delivery devices for the treatment of periodontitis
(Table 1).
21,23,26-34
Several different types of deliv-
ery devices (non-resorbable and bioabsorbable matri-
ces) have been developed.
23,26-50
Pharmacokinetics of Periodontal Local Delivery
Devices
In vivo evaluation of the pharmacokinetic perfor-
mance of local delivery systems is available for only
a small number of devices (Table 1).
21,23,26-34
Most
of these were sustained delivery devices with a half-
life of 1 day or less. Other devices (i.e., 5% clin-
damycin in Eudragit lms, 25% tetracycline in ethyl-
ene-vinyl acetate bers, and doxycycline polymer)
displayed a steady state of drug release, and a dura-
tion of antibacterial activities of 72,
23
264
21
and 168
hours,
34
respectively, at the time of removal.
Microbiological Results With Periodontal Local
Delivery Devices
Local delivery systems can result in a signicant sup-
pression of the subgingival microbiota (Table 2).
51-58
The number of drug applications needed to induce
microbial suppression with sustained delivery devices
(2 to 4 applications during the treatment period which
may last weeks to months) is different than controlled
delivery devices, which may need to be administered
only once.
The microbiological data reveal that even high con-
centrations of tetracycline, maintained over at least 7
days, failed to completely eliminate periodontal
pathogens from all treated sites.
56-60
Similarly, local application of antiseptics did not
achieve total pocket disinfection.
55
This is probably
due to the high bacterial load and biolms in the sub-
gingival environment.
CLINICAL EVALUATION OF PERIODONTAL
LOCAL DELIVERY DEVICES
The clinical efcacy of local drug delivery has been
evaluated primarily using several outcome measures:
reduced probing depths, increased clinical attach-
ment levels, decreased bleeding on probing, and
reduced disease progression. However, studies have
employed different designs and denitions of patient
populations, therefore, they should be considered
early proof of principle studies.
32,40-43,47,48,55,61-66
Large-scale, controlled, randomized clinical trials have
been reported for only a few devices.
66-72
These are
generally the delivery systems with regulatory
approval or pending approval by the U.S. Food and
Drug Administration (FDA) or the regulatory bodies
of the European Union.
At present, 5 products have become commercially
available: tetracycline fibers,

metronidazole gel,

minocycline ointment,

chlorhexidine chip,

and
doxycycline hyclate in a resorbable polymer.
#
126 The Role of Controlled Drug Delivery for Periodontitis
Actisite, Alza Corp., Mountain View, CA.
Elyzol, Dumex, Copenhagen, Denmark.
Dentomycine, Lederle, UK.
Periocline, Sunstar, Japan.
PerioChip, Peno Products Ltd., Jerusalem, Israel.
# Atridox, Atrix Labs, Ft. Collins, CO.
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Tetracycline Fibers
Tetracycline bers

are a non-resorbable cylindrical

drug delivery device made of a biologically inert,
plastic copolymer loaded with 25% tetracycline HCl
powder.
38
The ber is applied to completely ll the
pocket and is maintained in situ with a cyanoacry-
late adhesive for 7 to 10 days.
73,74
At the end of the
therapeutic period the ber must be removed. This is
a controlled delivery device that is able to maintain
concentrations of tetracycline in gingival fluid in
excess of 1,300 g/ml for a 7-day period,
21
with
mean concentrations of 43 g/ml in the supercial
portions of the soft tissue pocket wall.
75
Investigators
have shown that when multiple teeth are simultane-
ously treated, salivary concentrations range from 8
to 51 g/ml.
56
Serum levels, however, remain below
detection level.
34,76
Following application of tetracycline bers, a sup-
pression of the subgingival microbiota has been
observed using dark-eld microscopy, total cultivable
counts, selective media, and DNA probe identica-
tion of periodontal pathogens.
56-58,60,77,78
However,
bers releasing high local concentrations of tetracy-
cline maintained for 10 days were unable to eliminate
the bacteria in the periodontal pocket. When tetra-
cycline bers were compared with scaling and root
planing, a vehicle control, and an untreated control,
the tetracycline fibers resulted in a significant
improvement in all the tested outcome measures sim-
ilar in magnitude to the improvement from scaling
and root planing (Table 3).
58,68,79-83
Furthermore, an
additive effect of tetracycline ber therapy when used
in conjunction with mechanical debridement has been
demonstrated.
80,81
Among maintenance patients with non-respond-
ing sites to conventional care, combination therapy
(scaling and root planing plus tetracycline fiber)
was significantly better than root planing alone
(Table 3).
81,83
However, another clinical trial that
evaluated the adjunctive benet of tetracycline bers
in mandibular Class II furcations with persistent bleed-
ing reported signicant short-term reductions in prob-
ing depth and bleeding on probing only at 3 months
(Table 3).
82
These improvements were no longer sig-
nicant at 6 months.
82
The long-term therapeutic effect was addressed
preliminarily in a 12-month follow-up study that
included sites actively breaking down
56,80
and in a
large, controlled, randomized, single-blind, multi-cen-
ter, split-mouth study.
68,78,84
In this latter study, when
the efcacy of tetracycline bers was compared to
scaling and root planing alone or combination ther-
apy (Table 3), there were no signicant differences
in mean effects with regard to probing depth reduc-
tion or gain of clinical attachment.
68
The combined
treatment of scaling and root planing plus tetracy-
cline ber application, however, resulted in a statis-
tically significant lower incidence of disease pro-
gression than root planing alone (5% versus 9% of
the tested sites, N >200).
84
However, these data need
to be interpreted in light of the fact that there was no
maintenance during the 12-month monitoring period.
Metronidazole Gel
Metronidazole gel

is a bioabsorbable delivery device

containing 25% metronidazole benzoate in a matrix
consisting of a mixture of glyceryl mono-oleate and
sesame oil.
45
The gel is subgingivally applied with a
syringe and a blunt cannula. Decay of the drug con-
centration in crevicular uid follows an exponential
pattern which is compatible with a sustained drug
delivery.
29
Microbiological observations have indicated that
this delivery device has marginal effects with respect
to decreasing total anaerobic bacteria colony-form-
ing units in subgingival plaque.
52,53
This may be
attributed to the low number of bacteria susceptible
to metronidazole and/or the presence of bacterial
biolms, or the nding that biolm bacteria generally
display a slow rate of multiplication. A substantial
portion of the metronidazole gel may be swallowed,
or absorbed through the mucosa, as indicated by
peak plasma concentrations observed 2 to 8 hours
following administration.
85
The pivotal studies have
compared sequential applications of metronidazole
gel with a positive treatment control consisting of
scaling and root planing (Table 4).
69,83,86,87
In gen-
eral, there were no clinical differences between ther-
apies with regard to probing depth reduction and
decrease in prevalence of bleeding on prob-
ing.
52,69,83,86
Additional studies compared scaling and root plan-
ing to combined therapy (metronidazole plus scaling
and root planing).
88,89
The larger study reported a
statistically significant, but clinically insignificant,
improvement with combined therapy.
88
Another study
concluded that combined therapy was better than
scaling and root planing.
89
However, there were only
5 patients in this study, and they were monitored for
only 7 weeks.
89
At present, it is unclear if metron-
idazole gel provides a clinically signicant improve-
ment when used as an adjunct to scaling and root
planing. This product is not marketed in the United
States at this time.
Position Paper 127
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Minocycline Ointment
Minocycline ointment

