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The current model of disease patho-
genesis indicates that bacterial anti-
gens induce a host response associ-ated with deterioration of the
periodontal attachment appara-
tus.1,2 It is believed that components
of cell walls from gram-negative bac-
teria (eg, lipopolysaccharides)
induce cells such as monocytes and
macrophages to release cytokines.2
Cytokines are inflammatory media-
tors that can recruit other cells (eg,
fibroblasts) to produce inflammatory
agents such as prostaglandins andmatrix metalloproteinases (MMP).
Some prostaglandins (eg, PGE2) are
associated with alveolar bone
destruction, and a few MMPs (eg,
MMP-8 and MMP-9) are involved
with disease-induced collagen dis-
solution.2 Thus, it is recognized that
the host response can be both pro-
tective and destructive.3
During the 1980s, in vitro eval-
uations indicated that tetracyclinescould inhibit MMPs.4 Other in vivo
studies demonstrated that adminis-
tration of systemic doxycycline
results in decreased collagenase lev-
els in the gingival crevicular fluid
(GCF).5 In 1996, Crout et al6
Efficacy of Subantimicrobial-DoseDoxycycline in the Treatmentof Periodontal Diseases:A Critical Evaluation
Gary Greenstein, DDS, MS*
Controlled clinical trials that evaluate the benefits of adjunctive subantimicrobial-
dose doxycycline (SDD) with conventional therapy were selected for review. It
was deemed important to distinguish between statistically significant and clinical-
ly relevant results related to SDD use to help guide clinicians in selecting appro-
priate therapies. Several investigations demonstrated that SDD prescribed as an
adjunct to conventional therapy provides a statistically significant improvement
with respect to probing depth reduction, gain of clinical attachment, decreased
bleeding on probing, and reduced incidence of disease progression in patients
with chronic periodontitis. However, conflicting data were also noted in some
studies. Furthermore, it is suggested that the clinical relevance of improvements
obtained with SDD beyond those obtained with conventional therapy is debat-
able. Therefore, clinicians should interpret the data cautiously and differentiatebetween statistically significant and clinically relevant findings before altering
treatment regimens. (Int J Periodontics Restorative Dent 2004;24:528543.)
*Clinical Professor, Department of Periodontology, University of Medicine
and Dentistry of New Jersey, Newark.
Correspondence to: Dr Gary Greenstein, 900 West Main Street,
Freehold, New Jersey 07728. Fax: + 732 780-7798. e-mail:
The International Journal of Periodontics & Restorative Dentistry
528
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reported that oral administration of
low-dose doxycycline enhances the
gain of clinical attachment in the
absence of an antimicrobial effect.
More recently, a phase III clinical trialassessed the clinical efficacy of low-
dose doxycycline7; the drug (20 mg,
2 times a day) was referred to as sub-
antimicrobial-dose doxycycline
(SDD).7 Subsequently, the Food
and Drug Administration (FDA)
approved SDD (Periostat, Colla-
Genex) as an adjunct to scaling and
root planing in the treatment of
chronic periodontitis. Consequently,
the concept of modulating the hostresponse became a therapeutic
modality that could be employed by
clinicians. Host modulation therapy
is in an early stage of development;
however, it was deemed important
to distinguish between statistically
significant and clinically relevant find-
ings before clinicians alter treatment
regimens based on available data.
This commentary critically assesses
the data regarding the efficacy ofSDD to clarify its clinical utility.
Clinical study considerations
Regulatory agencies such as the
FDA require statistical evaluations
based on means of test and control
groups with respect to selected
parameters. Data from these groups
are compared to determine if thereis a statistically significant difference
between them. The term statisti-
cally significant denotes that the
detected difference between the
test and control groups did not usu-
ally occur by chance. However, the
term statistical significance should
not be interpreted to indicate that
the magnitude of the difference
between groups is large or impor-
tant.8,9
Furthermore, the mean valueused to calculate statistical signifi-
cance cannot be used to accurately
characterize expected clinical re-
sponses at individual sites because
the clinical outcomes could be more
or less than the mean results.
Clinical trials addressing the effi-
cacy of adjunctive SDD differed with
respect to investigatory protocols:
study populations, degree of dis-
ease severity, clinical procedures,study length, and duration of adjunc-
tive SDD therapy.6,7,1020 Some
salient features of evaluated studies
are listed in Table 1.
Diverse study protocols make it
difficult to compare results from dif-
ferent investigations. However,
trends concerning therapeutic effec-
tiveness can be identified; small
proof-of-principle studies (pilot stud-
ies) do not provide proof of thera-peutic efficacy,21 but rather evaluate
premises that need to be validated
in large clinical trials. Accordingly,
large investigations should be given
more credence when extrapolating
data to clinical practice. Currently,
only one large study (phase III clini-
cal trial) has addressed the efficacy of
SDD as an adjunct to scaling and
root planing,7 and another was
reported in abstract form.14 Thus,the phase III clinical trial is the focal
point of the following discussion.7
An additional large clinical trial used
supragingival scaling without root
planing and thus did not represent
routine therapy administered for the
management of chronic periodonti-
tis.13 Nevertheless, information
ascertained during that study pro-
vides additional evidence to support
the concept that SDD has a benefi-cial effect on periodontal status.
Several other investigations that
address the clinical utility of adjunc-
tive SDD are included here; how-
ever, they should be considered
proof-of-principle studies because
they had small study popula-
tions.6,11,12,15,1720
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Response of clinical
parameters to SDD
The following discussion pertains to
patients with chronic periodontitis
without systemic modifying factors
(eg, diabetes, smoking) or groups
of individuals with other specific
identifying characteristics (eg, insti-
tutionalized elderly persons); these
subjects are addressed later.
Bleeding on probing
The phase III trial demonstrated that
after scaling and root planing with
and without adjunctive SDD (9-
month duration), the percentage of
sites initially 0 to 3 mm and 4 to 6
models when studying rheumatoid
arthritis. He found that doxycycline
is associated with less destruction ofcollagen and bone but does not
exhibit antiinflammatory proper-
ties.22 In contrast, two other studies
noted a statistically significant
decrease of bleeding on probing
after adjunctive use of SDD; how-
ever, the number of sites bleeding
on probing at the beginning or end
of these investigations was not pub-
lished.13,16
There are mixed results regard-ing the ability of adjunctive SDD to
enhance the effects of mechanical
instrumentation with respect to
reducing bleeding on probing. The
phase III clinical trial indicates that
when scaling and root planing with
mm that bled on probing was sta-
tistically significantly lower in the
groups administered SDD; however,no significant improvement was
reported at probing depths that
were initially 7 mm (Table 2).7 After
treatment with and without adjunc-
tive SDD, 64% of the initial 4- to
6-mm pockets and 75% of the
7-mm-deep sites still bled on prob-
ing.7 After therapy, the high preva-
lence of bleeding on provocation
may have been due to patients not
receiving maintenance during the 9-month monitoring period. Other
investigations report that SDD does
not significantly decrease bleeding
on probing.6,11,12 Greenwald22 also
noted a lack of an antiinflammatory
effect provided by SDD in animal
Table 1 Variations among studies addressing the efficacy of adjunctive subantimicrobial-dosedoxycycline (SDD)
Type of Duration
Study periodontitis Instrumentation of study (mo) Duration of SDD
Crout et al6 (n = 14) Chronic* None (at baseline) 6 2 mo on, 2 mo off, 2 mo on
Caton et al7 (n = 196) Chronic Root planing 9 9 mo
Novak et al11 (n = 20) Generalized severe Debridement! 8 6 mo
Golub et al12 (n = 66) Refractory* Scaling 9 36 wk (12 wk on,12 wk off,12 wk on)
Ciancio and Ashley13 (n = 437) Chronic Supragingival scaling 9 9 mo
Preshaw et al14# (n = 210) Chronic Root planing 9 9 mo
Gapski et al15 (n = 24) Chronic Access surgery 6 6 mo
Walker et al16 (n = 76) Chronic Root planing 9 9 mo
Pflug et al17# (n = 24) Chronic Root planing** 3 3 mo
Engebretson et al18# (n = 45) Chronic/diabetics Root planing 3 3 mo
Al-Ghazi et al19# (n = 20) Chronic/diabetics Root planing 3 3 mo
Mohammad et al20# (n = 24) Chronic/elderly Root planing 9 9 mo
*Elevated collagenase level used as selection criterion.30-min scaling and prophylaxis 4 wk prior to baseline recording.1 h per quadrant.Approximately half of the patients were smokers.!45 to 65 min of root debridement 7 times during study prior to final measurements.Supra- and subgingival scaling for 30 min.#Abstract.**Several systemic antibiotics used in conjunction with root planing.Data to date reported for 3 mo.
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and without adjunctive SDD are
compared, SDD results in a statisti-
cally significant decrease of bleeding
on probing at shallow and moder-
ately deep probing sites.7 However,
these improvements could be char-
acterized as defined but limited,
since they represented a small per-
centage of the total bleeding sites.
Furthermore, the inability of SDD toenhance the reduction of bleeding
on probing at deep sites beyond
that attained with scaling and root
planing,7,11 and its ineffectiveness to
decrease the overall prevalence of
bleeding on probing, casts doubt on
the clinical utility of employing SDD
to reduce gingival inflammation.7,11
Probing depth
Mean probing depth reductions
obtained with scaling and root plan-
ing and SDD (combined therapy)
versus root instrumentation alone
are presented in Table 3. There was
a statistically significantly better
result with combined therapy in the
phase III clinical trial at sites initially
0 to 3 mm, 4 to 6 mm, and 7 mm
deep.7 In all probing depth cate-
gories, the mean improvement with
combined therapy when compared
to scaling and root planing alone
was less than 0.5 mm.
The phase III clinical trial indi-cates that combined therapy re-
sults in more sites attaining a 2-
mm probing depth reduction than
with scaling and root planing alone
(29.9% vs 22.0%).7 However, these
data include all sites in the study
initially 4 mm deep and therefore
cannot be accurately extrapolated
to any one individual. On the other
hand, they do identify a trend for
improvement associated with SDDadministration. It should also be
noted that patients were not pro-
vided maintenance therapy.7 Thus,
differences reported between
treatment methods may not have
been detected if patients received
supportive therapy during the 9-
month evaluation period. Con-
versely, it is possible that if main-
tenance was performed, the results
could have been even better in the
group administered SDD.