is a bioabsorbable sustained
delivery system consisting of 2% minocycline HCl in
a matrix of hydroxyethyl-cellulose, aminoalkyl-
methacrylate, triacetine, and glycerine. Magnesium
chloride is added to modify the drug release proper-
ties.
31
Minocycline is a bacteriostatic antibiotic; how-
ever, no data are available regarding the extent of its
subgingival drug reservoir. A controlled, randomized,
clinical trial compared the adjunctive effect of minocy-
cline ointment (4 administrations of drug at weekly
intervals) or vehicle control to a single session of
128 The Role of Controlled Drug Delivery for Periodontitis
Table 1.
Pharmacokinetic Parameters Following Local Delivery of Different Antimicrobial
Formulations in the Periodontal Pocket
Antibiotic Concentration Delivery Type of Intrinsic Decay
(%) Device Delivery Substantivity
Ooxacin 0.1 Irrigation Local No Exponential
Clindamycin 0.1 Irrigation Local Slight Exponential
Tetracycline 1 Irrigation Local Yes Exponential
Tetracycline 20 Dialysis tubing Sustained Yes Exponential
(nonresorbable)
Metronidazole 8 Polyvinylalcohol Sustained No Exponential
strips (absorbable)
Metronidazole 25 Glyceryl monooleate Sustained No Exponential
plus sesame oil gel
(absorbable)
Minocycline 2 LS-007 gel Sustained Yes Double
(absorbable) exponential
Ooxacin 10 OH-propyl cellulose Sustained No Double
plus methacrylic acid exponential
particles (absorbable)
Tetracycline 50 Cross-linked collagen Sustained Yes Exponential
strips or gel (absorbable)
Clindamycin 5 Basic polymethacrylate Controlled Slight Pseudo zero-
lms and methacrylic acid order
copolymer, Type A, B, C
lms (absorbable)
Tetracycline 25 Ethylene-vinyl acetate Controlled Yes Pseudo zero-
monolytic bers order
(nonresorbable)
Chlorhexidine 34 Cross-linked gelatin Controlled Yes Exponential
(absorbable)
Doxycycline 8.5 Polymer Controlled Yes
* Estimated from the data displayed in the reference under the assumption of a single compartment open model.
MIC-90 from references 106 and 107.
Time of expected antibacterial activity estimated from the half time and the MIC-90.
Not applicable.
Not determined.
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J Periodontol January 2000
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scaling and root planing (Table 5).
71
The results indi-
cated that the combination of the ointment with scal-
ing and root planing was signicantly better than the
vehicle control in pockets 7 mm when probing
depths were evaluated at 1 and 3 months. No sig-
nicant differences were observed in clinical attach-
ment levels or a bleeding index. A more recent study
which lasted 18 months compared the additive effects
of mechanical debridement and minocycline oint-
ment to debridement plus a vehicle control and
reported that no additive benet was obtained in the
minocycline group in pockets 5 mm or 7 mm.
90
Position Paper 129
Table 1. (continued)
Pharmacokinetic Parameters Following Local Delivery of Different Antimicrobial
Formulations in the Periodontal Pocket
Duration of Half-time MIC-90 Steady State t-MIC-90 Reference
Drug Reservoir (hours)* g/mL

Concentration g/mL (hours)

NA

0.03 4 NA 0.28 Higashi et al.

26
NA 0.9 32 NA 1.7 Higashi et al.
23
NA 4.2 50 NA 21 Tonetti et al.
21
<24 hours 1.7 50 NA 21 Goodson et al.
27
ND

8.2 32 NA 40 Passler and Nossek.

28
<12 hours 3.4 32 NA 16 Stoltze
29,30
ND 3.9 16 NA 21 Satomi et al.
31
ND 2.4 4 NA 23 Higashi et al.
26
ND 26 50 NA 182 Minabe et al.
32
72 hours NA 32 150 >72 Higashi et al.
23
>240 hours NA 50 1590 264 Tonetti et al.
21
>200 hours 72 100 NA 235 Soskolne et al.
33
>7 days NA NA >148 NA Stoller et al.
34
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Minocycline ointment is not marketed in the United
States at this time.
Chlorhexidine Chip
This product