Data from a study by Preshaw et
al14 support the findings of Caton
et al.7 Preshaw et al14 report that
combined therapy results in a statis-tically significantly greater reduction
of probing depth than scaling and
root planing alone at sites initially 4
to 6 mm and 7 mm deep. The
mean probing depth reductions
beyond scaling and root planing
were 0.33 mm and 0.54 mm, respec-
tively, at sites initially 4 to 6 mm and
7 mm deep.
Novak et al11 compared the effi-
cacy of ultrasonic instrumentationwith and without SDD (prescribed
for 6 months) in a previously un-
treated population with generalized
chronic severe periodontitis. Patients
received root debridement sessions
4 weeks in a row (1 hour per session)
Table 2 Sites bleeding on probing (%) at completion of studies,grouped by initial probingdepth (mm)
Combined therapy* Scaling and root planing
Study 03 46 7 03 46 7 Statistical significance
Caton et al7 39 64 75 46 70 80
Novak et al11 41 53 60 37 44 50 Not reduced
Golub et al12 Numeric data not reported Not reduced
Ciancio and Ashley13 Numeric data not reported Reduced with SDD
Walker et al16 Numeric data not reported Reduced with SDD
Crout et al6 Numeric data not reported No reduction of GI!
*Subantimicrobial-dose doxycycline (SDD) + root planing.Statistically significant.Not statistically significant.Ultrasonic debridement used with combined therapy.!Gingival Index (GI) of 2 = bleeding on probing.
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and then at each recall visit after ini-
tial therapy at 1, 3, and 5.2 months,
for a total of seven sessions beforefinal measurements and mainte-
nance 8 months after study initia-
tion.11 Adjunctive SDD obtained a
statistically significantly greater prob-
ing depth reduction than root de-
bridement alone at sites initially 7
mm deep (3.02 mm vs 1.42 mm) but
did not provide any benefit beyond
root debridement alone at locations
with original probing depths of 0 to
3 mm or 4 to 6 mm.11An initial probing depth cate-
gory of 7 mm was used to delin-
eate data in these studies.7,11
Furthermore, only the amount of
improvement was reported, and the
initial or final mean probing depths
periodontitis. However, the limited
magnitude of change induced by
SDD may not provide a clinically rel-
evant benefit at any particular site.
This statement is made in light ofthe fact that individual therapists can
interpret clinical significance differ-
ently. Thus, it is important to con-
sider the severity of defects that
need to be treated and forecast
whether the benefits provided by
SDD will help achieve desired clini-
cal outcomes.
Clinical attachment level
The phase III clinical trial compares
the efficacy of root planing with and
without SDD and reports that com-
bined therapy results in a statistically
significantly greater gain of clinical
attachment than scaling and root
planing alone at sites initially 4 to 6
mm and 7 mm deep (Table 4).7
With regard to all levels of initial
probing depths, the mean differ-ences between test and control
groups were 0.4 mm. After com-
bined therapy, the number of sites
that attained 2-mm gain of clinical
attachment was greater than that
achieved with scaling and root plan-
ing alone (34.3% vs 30.7%; Table 5).7
The mean gain of clinical attach-
ment with respect to probing depth
reduction was larger than usually
reported in the literature in the testand control groups. The amount of
clinical attachment gain varies, but it
is often around half of the probing
depth reduction.23,24 In the phase III
trial, with and without SDD, the
amount of clinical attachment gain
in these categories in the test and
control groups were not included.
Therefore, it is unknown if a satis-factory endpoint was achieved.
There are additional conflicting data
within the literature concerning
probing depth reduction associated
with SDD administration. For in-
stance, other studies that address
the development of bacterial resis-
tance to antibiotics16 or disease pro-
gression12 do not report a statisti-
cally significantly greater probing
depth reduction when adjunctiveSDD is administered in conjunction
with root instrumentation.
Scaling and root planing plus
SDD may statistically significantly
enhance mean probing depth
reduction in patients with chronic
Table 3 Probing depth reduction (mm), grouped by initialprobing depth (mm)
Combined therapy* Scaling and root planing
Study 46 7 46 7
Caton et al7 0.95 1.68 0.69 1.20
Novak et al11 1.20 3.02 0.97 1.42
Preshaw et al14 1.29 2.31 0.96 1.77
Ciancio and Ashley13 0.71 1.39 0.46 0.96
Walker et al16 No significant differences (numeric data not reported)
Golub et al12 No significant differences (numeric data not reported)
Crout et al6 ! 1.80 ! 0.40
Specific patient populations
Gapski et al15# Access surgery + SDD = 3.3 vs access surgery 2.1 mm
Engebretson et al18** No significant differences (numeric data not reported)
Al-Ghazi et al19** 1.7-mm greater reduction with SDD
Mohammad et al20 1.64 4.34 0.69 0.70
*Subantimicrobial-dose doxycycline (SDD) + root planing.Statistically significant difference between test and control groups.Ultrasonic debridement used for combined therapy.Abstract.!Data not reported.Estimated from bar graph.#Data reported for sites initially 6 mm deep.**Diabetic patients.Institutionalized elderly patients.