is a bioabsorbable local delivery device

comprised of 34% chlorhexidine gluconate in a cross-
linked gelatin matrix. Each chip is a 5 mm long, 5
mm wide, 1 mm thick pliable strip loaded with 2.5
mg of chlorhexidine gluconate. This controlled deliv-
ery system is gently pushed into the pocket, and
chlorhexidine has been detected in gingival uid in
excess of 125 g/mL for 1 week following a single
application.
33
Two large scale randomized multicen-
ter trials have assessed the efcacy of chlorhexidine
chip plus scaling and root planing.
70,72
One study
was performed using an intra-individual design
70
while the other had a parallel arm design.
72
In both
investigations, chlorhexidine chips were applied in
pockets 5 to 8 mm deep; chip applications were
repeated at 3 and/or 6 months if pockets in the test
group remained 5 mm or deeper. The control treat-
ment, scaling and root planing, was not repeated in
pockets not responding to the first round of treat-
ment. Data analyses indicated that attachment level
gains and probing depth reductions were statistically
signicantly better in the combined treatment group
than in the scaling and root planing group (Table
6).
70,72
It can be concluded that there was a dened,
but limited, improvement associated with chip place-
ment. In addition, the number of sites reported with
a decrease of 2 mm probing depth was greater in
patients with combined therapy.
70,72
Doxycycline Polymer
A biodegradable formulation containing 10% by
weight doxycycline (DOX), 33% by weight poly (DL-
lactide) and 57% by weight NMP (N-methyl-2-pyrroli-
done)
#
is available for the treatment of chronic adult
periodontitis. An initial study reported that doxycy-
cline hyclate applied in a vehicle was superior to 5%
sanguinarine chloride or the vehicle alone for attain-
ing probing depth reduction and gaining clinical
attachment (Table 7).
66
The duration of the study
was 9 months and drugs were administered at base-
line and after 4 months. Subsequently, 2 large, ran-
domized controlled clinical trials compared the equiv-
130 The Role of Controlled Drug Delivery for Periodontitis
Table 2.
Comparison of Pharmacokinetic and Microbiologic Parameters Following Local
Delivery of Different Antimicrobial Formulations in the Periodontal Pocket
Antimicrobial Concentration in Delivery Device Type of Delivery t-MIC
90
(hours)*
Carrier (%)
Ooxacin 10 OH-propyl cellulose plus methacrylic Sustained 23
acid particles (resorbable)
Metronidazole 25 Glyceryl mono-oleate Sustained 16
plus sesame oil gel (resorbable)
Metronidazole 25 Glyceryl mono-oleate plus sesame Sustained 16
oil gel (resorbable)
Minocycline 2 OH-ethyl cellulose plus aminoalkyl Sustained 21
methacrylate plus . . . (resorbable)
Chlorhexidine 30 Ethyl cellulose plus PEG (resorbable) Sustained NA
Tetracycline 25 Ethylene-vinyl acetate monolytic Controlled 264
bers (non-resorbable)
Tetracycline 25 Ethylene-vinyl acetate monolytic Controlled 264
bers (non-resorbable)
Tetracycline 25 Ethylene-vinyl acetate monolytic Controlled 264
bers (non-resorbable)
* The expected total time of antibacterial activity based on the assumptions in Table 1.
Not available.
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alency of the doxycycline polymer alone to scaling
and root planing and indicated there was no difference
between the therapies with regard to probing depth
reduction or gain of clinical attachment (Table 7).
67
These studies lasted 9 months and were conducted
on patients attending maintenance visits. All treat-
ments were repeated at baseline and at 4 months. In
evaluating the results of this study, it should be noted
that the study populations had previously undergone
scaling and root planing. Thus, an interpretation of
the data to indicate that application of the delivery
system is equivalent to scaling and root planing is
questionable. Accordingly, the issue as to whether
the local drug delivery should be used as a monother-
apy remains controversial. It seems prudent that use
of antibiotics should be avoided if the same results
can be achieved with conventional care. However, it
needs to be noted that an increased level of bacter-
ial resistance has not persisted 6 months after local
drug delivery with a variety of drugs.
91-93
In this
regard, long-term studies are needed.
At present there are no data available regarding the
ability of doxycycline polymer to enhance periodon-
tal health when used in conjunction with root plan-
ing. However, there is potential that disruption of
biolms and removal of calculus prior to local drug
delivery may enhance results.
Comparative Studies
A comparison of the relative efcacy of the tetracy-
cline ber, metronidazole gel, and minocycline oint-
ment delivery systems as adjuncts to root planing
was performed at sites that did not respond to
mechanical therapy.
83,94
Scaling and root planing
was the control therapy. All 3 locally applied antimi-
crobial delivery systems provided some benefit
beyond scaling and root planing alone. However, only
tetracycline bers demonstrated a signicant advan-
tage over the control therapy in the treatment of per-
sistent periodontal lesions.
83,94
Reducing the Need for Surgery
One investigation addressed the effect of sequential
systemic and/or local drug delivery on the perceived
need for periodontal surgical treatment.
95
The results
indicated that scaling and root planing with or with-
out antibiotic usage may lead to a decrease in the per-
Position Paper 131
Table 2. (continued)
Comparison of Pharmacokinetic and Microbiologic Parameters Following Local
Delivery of Different Antimicrobial Formulations in the Periodontal Pocket
Number Scaling/Root Spirochetes
of Applications Planing Decrease Log
10
CFU/mL (% decrease from baseline) Reference
2 Yes 1.6 48 Kimura et al.
51
2 Yes 0.5 NA

Pedrazzoli et al.
52
2 No 0.4 NA Walker et al.
53
4 Yes 1.7 97 Nakagawa et al.
54
3 No 2.4 99 Stabholz et al.
55
1 No 1.5 92 Goodson et al.
56
1 No 1.7 NA Maiden et al.
57
1 No 2 66 Heijl et al.
58
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ceived need for surgery. This is consistent with the
notion that the need for surgery should be established
at periodontal re-evaluation, after sufcient time has
elapsed for healing to occur. The hypothesis that sys-
temic and/or local delivery of antimicrobials in com-
bination with instrumentation might reduce the need
for surgery requires further evaluation in well designed
longitudinal, long-term studies.
Adverse Reactions
An advantage of local delivery is the likelihood of
reducing the incidence of adverse effects associated
with systemic administration.
27,74,96
However, local
delivery of antimicrobial agents requires the same
caution as the systemic use of drugs. For instance,
it should not be used in subjects with a known allergy
to the active drug. Additionally, local drug delivery
does not preclude the possible selection of resistant
bacterial strains in the pocket or the overgrowth of
intrinsically resistant organisms. To date, there is a
paucity of data addressing the issue of an increase
in bacterial resistance following local delivery of
antimicrobials.
91-93
The data available indicate that
any increase in proportions of resistant strains imme-
diately after local delivery is followed by a return to
baseline levels after 3 to 6 months.
91-93
This sug-
gests that there is selection of resistant strains rather
than emergence of new resistant bacteria. Additional
132 The Role of Controlled Drug Delivery for Periodontitis
Table 3.
Summary of Clinical Studies of Tetracycline Fibers
Reference Population Design Type of Study N Subjects
Controlled
Goodson et al.
80
Adult periodontitis Split mouth randomized 10
single-blind
Controlled
Goodson et al.
79
Adult periodontitis Split mouth (single sites randomized 107
treated after prophylaxis) single-blind
multi-center
Controlled
Heijl et al.
58
Adult periodontitis Split mouth randomized 10
single-blind
Controlled
Newman et al.
81
Maintenance patients with Split mouth randomized 113
non-responding sites single-blind
multi-center
Controlled
Drisko et al.
68
Adult periodontitis Split mouth randomized 122
single-blind
multi-center
Controlled
Tonetti et al.
82
Bleeding furcations in Parallel group design randomized 20
maintenance patients single-blind
Controlled
Kinane and Radvar
83
Adult periodontitis Parallel group design randomized 79
single-blind
* Not available.
Numerical value approximated from graphic display of data.
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long-term studies are needed to address this impor-
tant issue.
The occurrence of oral candidiasis, pain on inser-
tion of the delivery device, development of abscesses,
tooth sensitivity, patient acceptability, and interfer-
ence with taste all appear to be minimal after local
drug delivery.
68,69,71,80-82,84,85,88,91-94,96
To date, the
best sources for descriptions of adverse reactions
associated with the use of local drug delivery devices
are the labeling inserts which accompany commer-
cially available products.
In general, the use of antibiotics for the treatment
of periodontal disease should be highly selective
because of potential problems with bacterial resis-
tance. To avoid overgrowth of commensal organisms
such as Candida or creation of resistant microor-
ganisms, local delivery devices should be used with
caution in patients with a history of immune defi-
ciencies or repeated antibiotic usage. Local delivery
of antiseptics, such as chlorhexidine, may minimize
possible adverse effects attributed to antibiotics.
Additional Factors to Be Considered
As more delivery devices become commercially avail-
able, additional information will be needed regarding
what types of lesions and diseases can be best treated
with each medicament. Furthermore, it will need to
be determined if local drug delivery is best utilized as
Position Paper 133
Table 3. (continued)
Summary of Clinical Studies of Tetracycline Fibers
Observation Period Regimen Treatment Decreases in PD(mm) Increases in AL(mm) Decrease in %
Sites With BOP
12 months Single application Untreated 0.43 0.23
S/RP 0.54 0.50 NA
Fibers 0.57 0.54
Fibers+S/RP 0.93 0.76
2 months Single application Untreated 0.46 0.38 23.4
S/RP 0.67 0.40 26.2
Vehicle control 0.57 0.41 20.6
Fibers 1.02 0.65 50.5
2 months 2 consecutive Untreated 0.02 +4
applications S/RP 1.78 NA* 81
Fibers 1.98 82
Fibers+S/RP 2.15 83
6 months Single application S/RP 1.08 1.08 50
Fibers+S/RP 1.81 1.56 63
12 months Single application; S/RP 1.1