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was similar to the probing depth
reduction.7 This could be due to
measurement error. Furthermore, it
is difficult to explain the finding that
the percentage of sites gaining
2or 3 mm of clinical attachment
was greater than the percentage of
sites manifesting 2- or 3-mm
probing depth reductions. It is not
possible to have more sites gaining
2 or 3 mm of clinical attachment
than sites demonstrating 2- or
3-mm probing depth reduction, un-
less the gingiva coronally migrated
and pocketing remained the same or
increased. These results may reflecta substantial amount of measure-
ment error and would affect other
calculations regarding the efficacy
of SDD (eg, gain of clinical attach-
ment, incidence of disease activity).
Preshaw et al14 support the find-
ings of Caton et al,7 indicating that
combined therapy results in a statis-
tically significant gain of clinical
attachment at sites initially 4 to 6
mm and 7 mm deep. The gain ofclinical attachment and probing
depth reduction were virtually the
same for patients with initial probing
depths of 4 to 6 mm. With respect to
7-mm pockets, patients treated
with and without SDD demonstrated
a gain of clinical attachment that
accounted for approximately 90%
of the probing depth reduction.
Novak et al11 found no statisti-
cally significant gain of clinicalattachment when combined therapy
was compared to root debridement
alone at sites initially 0 to 3 mm, 4 to
6 mm, and 7 mm deep. If a larger
number of patients were enrolled,
the clinical attachment gain after
Table 4 Gain of clinical attachment (mm),grouped by initialprobing depth (mm)
Combined therapy* Scaling and root planing
Study 46 7 46 7
Caton et al7 1.03 1.55 0.86 1.17
Novak et al11 0.56 1.78 1.00 1.24
Preshaw et al14 1.27 2.09 0.94 1.59
Ciancio and Ashley13 0.67 1.27 0.44 0.95
Walker et al16 No significant differences (numeric data not reported)
Golub et al12 No significant differences (numeric data not reported)
Crout et al6! 0.5-mm gain with SDD vs 0.2-mm loss with placeboSpecific patient populations
Gapski et al15 Access surgery + SDD = 1.8 vs access surgery 1.1 mm
Engebretson et al18# No significant differences (numeric data not reported)
Al-Ghazi et al19# 1.6-mm greater gain with SDD
Mohammad et al20** Data not reported
*Subantimicrobial-dose doxycycline (SDD) + root planing.Statistically significant difference between test and control groups.Ultrasonic debridement used for combined therapy.Abstract.!Data reported for all sites (5 selected sites per patient).Data reported for sites initially 6 mm deep.#Diabetic patients.**Institutionalized elderly patients.
Table 5 % of sites with increased clinical attachment related to% of sites with reduced probing depth*7
Procedure Probing depth reduction Clinical attachment gain
Combined 2 mm 29.9 (1,040/3,477) 34.3 (1,193/3,477)
3 mm 7.9 (275/3,477) 12.5 (435/3,477)
Scaling and root planing 2 mm 22.0 (755/3,435) 30.7 (1,054/3,435)
3 mm 4.7 (162/3,435) 10.0 (343/3,435)
*At sites initially 4 mm deep.Subantimicrobial-dose doxycycline (SDD) + root planing.
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adjunctive SDD might have been
statistically significant. At sites 7
mm deep in the test and control
groups, the amount of clinical attach-
ment gain was similar to the im-provement reported by Caton et al.7
However, in Novak et als study, this
represented around half the probing
depth reduction.
Several other studies report con-
flicting results. For example, when
Walker et al16 assessed the effect of
combined therapy on the microflora,
they also evaluated clinical alter-
ations at microbiologically moni-
tored sites. They found no statisti-cally significant gains of clinical
attachment at sites treated with or
without SDD. Similarly, a small study
that employed supra- and subgingi-
val scaling for 30 minutes per patient
reports that SDD does not result in a
statistically significant gain of clinical
attachment among patients with
sites demonstrating high collage-
nase levels.12 On the other hand,
Ciancio and Ashley13 demonstratedthat SDD used in conjunction with
supragingival scaling results in a sta-
tistically significantly greater gain of
clinical attachment than supragingi-
val scaling alone. There was a large
gain of clinical attachment related to
the size of the probing depth reduc-
tion in the test and control groups.13
Several clinical trials indicate that
when mechanical instrumentation
with and without SDD are compared,there is a statistically significantly
greater gain of clinical attachment
with SDD use.7,13,14 These mean
improvements are defined but lim-
ited in size ( 0.4 mm). Furthermore,
several investigations did not find
instrumentation without adjunctive
SDD.
From another perspective, the
number of 7-mm-deep sites that
need to be treated with adjunctiveSDD to avoid disease progression (
2-mm loss of clinical attachment) at
one additional 7-mm-deep site
can be calculated. This calculation is
referred to as the number needed to
treat (NNT) and is the inverse of the
difference between the proportion
of events in the test and control
groups (NNT = 1/Pc Pt).25 NNT
would be calculated as follows:
1/0.036 0.003 = 30 (95% confi-dence interval 21 to 58). Therefore,
on average, compared to scaling
and root planing alone, 30 7-mm
sites need to be treated with adjunc-
tive SDD to avoid disease progres-
sion at one additional 7-mm
pocket. Furthermore, clinicians are
faced with the dilemma of selecting
patients who would most likely ben-
efit from SDD use, as the difference
in disease progression between thetwo groups is small. On the other
hand, the number of deteriorating
sites is usually small during a study;
therefore, the difference in disease
activity recorded in the phase III trial
is proportionately large and clinically
relevant.7
Novak et al11 also report statis-
tically significantly less disease pro-
gression in patients administered
SDD. The proportion of sites ini-tially 7 mm deep manifesting dis-
ease progression (threshold = 4-
mm increase in probing depth)
among individuals administered
ultrasonic debridement and SDD
was 0.12%, versus 0.68% in patients
statistically significant gains of clini-
cal attachment after employing
SDD11,12,15,16; therefore, these data
need to be interpreted cautiously.
Incidence of diseaseprogression
Several investigations indicate that
SDD in conjunction with conven-
tional therapy decreases the number
of sites experiencing disease pro-
gression.7,11,12 When Caton et al7
compared the incidence of clinical
attachment loss ( 2 mm) in groupsthat underwent scaling and root
planing with and without SDD, they
noted that at pockets initially 7
mm deep, the number of sites man-
ifesting loss of clinical attachment
was statistically significantly lower in
individuals who received combined
therapy (0.3% vs 3.6% of the treated
sites). However, at initial probing
depths of 0 to 3 mm or 4 to 6 mm,
the incidence of disease progres-sion was not significantly lower after
combined therapy. At sites 7 mm
deep, the relative percentage of
benefit with regard to inhibiting
more deterioration after using SDD
can be calculated: 3.6% 0.3%/3.6%
= 92% less disease progression with
combined therapy. However, the rel-
ative importance of this calculation
can be misleading: After scaling and
root planing, at locations initially 7 mm deep, 96.4% of the sites did
not experience 2-mm loss of clin-
ical attachment. Thus, the issue of
the value of treating all patients with
SDD arises, as most deep pockets
responded favorably to mechanical
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Volume 24, Number 6, 2004
who underwent only root debride-
ment. Clinicians need to interpret a
difference of 0.56% less disease
progression with respect to its clin-
ical relevance.Golub et al12 evaluated the effi-
cacy of SDD to inhibit disease pro-
gression at sites in patients with ele-
vated collagenase levels. All
individuals underwent 30 minutes of
supra- and subgingival instrumenta-
tion. Then, half of the patients were
administered a variety of SDD regi-
mens for different periods. Patients
treated with SDD (20 mg, 2 times a
day for 12 weeks on, 12 weeks off,and 12 weeks on) experienced less
disease progression than individu-
als who were only mechanically
instrumented. The loss of clinical
attachment with regard to this spe-
cific therapeutic regimen in the test
and control groups was, respectively,
0.3 mm and 0.8 mm. The finding of
clinical attachment loss in both
groups after subgingival instrumen-
tation differs from that usually foundin the literature. Most studies that
employ root planing report a gain
of clinical attachment.7,11,14,15,24
Patients with elevated collagenase
levels may represent a group of indi-
viduals who are refractory to con-
ventional therapy, or the 30 minutes
allocated for supra- and subgingival
instrumentation may have been in-
sufficient.
Clinicians need to decide if thereported improvements in inhibiting
disease progression warrant SDD
administration. This decision is com-
plicated by the fact that on a yearly
basis, disease progression only
occurs in a small percentage of
patients with periodontitis.2628
Furthermore, calculation of the
mean number of sites experiencing
disease activity in a group of patients
is misleading because a large per-centage of the sites experiencing
loss of clinical attachment are usually
found in a small percentage of the
patients. Thus, using mean data from
study populations to help decide
which patients to treat can result in
an erroneous basis for therapy.
Accordingly, clinicians need to try to
determine who will most benefit
from adjunctive therapy based on
history of disease occurrence, sever-ity of the periodontal problem, med-
ical history, and a variety of other
factors that can be used conceptu-
ally to construct a patient risk profile.
Utility of SDD as an adjunct
to periodontal surgery
Gapski et al15 address the efficacy of
access flap surgery with and with-out supplemental SDD for 6 months
among individuals (n = 24) previ-
ously unresponsive to scaling and
root planing. They note that individ-
uals administered SDD demon-
strated a statistically significantly
greater probing depth reduction at
sites initially 6 mm deep (3.3 mm
vs 2.1 mm); however, there was no
statistically significantly greater gain
of clinical attachment (1.8 mm vs 1.1mm). The latter result may be due to
the small study population. SDD
administration also resulted in a
greater reduction of levels of ICTP (a
carboxyterminal fragment of type 1
collagen, which is a marker for bone
resorption).
With respect to these data, sev-
eral issues need to be discussed.
This was a proof-of-principle study
with a small study population. Theterm access surgery was used
instead of pocket elimination or
regenerative surgeries; thus, the
results are specific for a particular
surgical technique. Larger study
populations and additional investi-
gations are needed to assess the
adjunctive use of SDD before any
judgment can be rendered with
regard to its ability to improve sur-
gical results.
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536
The International Journal of Periodontics & Restorative Dentistry
levels (7.6% to 6.3%). There was no
change in HbA1c levels in the
groups administered antimicrobial-
dose doxycycline (7.6% to 7.8%) or
the placebo (8.2% to 8.3%).Another study compared the
efficacy of scaling and root planing
with and without SDD (n = 20)
among individuals with generalized
periodontitis who were either type 1
or 2 diabetics.19 In the group admin-
istered SDD for 3 months, there was
a statistically significant benefit in
diabetics with regard to reduction
of probing depth (2.21 mm vs 0.43
mm) and gain of clinical attachment(2.21 mm vs 0.48 mm). Furthermore,
there was a decrease in HbA1c asso-
ciated with use of SDD. This proof-
of-principle study demonstrated the
potential benefit of using SDD in a
diabetic population; however, addi-
tional studies in larger diabetic pop-
ulations are needed to verify these
results.