1.2 60
no further therapy 10 day bers 1.1 1.2 60
20 day bers 1.3 1.3 60
10 day bers+S/RP 1.5 1.5 60
3 months Single application S/RP 0.8 0.7 52
Fibers+S/RP 1.6 0.9 70
6 months Single application S/RP 0.71 0.54 38
Fibers+S/RP 1.38 0.69 43.8
2002_IPC_AAP_553060 2/15/00 9:19 AM Page 133
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Academy Report
a monotherapy or as an adjunctive aid. Based on
current knowledge, several aspects of local drug ther-
apy need to be considered when establishing a treat-
ment plan. These include indication, magnitude of
change, clinical effectiveness, etc.
Following local antimicrobial therapy, as after any
form of periodontal therapy, supragingival plaque
control is essential for the achievement of signicant
clinical improvements.
97,98
Therefore, local drug
delivery should not be substituted for meticulous oral
hygiene. In addition, one study addressing the use of
local drug delivery demonstrated that cigarette smok-
ing has been shown to have a negative effect on the
outcomes of all forms of periodontal therapy, includ-
ing local delivery of antimicrobials.
99
To date, evidence that local delivery may provide
benefits in the non-surgical control of furcation
involvement is limited. Two studies which examined
134 The Role of Controlled Drug Delivery for Periodontitis
Table 4.
Summary of Controlled Clinical Studies of Metronidazole Gel
Reference Population Design Type of Study N Subjects
Klinge et al.
86
Adult periodontitis Split mouth Controlled 61
randomized
single-blind
multi-center
Ainamo et al.
69
Adult periodontitis (some history Split mouth Controlled 206
of previous treatment) randomized
single-blind
multi-center
Stelzel and Recall Split mouth Controlled 30
Flores-de-Jacoby
88
randomized
Kinane and Radvar
83
Adult periodontitis Parallel group Controlled 79
randomized
single-blind
Rudhart et al.
87
Recall Split mouth Controlled 46
randomized
single-blind
* Not available.
Numerical value approximated from graphical display of data.
Table 5.
Summary of Clinical Studies of Minocycline Ointment*
Reference Population Design Type of Study N Subjects
van Steenberghe et al.
71
Chronic adult periodontitis Parallel group Controlled randomized 103
double-blind
Timmerman et al.
90
Chronic adult periodontitis Parallel group Controlled randomized 20
double-blind
Kinane and Radvar
83
Adult Periodontitis Parallel group Controlled randomized 79
single-blind
* Several other studies on minocycline gel have been published in the Japanese literature; see reference 71 for discussion.
2002_IPC_AAP_553060 2/15/00 9:19 AM Page 134
J Periodontol January 2000
Academy Report
the efficacy of local drug delivery in furcations
demonstrated signicant short term improvement fol-
lowing repeated application of tetracycline immobi-
lized in collagen films
100
or ethylene-vinyl acetate
bers.
82
Whether to administer an antimicrobial agent
locally or systemically is of great practical impor-
tance. Local delivery devices are logical adjuncts for
the treatment of a few, localized non-responding sites
in an otherwise controlled patient. Systemic admin-
istration, on the other hand, may prove to be most
benecial as an adjunct to control infections at mul-
tiple sites in patients with persistent disease.
With regard to patients infected with tissue inva-
sive organisms (e.g., Actinobacillus actinomycetem-
comitans), there is a dearth of data addressing
whether local drug delivery will provide effective treat-
ment. Therefore, individuals non-responsive to con-
Position Paper 135
Table 4. (continued)
Summary of Controlled Clinical Studies of Metronidazole Gel
Observation Period Regimen Treatments Decreases in Increases in Decrease in %
PD (mm) AL (mm) Sites With BOP
3 months Various applications 2 metronidazole 25% 1.2 NA* 43
over 2 weeks 2 metronidazole 15% 1.0 NA 49
4 metronidazole 25% 1.2 NA 40
1 S/RP 1.3 NA 41
6 months 2 applications 2 metronidazole 25% 1.3 NA 32
1 S/RP 1.5 NA 39
6 months 2 applications 2 metronidazole 25% 1.3 NA 50