Elderly people
Mohammad et al20 address the util-
ity of SDD in a geriatric institutional-
ized population (n = 24) in a 9-month
study. A standardized episode of
root planing was administered. The
authors report a significant improve-
ment in individuals administered
SDD in conjunction with scaling and
root planing with respect to probingdepth reduction in the test and con-
trol groups: 4.34 mm versus 0.7 mm
at sites initially 7 mm and 1.64
mm versus 0.69 mm at sites initially
4 to 6 mm. The benefit obtained at
the deep sites is unusually large, and
Use of SDD in specific
study populations
Smokers
Preshaw et al29 recently reanalyzed
their data on the effect of scaling
and root planing with and without
SDD in smokers and nonsmokers (n
= 210; 67 smokers). Adjunctive SDD
provided a statistically significant
benefit in both smokers and non-
smokers. Among smokers, when
adjunctive therapy with SDD was
compared to a placebo, the in-
creased probing depth reduction atsites initially 4 to 6 mm and 7 mm
deep were as follows: 1.19 mm ver-
sus 0.93 mm and 2.25 mm versus
1.89 mm. The increased gains of
clinical attachment at sites initially 4
to 6 mm and 7 mm deep were
1.19 mm versus 0.85 mm and 2.02
mm versus 1.88 mm. There was no
statistically significant difference
between results in smokers and non-
smokers administered SDD.
Diabetics
Engebretson et al18 compare the
efficacy of scaling and root planing
with and without SDD or antimicro-
bial-dose doxycycline in 45 individ-
uals who had untreated periodonti-
tis and type 2 diabetes. After 3
months of SDD administration, therewas no statistically significant
improvement in monitored clinical
parameters. However, individuals
administered SDD did demonstrate
a statistically significant reduction of
glycosylated hemoglobin (HbA1c)
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537
Volume 24, Number 6, 2004
additional investigations are needed
to verify the benefit of SDD admin-
istration in elderly people.
Other SDD considerations
Comparison to other treatmentmethods
Ideally, the efficacy of therapeutic
methods should only be compared
if they were assessed in a controlled
clinical trial. However, it is reason-
able to evaluate results from other
studies and judge whether treat-ment methods routinely provided
desired clinical outcomes. This is
rational, as it is not possible to con-
duct clinical trials to compare the
efficacy of procedures (eg, scaling
and root planing plus SDD) to all
other types of therapies. For exam-
ple, Table 6 lists the results of several
treatments. It appears that at prob-
ing depths 7 mm, scaling and root
planing plus adjunctive SDD,7 scal-ing and root planing alone,24 tetra-
cycline fibers and scaling and root
planing,30 minocycline polymer plus
scaling and root planing,31 metron-
idazole plus scaling and root plan-
ing,32,33 and irrigation with povidone
iodine via an ultrasonic device34 all
produce probing depth reductions
1.6 mm. Similarly, amoxicillin used
in conjunction with scaling and root
planing35 and repeated scaling androot planing produce mean probing
depth reductions 1.6 mm when all
probing sites are pooled.3638
A recent clinical trial compared
the utility of scaling and root planing
alone, and scaling and root planing
Table 6 Representative results of different therapies (mm)
Probing depth Clinical
Procedure reduction attachment gain
SDD + SC/RP7
*Pockets 46 mm 1.03 0.95
Pockets 7 mm 1.68 1.55
SC/RP24
Pockets 46 mm 1.29 0.55
Pockets 7 mm 2.16 1.29
Repeated SC/RP36 3.2
Repeated SC/RP37 2.2
Local drug delivery
Tetracycline fibers + SC/RP30
Pockets 46 mm 1.0 1.1
Pockets 7 mm 2.1 1.2
Minocycline microspheres + SC/RP31
Pockets 5 mm 1.32
Pockets 6 mm 1.46 Pockets 7 mm 1.99
Povidone iodine + ultrasonic debridement34
Pockets 7 mm 3.0
Systemic antibiotics
Metronidazole + SC/RP32
Pockets 46 mm 1.22 0.79
Pockets 7 mm 2.83 1.69
Metronidazole + SC/RP33
Pockets 46 mm 0.75 0.40
Pockets 7 mm 1.91 0.86
Amoxicillin + SC/RP35 2.5 2.0
*Periostat.
Actisite, Alza.Arestin, Orapharma.All probing sites.SDD = subantimicrobial-dose doxycycline; SC/RP = scaling and root planing.
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538
The International Journal of Periodontics & Restorative Dentistry
plus azithromycin (500 mg for 3
days), metronidazole (250 mg, 3
times a day for 14 days), or SDD (20
mg, 2 times a day for 3 months).17
There were no significant differencesbetween treated groups with respect
to complete-mouth mean probing
depth reduction or gain of clinical
attachment (Table 7). At pockets ini-
tially 6 mm, the best results were
obtained with metronidazole.17
Thus, prior to selecting a treat-
ment method, clinicians should con-
sider a variety of treatment modali-
ties, taking into consideration a
patients past medical and dentalhistories. For patients who do not
respond to conventional treatment,
it may be more expedient and less
costly to prescribe an adjunctive sys-
temic or locally delivered antibiotic
to determine if a desired outcome
could be achieved prior to adminis-
tering SDD for several months.