1 S/RP 1.5 NA 50
6 months Single application S/RP 0.71 0.54 38
Metronidazole 25% 0.93 0.54 33.2
and RP
175 days 2 applications 2 S/RP 1.6 0.50 NA
2 metronidazole 25% 1.6 0.70 NA
Table 5. (continued)
Summary of Clinical Studies of Minocycline Ointment*
Observation Period Regimen Treatment Decreases in Gains in Decrease in
PD (mm) AL (mm) Bleeding Index
3 months 4 applications once RP + 4 minocycline 2% 1.7 0.8 1.2
every 2 weeks RP + 4 vehicle 2% 1.4 0.8 1.0
18 months 7 applications over RP + 7 minocycline 2% 1 0.5 1.2
12 months RP + 7 vehicle 2% 0.95 0.3 1.1
6 months Single application S/RP 0.71 0.54
Minocycline 2% + RP 1.10 0.57
2002_IPC_AAP_553060 2/15/00 9:19 AM Page 135
Table 6.
Summary of Clinical Studies of Chlorhexidine Chip
Reference Population Design Type of Study N Subjects
Soskolne et al.
70
Chronic adult periodontitis Split mouth Controlled 118
randomized
double-blind
multi-center
Jeffcoat et al.
72
Chronic adult periodontitis Parallel group Controlled 447
randomized
double-blind
multi-center
Volume 71 Number 1
Academy Report
ventional therapy plus local drug delivery may require
microbiological testing and administration of systemic
drugs.
At present, there are limited data with respect to
the use of local delivery in the treatment of specic
diseases (e.g., localized juvenile periodontitis) and
there is scant data concerning osseous repair in angu-
lar bony defects after local drug delivery.
101
Thus,
clinicians need to select therapies in accordance with
desired treatment outcomes. In addition, only one
article with a limited number of patients has provided
long-term data (5 years) after local drug delivery.
102
Therefore, after all types of treatment, patients should
be carefully monitored to ensure clinical improve-
ments are maintained.
SUMMARY
Current data suggest that local delivery of antimi-
crobials into a periodontal pocket can improve peri-
odontal health. However, these drug delivery systems
do not provide a superior result when compared to
scaling and root planing. Therefore, the benets of uti-
lizing local delivery systems as a monotherapy are
questionable. In conjunction with scaling and root
planing, the adjunctive use of local drug delivery may
enhance the results in sites that do not respond to
conventional therapy. A few, localized persistent
lesions, in otherwise well controlled patients, may
offer the greatest potential for success with this treat-
ment modality.
It can be concluded that the adjunctive use of local
drug delivery may provide a dened, but limited, ben-
eficial response. However, the magnitude of the
change anticipated by combined therapy must be
interpreted in light of the severity of the defects being
treated. Therefore, clinicians will need to make treat-
ment decisions based on the desired outcomes of
therapy. Furthermore, concerns with respect to the
impact of widespread antibiotic use in dentistry sug-
gest that local delivery devices should only be used
in specic areas where conventional forms of therapy
may fail to control the infection. Therefore, as with
systemic antimicrobial therapy, local antimicrobial
therapy should not be used routinely in situations
when efcacious results can be accomplished with
scaling and root planing.
136 The Role of Controlled Drug Delivery for Periodontitis
Table 7.
Summary of Clinical Studies Using Doxycycline Polymer Delivery
Reference N patients Type of Length of N Drug Control Probing Depth Attachment Gain
Patients Study Applications Reduction
Dox S/RP Dox S/RP
Garrett et al.
67
375 Maintenance 9 months 2 (0,4 months) Root planing 1.1 mm 0.9 mm 0.9 mm 0.7 mm
383 Maintenance 9 months 2 (0,4 months) Root planing 1.3 mm 1.3 mm 0.8 mm 0.9 mm
Polson et al.
66
179 Maintenance 9 months 2 (0,4 months) Vehicle 1.80 mm 1.00 mm
2002_IPC_AAP_553060 2/15/00 9:19 AM Page 136
J Periodontol January 2000
Academy Report
ACKNOWLEDGMENTS
The authors of this paper are Drs. Gary Greenstein
and Maurizio Tonetti. Members of the 1998-1999
Research, Science and Therapy Committee include
Drs. David L. Cochran, Chair; Timothy Blieden; Otis
J. Bouwsma; Robert E. Cohen; Petros Damoulis; Con-
nie Drisko; James B. Fine; William W. Hallmon;
James E. Hinrichs; Martha Somerman; Gary Green-
stein, Board Liaison; Vincent J. Iacono, Board Liai-
son; Robert J. Genco, Consultant; Marjorie K. Jeff-
coat, Consultant. Dr. Thomas Van Dyke also
contributed to this paper.
REFERENCES
1. Goodson J. Pharmacokinetic principles controlling
efficacy of oral therapy. J Dent Res 1989;68:1625-
1632.
2. Saglie R, Newman MG, Carranza FA, et al. Bacterial
invasion of gingiva in advanced periodontitis in
humans. J Periodontol 1982;53:217-222.
3. Adriaens PA, De Boever JA, Loesche WJ. Bacterial
invasion in root cementum and radicular dentin of
periodontally diseased teeth in humans. J Periodontol
1988;59:222-230.
4. Saglie FR. Bacterial invasion and its role in the patho-
genesis of periodontal disease. In: Hamada S, Holt
SC, McGhee Jr, eds. Periodontal Disease: Pathogens
and Host Immune Responses. Tokyo: Quintessence
Publishing Co.; 1991:27-40.
5. Pitcher G, Newman H, Strahan J. Access to subgin-
gival plaque by disclosing agents using mouthrinses
and direct irrigation. J Clin Periodontol 1980;7:300-
308.
6. Eakle W, Ford C, Boyd R. Depth of penetration in
periodontal pockets with oral irrigation. J Clin Peri-
odontol 1986;13:39-44.
7. Anwar H, Strap J, Costerton J. Establishment of aging
biolms: Possible mechanism of bacterial resistance
to antimicrobial therapy. Antimicrob Agents Chemother
1992;36:1347-1351.
8. Cargill K, Pyle B, Sauer R, et al. Effects of culture
conditions and biolm formation on the iodine sus-
ceptibility of Legionella pneumophila. Can J Micro-
biol 1992;38:423-429.
9. Brown M, Gilbert P. Sensitivity of biolms to antimi-
crobial agents. J Appl Bacteriol 1993;74(Suppl.):87S-
97S.
10. Vorachit M, Lam K, Jayanetra P, et al. Resistance of
Pseudomonas pseudomallei growing on a biolm on
silastic discs to ceftazidime and co-trimoxazole.
Antimicrob Agents Chemother 1993;37:2000-2002.
11. Benet L, Kroetz D, Sheiner L. Pharmacokinetics: The