Conceptually, if the bacterial chal-
lenge can be diminished, it may be
possible to avoid the need to pre-scribe a drug to alter the host re-
sponse.
Development of resistantstrains of bacteria
Several investigations that assessed
the effect of SDD on the microflora
demonstrate that the drug did not
alter the proportions of bacteria orinduce drug resistance among
patients who used it for 9 consecu-
tive months.7,16,39 However, no data
are available to determine if multi-
ple applications of SDD or pro-
longed use past 9 months result in
Table 8 % of strains susceptible to various concentrations ofdoxycycline:Common anaerobic bacteria44
No. of 0.5 g/mL 1.0 g/mLOrganism strains concentration* concentration*
Gram positive
Peptostreptococcus 59 45 45
Streptococcus 10 70 90
Clostridium perfringens 8 67 67
Actinomyces 16 63 69
Gram negative
Cocci 26 58 69
Fusobacterium 34 94 94
Prevotella melaninogenica 67 75 78
Other Bacteriodes 72 33 35
*Inhibitory concentration of doxycycline.
Table 7 Results of four periodontal therapies after 3 months17
Duration Mean probing depth
of reduction (clinical attachment
Procedure n administration level gain), in mm
SC/RP 6 Initial 0.42 (0.22)
SC/RP + azithromycin 6 3 d 0.32 (0.06)
SC/RP + metronidazole 5 14 d 0.42 (0.36)
SC/RP + SDD 8 3 mo 0.34 (0.23)
SC/RP = scaling and root planing;SDD = subantimicrobial-dose doxycycline.
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development of antibiotic-resistant
bacterial strains. Administration of
20 mg of SDD (2 times a day) pro-
vides a serum level of doxycycline of
around 0.6 to 0.8 g/mL.16
How-ever, the exact concentration of
doxycycline in the GCF is unclear.
Sakellari et al40 suggest that it would
be around 70% of the serum level.
However, others report that the level
of tetracyclines in GCF is higher than
the serum level.4143 At present, the
amount of doxycycline in the GCF
after ingestion of 20-mg SDD (2
times a day) is unresolved. A con-
centration of 1 g/mL of doxycy-cline is considered a therapeutic
dose to kill bacteria.16 Thus, SDD
provides a subantimicrobial dose
and obtains an improved clinical
result by inhibiting certain MMPs. It
should be noted that the expected
serum level of doxycycline (0.6 to
0.8 g/mL) is greater than the con-
centration needed to kill many
microorganisms in vitro (Table 8)44;
it cannot be assumed that the levelof doxycycline delivered with SDD
did not destroy any bacteria.
Duration of therapy
Several clinical trials administered
SDD for 9 months.7,13,14,16 In the
phase III clinical trial, which lasted 9
months, Caton et al7 achieved
around 90% of the final clinical resultswithin 3 months. This seems reason-
able, as others indicate that SDD (2
times a day) needs to be adminis-
tered for 12 consecutive weeks to
maximally lower collagenase levels
(47% reduction).12 The duration for
which adjunctive SDD needs to be
administered to obtain optimal
results is unknown. It appears that 3
months of adjunctive SDD achieves
most of the therapys potential ben-efits in patients with chronic peri-
odontitis. However, prolonged drug
use (eg, 9 months) may improve the
results.
Areas for further research
Studies are underway to explore the
potential benefits of host modula-
tion among several patient popula-tions (eg, immunocompromised
people, smokers, individuals under-
going orthodontic movement). Host
modulation with SDD also is being
tested as an adjunct to surgical and
nonsurgical therapy. It would also
be enlightening if additional com-
parative studies were conducted to
determine if conventional therapy
plus systemic antibiotics delivered
for 1 week provides a result similar to6 to 9 months of adjunctive SDD.
Numerous other issues need eluci-
dation (eg, effect of SDD on all the
MMPs, precise relationship between
select MMPs and clinical periodon-
tal status, effect of SDD applications
on the microflora when it is admin-
istered several times for a few
months each time, long-term bene-
fits of using SDD).
539
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Conclusion
Modulation of the host response
with SDD as an adjunct to mechani-
cal instrumentation has scientificmerit, and there appear to be no
adverse side-effects. This concept is
supported by the finding that SDD
provides statistically significant
improvements beyond scaling and
root planing among patients with
chronic periodontitis.7,14 However,
clinicians need to cautiously inter-
pret the clinical relevance of statisti-
cally significant findings, as it is
debatable whether the magnitudeof SDDs improvements beyond scal-
ing and root planing is clinically rel-
evant in all patients. With respect to
its use as an adjunct to ultrasonic
debridement11 or surgical therapy,15
or in particular treatment popula-
tions (eg, diabetics, institutionalized
elderly persons),1820 there is too lit-
tle information to render judgment.
At present, therapists must decide
on an individual basis if they think apatient will benefit from SDD admin-
istration based on medical and den-
tal histories.