dynamics of drug absorption, distribution and elimi-
nation. In: Hardman JG, Goodman Gilman A, Lim-
bird L, eds. The Pharmacological Basis of Therapeu-
tics, 9th ed. New York: The McGraw-Hill Companies;
1996;3-27.
12. Rvlla G, Le H, Schitt C. Retention of chlorhexi-
dine in the human oral cavity. Arch Oral Biol 1971;
16:1109-1116.
13. Emilson C, Ericson T, Heyden G, et al. Uptake of
chlorhexidine to hydroxyapatite. J Periodont Res
1973;8(Suppl. 12):17-21.
14. Bonesvoll P, Lkken P, Rlla G, et al. Retention of
chlorhexidine in the human oral cavity after mouth
rinses. Arch Oral Biol 1974;19:209-212.
15. Bonesvoll P. Retention and plaque inhibiting effect in
man of chlorhexidine after multiple mouth rinses and
retention and release of chlorhexidine after tooth-
brushing with a chlorhexidine gel. Arch Oral Biol
1978;23:295-300.
16. Gjermo P, Bonesvoll P, Rlla G. Relationship between
plaque inhibiting effect and retention of chlorhexi-
dine in the oral cavity. Arch Oral Biol 1974;19:1031-
1034.
17. Bonesvoll P, Lkken P, Rlla G. Inuence of concen-
tration, time, temperature and pH on the retention of
chlorhexidine in the human oral cavity after mouth
rinses. Arch Oral Biol 1974;19:1025-1029.
18. Baker P, Evans R, Coburn R, et al. Tetracycline and
its derivatives strongly bind to and are released from
the tooth surface in active form. J Periodontol 1983;
54:580-585.
19. Bjrvatn K, Skaug N, Selvig K. Inhibition of bacterial
growth by tetracycline impregnated enamel and
Position Paper 137
Table 6. (continued)
Summary of Clinical Studies of Chlorhexidine Chip
Observation Period Regimen Treatments Decreases in PD (mm) Gains in CAL (mm)
6 months Single application S/RP 0.70 mm 0.47 mm
S/RP + chip 1.16 mm 0.31 mm
9 months Single application S/RP 0.65 mm 0.58 mm
S/RP + chip 0.95 mm 0.75 mm
S/RP + placebo 0.69 mm 0.55 mm
2002_IPC_AAP_553060 2/15/00 9:19 AM Page 137
Volume 71 Number 1
Academy Report
dentin. Scand J Dent Res 1984;92:508-511.
20. Bjrvatn K, Skaug N, Selvig K. Tetracycline impreg-
nated enamel and dentin: duration of antibacterial
activity. Scand J Dent Res 1985;93:192-195.
21. Tonetti M, Cugini M, Goodson J. Zero-order delivery
with periodontal placement of tetracycline loaded eth-
ylene vinyl acetate fibers. J Periodont Res 1990;
25:243-249.
22. Demirel K, Baer P, McNamara T. Topical application
of doxycycline on periodontally involved root surfaces
in vitro: comparative analysis of substantivity on
cementum and dentin. J Periodontol 1991;62:312-
316.
23. Higashi K, Matsushita M, Morisaki K, et al. Local drug
delivery systems for the treatment of periodontal dis-
ease. J Pharmacobiodyn 1991;14:72-81.
24. Langer R, Peppas N. Present and future applications
of biomaterials in controlled drug delivery systems.
Biomaterials 1981;2:201-214.
25. Langer R. New methods of drug delivery. Science
1990;249:1527-1533.
26. Higashi K, Morisaki K, Hayashi S, et al. Local ooxacin
delivery using a controlled-release insert (PT-01) in
the human periodontal pocket. J Periodont Res
1990;25:1-5.
27. Goodson JM, Haffajee A, Socransky SS. Periodontal
therapy by local delivery of tetracyline. J Clin Peri-
odontol 1979;6:83-92.
28. Passler R, Nossek H. Investigations for the concen-
tration and duration of the effect of metronidazole in
the periodontal pockets after local application. Zahn
Mund Kieferheilkd Zentralb 1989;77:12-16.
29. Stoltze K. Concentration of metronidazole in peri-
odontal pockets after application of a metronida-
zole 25% dental gel. J Clin Periodontol 1992;19:698-
701.
30. Stoltze K. Elimination of elyzol 25% dental gel matrix
from periodontal pockets. J Clin Periodontol 1995;
22:185-188.
31. Satomi A, Uraguchi R, Noguchi T, et al. Minocycline
HCl concentration in periodontal pockets after admin-
istration of LS-007. J Jpn Periodont Assoc 1987;
29:937-943.
32. Minabe M, Takeuchi K, Tomomatsu E, et al. Clinical
effects of local application of collagen lm immobi-
lized tetracycline. J Clin Periodontol 1989;16:291-
294.
33. Soskolne WA, Chajek T, Flashner M, et al. An in vivo
study of the chlorhexidine release prole of the Perio
Chip in the gingival crevicular uid, plasma and urine.
J Clin Periodontol 1998;25:1017-1021.
34. Stoller NH, Johnson LR, Trapnell S, Harrold CQ, Gar-
rett S. The pharmacokinetic prole of a biodegradable
controlled-release delivery system containing doxy-
cycline compared to systemically delivered doxycy-
cline in gingival crevicular uid, saliva, and serum. J
Periodontol 1998;69:1085-1091.
35. Coventry J, Newman H. Experimental use of a slow
release device employing chlorhexidine gluconate in
areas of acute periodontal inammation. J Clin Peri-
odontol 1982;9:129-133.
36. Addy M, Rawle L, Handley R, et al. The development
and in vitro evaluation of acrylic strips and dialysis
tubing for local drug delivery. J Periodontol 1982;
53:693-699.
37. Friedman M, Golomb G. New sustained release
dosage form of chlorhexidine for dental use. J Peri-
odont Res 1982;17:323-328.
38. Goodson J, Holborow D, Dunn R, et al. Monolithic
tetracycline containing bers for controlled delivery
to periodontal pockets. J Periodontol 1983;54:575-
579.
39. Golomb G, Friedman M, Soskolne A, et al. Sustained
release device containing metronidazole for peri-
odontal use. J Dent Res 1984;63:1149-1152.
40. Noguchi T, Izumizawa K, Fukuda M, et al. New method
for local drug delivery using bioresorbable base mate-
rial in periodontal therapy. Bull Tokyo Med Dent Univ
1984;31:145-153.
41. Minabe M, Uematsu A, Nishijima K, et al. Applica-
tion of a local delivery system to periodontal therapy.
I. Development of the collagen preparations immobi-
lized tetracycline. J Jpn Assoc Periodontol 1987;
29:919-929.
42. Deasy PB, Collins AE, MacCarthy DJ, et al. Use of
strips containing tetracycline hydrochloride or metro-
nidazole for the treatment of advanced periodontal
disease. J Pharm Pharmacol 1989;41:694-699.
43. Eckles TA, Reinhardt RA, Dyer JK, et al. Intracrevic-
ular application of tetracycline in white petrolatum for
the treatment of periodontal disease. J Clin Periodontol
1990;17:454-462.
44. Steinberg D, Friedman M, Soskolne A, et al. A new
degradable controlled release device for treatment of
periodontal disease: In vitro release study. J Peri-
odontol 1990;61:393-398.
45. Norling T, Lading P, Engstrvm S, et al. Formulation
of a drug delivery system based on a mixture of
monoglycerides and triglycerides for use in the treat-
ment of periodontal disease. J Clin Periodontol
1992;19:687-692.
46. Sauvetre E, Glupczynsky Y, Labbe M, et al. The effect
of clindamycin gel insert in periodontal pockets, as
observed on smears and cultures. Infection 1993;
21:245-247.
47. Jones AA, Kornman KS, Newbold DA, et al. Clinical
and microbiological effects of controlled-release
locally delivered minocycline in periodontitis. J Peri-
odontol 1994;65:1058-1066.
48. Jeong S-N, Han S-B, Lee S-W, et al. Effects of tetra-
cycline containing gel and a mixture of tetracycline
and citric acid containing gel on non-surgical peri-
odontal therapy. J Periodontol 1994;65:840-847.
49. Gates K, Grad H, Birek P, et al. A new bioerodible
polymer insert for the controlled release of metro-
nidazole. Pharm Res 1994;11:1605-1609.
50. Roskos K, Fritzinger B, Rao S, et al. Development of
a drug delivery system for the treatment of periodontal
disease based on bioerodible poly(ortho esters). Bio-
materials 1995;16:313-317.
51. Kimura S, Toda H, Shimabukuro Y, et al. Topical
chemotherapy in human periodontitis using a new
controlled-release insert containing ofloxacin. 1.
Microbiological observation. J Periodont Res 1991;
138 The Role of Controlled Drug Delivery for Periodontitis
2002_IPC_AAP_553060 2/15/00 9:19 AM Page 138
J Periodontol January 2000
Academy Report
26:33-41.
52. Pedrazzoli V, Kilian M, Karring T. Comparative clini-
cal and microbiological effects of topical subgingival
application of metronidazole 25% dental gel and scal-
ing in the treatment of adult periodontitis. J Clin Peri-
odontol 1992;19:715-722.
53. Walker C, Magnusson I, Hefti A, et al. Effect of metro-
nidazole-containing dental gel on the periodontal
microflora. J Dent Res 1995;74(Spec. Issue):481
(Abstr. 646).
54. Nakagawa T, Yamada S, Oosuka Y, et al. Clinical and
microbiological study of local minocycline delivery
(Periocline) following scaling and root planing in recur-
rent periodontal pockets. Bull Tokyo Dent Coll
1991;38:63-70.
55. Stabholz A, Sela M, Friedman M, et al. Clinical and
microbiological effects of sustained release chlorhex-
idine in periodontal pockets. J Clin Periodontol
1986;13:783-788.
56. Goodson JM, Hogan PE, Dunham SL. Clinical
response following periodontal treatment by local drug
delivery. J Periodontol 1985;56(Suppl.):81-87.
57. Maiden M, Tanner A, McArdle S, et al. Tetracycline
ber therapy monitored by DNA probe and cultural
methods. J Periodont Res 1991;26:452-459.
58. Heijl L, Dahlen G, Sundin Y, et al. A 4-quadrant com-
parative study of periodontal treatment using tetra-
cycline containing drug delivery bers and scaling. J
Clin Periodontol 1991;18:111-116.
59. Morrison S, Cobb C, Kazakos G, et al. Root surface
characteristics associated with subgingival placement
of monolithic tetracycline-impregnated bers. J Peri-
odontol 1992;63:137-143.
60. Mombelli A, Tonetti M, Lehmann B, et al. Topo-
graphic distribution of black-pigmenting anaerobes
before and after periodontal treatment by local deliv-
ery of tetracycline. J Clin Periodontol 1996;23:906-
913.
61. Lindhe J, Heijl L, Goodson JM, et al. Local tetracy-
cline delivery using hollow ber devices in periodon-
tal therapy. J Clin Periodontol 1979;6:141-149.
62. Wan Yusof WZA, Newman HN, Strahan JD, et al. Sub-
gingival metronidazole in dialysis tubing and subgin-
gival chlorhexidine irrigation in the control of chronic
inammatory periodontal disease. J Clin Periodontol
1984;11:166-175.
63. Addy M, Hassan H, Moran J, et al. Use of antimicro-
bial containing acrylic strips in the treatment of
chronic periodontal disease. A 3 month follow-up
study. J Periodontol 1988;59:557-564.
64. Linden GJ, Newman HN. The effects of subgingival
irrigation with low dosage metronidazole on peri-
odontal inammation. J Clin Periodontol 1991;18:177-
181.
65. Unsal E, Akkaya M, Walsh TF. Inuence of a single
application of subgingival chlorhexidine gel or tetra-
cycline paste on the clinical parameters of adult peri-
odontitis patients. J Clin Periodontol 1994;21:351-355.
66. Polson A, Garrett S, Stoller N, et al. Multi-center com-
parative evaluation of subgingivally delivered san-
guinarine and doxycycline in the treatment of peri-
odontitis. II. Clinical results. J Periodontol 1997;
68:119-126.
67. Garrett S, Johnson L, Drisko CH, et al. Two multi-
center studies evaluating locally delivered doxycy-
cline hyclate, placebo control, oral hygiene, and scal-
ing and root planing in the treatment of periodontitis.
J Periodontol 1999;70:490-503.
68. Drisko CL, Cobb CM, Killoy WJ, et al. Evaluation of
periodontal treatments using controlled-release tetra-
cycline fibers: clinical response. J Periodontol
1995;66:692-699.
69. Ainamo J, Lie T, Ellingsen B, et al. Clinical responses
to subgingival application of a metronidazole 25%
dental gel compared to the effect of subgingival scal-
ing in adult periodontitis. J Clin Periodontol 1992;
19:723-729.
70. Soskolne W, Heasman P, Stabholz A, et al. Sustained
local delivery of chlorhexidine in the treatment of peri-
odontitis: a multi-center study. J Periodontol 1997;68:
32-38.
71. van Steenberghe D, Bercy P, Kohl J, et al. Subgingi-
val minocycline hydrochloride ointment in moderate
to severe chronic adult periodontitis: a randomized,
double-blind, vehicle-controlled, multi-center study. J
Periodontol 1993;64:637-644.
72. Jeffcoat M, Bray K, Ciancio S, et al. Adjunctive use
of a subgingival controlled-release chlorhexidine chip
reduces probing depths and improves attachment
level compared with scaling and root planing alone.
J Periodontol 1998;69:989-997.
73. Goodson J, Cugini M, Kent R, et al. Multi-center eval-
uation of tetracycline ber therapy: I. Experimental
design, methods and baseline data. J Periodont Res
1991;26:361-370.
74. Tonetti M, Pini-Prato G, Cortellini P. Principles and
clinical applications of periodontal controlled drug
delivery with tetracycline fibers. Int J Periodontics
Restorative Dent 1994;14:421-435.
75. Ciancio S, Cobb C, Leung M. Tissue concentration
and localization of tetracycline following site specic
tetracycline ber therapy. J Periodontol 1992;63:849-
853.
76. Rapley J, Cobb C, Killoy W, et al. Serum levels of
tetracycline during treatment with tetracycline-con-
taining bers. J Periodontol 1992;63:817-820.
77. Goodson J, Tanner A, McArdle S, et al. Multi-cen-
ter evaluation of tetracycline fiber therapy. III. Micro-
biological response. J Periodont Res 1991;26:380-
391.
78. Lowenguth RA, Chin I, Caton JG, et al. Evaluation of
periodontal treatments using controlled-release tetra-
cycline bers: microbiological response. J Periodon-
tol 1995;66:700-707.
79. Goodson J, Cugini M, Kent R, et al. Multicenter eval-
uation of tetracycline fiber therapy: II. Clinical
response. J Periodont Res 1991;26:371-379.
80. Goodson J, Offenbacher S, Farr D, et al. Periodontal
disease treatment by local drug delivery. J Periodon-
tol 1985;56:265-272.
81. Newman M, Kornman K, Doherty F. A 6-month multi-
center evaluation of adjunctive tetracycline ber ther-
apy used in conjunction with scaling and root plan-
ing in maintenance patients: Clinical results. J
Position Paper 139
2002_IPC_AAP_553060 2/15/00 9:19 AM Page 139
Volume 71 Number 1
Academy Report
Periodontol 1994;65:685-691.
82. Tonetti M, Cortellini P, Carnevale G, Cattabriga M, De-
Sanctis M, Pini-Prato G. A controlled multicenter study
of adjunctive use of tetracycline periodontal bers in
mandibular Class II furcations with persistent bleed-
ing. J Clin Periodontol 1998;25:737-745.
83. Kinane DF, Radvar M. A 6-month comparison of 3
periodontal local antimicrobial therapies in persistent
periodontal pockets. J Periodontol 1999;70:1-7.
84. Michalowicz BS, Pihlstrom BL, Drisko CL, et al. Eval-
uation of periodontal treatments using controlled-
release tetracycline bers: maintenance response. J
Periodontol 1995;66:708-715.
85. Stoltze K, Stellfeld M. Systemic absorption of metro-
nidazole after application of metronidazole 25% den-
tal gel. J Clin Periodontol 1992;19:693-697.
86. Klinge B, Attstrom R, Karring T, et al. Three regimens
of topical metronidazole compared with subgingival
scaling on periodontal pathology in adults. J Clin Peri-
odontol 1992;19(9 Pt. 2):708-714.
87. Rudhart A, Purucker P, Kage A, Hopfenmuller W,
Bernimoulin JP. Local metronidazole application in
maintenance patients. Clinical and microbiological
evaluation. J Periodontol 1998;69:1148-1154.
88. Stelzel M, Flores-de-Jacoby L. Topical metronidazole
application compared with subgingival scaling. A clin-
ical and microbiological study on recall patients. J
Clin Periodontol 1996;23:24-29.
89. Noyan O, Yilmaz S, Kuru B, Kadir T, Acar O, Buget
E. A clinical and microbiological evaluation of sys-
temic and local metronidazole delivery in adult peri-
odontitis patients. J Clin Periodontol 1997;24:158-
165.
90. Timmerman M, van der Weijden G, van Steenbergen
T, et al. Evaluation of the long term efcacy and safety
of locally applied minocycline in adult periodontitis
patients. J Clin Periodontol 1996;23:707-716.
91. Larsen T. Occurrence of doxycycline resistant bacte-
ria in the oral cavity after local administration of doxy-
cycline in patients with periodontal disease. Scand J
Infect Dis 1991;23:89-95.
92. Goodson J, Tanner A. Antibiotic resistance of the sub-
gingival microbiota following local tetracycline ther-
apy. Oral Microbiol Immunol 1992;7:113-117.
93. Preus H, Lassen J, Aass A, et al. Bacterial resistance
following subgingival and systemic administration of
minocycline. J Clin Periodontol 1995;22:380-384.
94. Radvar M, Pourtaghi N, Kinane DF. Comparison of 3
periodontal local antibiotic therapies in persistent peri-
odontal pockets. J Periodontol 1996;67:860-865.
95. Loesche W, Giordano J, Rau C, et al. Nonsurgical
treatment of patients with periodontal disease. Oral
Surg Oral Med Oral Pathol 1996;81:533-543.
96. Nord CE, Edlund C. Ecological effects of antimicro-
bial agents on the human intestinal microora. Microb
Ecol Health Dis 1991;4:193-207.
97. Kornman KS. Controlled-release local delivery antimi-
crobials in periodontics: Prospects for the future. J
Periodontol 1993;64:782-791.
98. Kornman K, Newman M, Moore D, et al. The inuence
of supragingival plaque control on clinical and micro-
biological outcomes following the use of antibiotics
for the treatment of periodontitis. J Periodontol
1994;65:848-854.
99. Kinane DF, Radvar M. The effect of smoking on
mechanical and antimicrobial periodontal therapy. J
Periodontol 1997;68:467-72.
100. Minabe M, Takeuchi K, Nishimura T, et al. Thera-
peutic effects of combined treatment using tetracy-
cline-immobilized collagen lm and root planing in
periodontal furcation defects. J Clin Periodontol
1991;18:287-290.
101. Fourmousis I, Tonetti MS, Mombelli A, Lehmann B,
Lang NP, Bragger U. Evaluation of tetracycline ber
therpay with digital image analysis. J Clin Periodon-
tol 1998;25:737-745.
102. Wilson TG, McGuire MK, Greenstein G, Nunn M.
Tetracycline bers plus scaling and root planing ver-
sus scaling and root planing alone: Similar results
after 5 years. J Periodontol 1997;68:1029-1032.
Individual copies of this position paper may be obtained by
contacting the Scientic, Clinical and Educational Affairs
Department at the American Academy of Periodontology,
Suite 800, 737 N. Michigan Avenue, Chicago, IL 60611-
2690; voice: 312/573-3230; fax: 312/573-3234; e-mail:
adriana@perio.org. Members of the American Academy of
Periodontology have permission of the Academy, as copy-
right holder, to reproduce up to 150 copies of this docu-
ment for not-for-prot, educational purposes only. For infor-
mation on reproduction of the document for any other use
or distribution, please contact Rita Shafer at the Academy
Central Ofce, voice: 312/573-3221; fax: 312/573-3225;
e-mail: rita@perio.org.
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