Consideration should also be
given to other treatment modalities
that may produce similar therapeu-
tic outcomes more quickly and less
expensively than host modulation
with SDD for several months. Ulti-
mately, clinicians need to employ
treatments that provide desired clin-ical outcomes. In this respect, it is
important to focus on the fact that
periodontitis is an infectious disease;
therefore, reduction of the bacterial
challenge may preclude the need to
modify the host response. Eventually,
it may be determined that patients
who develop recurrent or refractory
chronic or aggressive periodontitis,
smokers, and systemically compro-
mised individuals may benefit fromadjunctive SDD therapy. However,
these scenarios need to be validated
in controlled clinical trials.
Addendum
Since the acceptance of this manu-
script, a systematic review and sev-
eral studies regarding the ability of
SDD to enhance periodontal therapywere published.
A systematic review discusses
host modulation using adjunctive
SDD in the treatment of chronic peri-
odontitis.45 A meta-analysis indicated
that when mechanical instrumenta-
tion with and without adjunctive SDD
are compared, patients administered
SDD experience a statistically signif-
icantly greater probing depth reduc-
tion and gain of clinical attachment.Increased probing depth reductions
associated with SDD use at sites ini-
tially 4 to 6 mm and 7 mm deep
were, respectively, 0.448 mm and
0.481 mm. Increased gains of clinical
attachment with SDD at pockets ini-
tially 4 to 6 mm and 7 mm deep
were, respectively, 0.442 mm and
0.452 mm. The meta-analysis pro-
vides a relative measure of improve-
ment, as the normalized effect is themean difference between monitored
groups divided by the standard devi-
ation of the difference; thus, the real
mean is adjusted by the variability of
the studies. A consensus report
attached to that article concludes
that there is evidence to support
the use of SDD as an adjunct to
mechanical instrumentation in the
treatment of chronic periodontitis,
and the clinicians decision to useSDD therapy remains a matter of
individual clinical judgment, based
on the phase of treatment and the
patients status and preferences.45
Emingil et al46 compared the
efficacy of scaling and root planing
with and without adjunctive SDD (3-
month drug regimen). The study
lasted 12 months and included 30
patients with chronic periodontitis. It
assessed both clinical parametersand the GCF level of MMP-8. In the
group administered SDD, the final
complete-mouth mean probing
depth was statistically significantly
lower than in the group not admin-
istered SDD (reduced from 3.62 to
2.03 mm vs 3.97 to 2.65 mm).
Similarly, the final Gingival Index was
lower among patients provided SDD
(1.74 to 0.46 vs 1.91 to 0.86). The
gain of clinical attachment was notstatistically significantly different
between treatment groups. The
GCF level of MMP-8 among patients
given SDD was lower at 3 months
(50% less) and 6 months (70% less);
however, at 12 months, there was
no difference between treatment
groups. The authors conclude that
their data provide additional infor-
mation about the usefulness of SDD
therapy and that the greatest bene-fits occur at about 9 months.
Choi et al47 also compared the
efficacy of scaling and root planing
with and without adjunctive SDD
(the drug was administered for 120
days). Clinical parameters (probing
540
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depth, clinical attachment level, and
bleeding on probing) and the effect
of SDD on GCF levels of MMP-8,
MMP-9, tissue inhibitor of MMPs
(TIMP)-1, and interleukin (IL)-6 wereevaluated every 30 days. Thirty-two
patients with incipient to moderate
periodontitis were included in the
study. Patients administered SDD
demonstrated a statistically signifi-
cantly smaller final probing depth
than individuals who underwent scal-
ing and root planing alone (5.4 to 3.8
mm vs 5.5 to 4.4 mm). Associated
with SDD use was also less clinical
attachment loss (6.4 to 4.2 mm vs 6.1to 5.5 mm) and a reduced bleeding
index (1.0 to 0.3 vs 1.2 to 0.5).
Patients receiving SDD demon-
strated statistically significantly
decreased levels of MMP-8 (407.1 to
63.8 ng/mL vs 378.7 to 168.1
ng/mL). However, for TIMP-1, MMP-
9, and IL-6, there were no differences
between treatment groups. The
investigators conclude that im-
proved clinical parameters reflectbetter control of MMP-8 levels.
Lee et al48 compared the effi-
cacy of low-dose flurbiprofen (LDF),
SDD, and a combination of the two
drugs to determine their effect on
MMPs and endogenous protease
inhibitors among patients under-
going mucoperiosteal flap surgery.
Nineteen patients with chronic peri-
odontitis were divided into three
groups, and the drugs were admin-istered for 3 weeks. Gingival tissues
were biopsied before and after
drug therapy. Gingival Index and
probing depth were not affected
by a 3-week drug regimen. Longer-
term drug regimens may induce
azithromycin, metronidazole, SDD,
and scaling and root planing groups
were 5.9%, 3.8%, 2.1%, and 1.7%,
respectively (statistically signifi-
cantly different). The proportions ofsites that lost 2 mm of attach-
ment for the same therapies were
0.6%, 0.4%, 0.9%, and 0.9%,
respectively. Those authors con-
clude that patients receiving azith-
romycin or metronidazole showed
the greatest proportion of sites
gaining 2 mm of clinical attach-
ment and the smallest number of
sites losing 2 mm of clinical
attachment.
improved clinical parameters. With
regard to inhibition of MMPs and
neutral proteases, LDF had no
effect on collagenase, gelatinase, or
elastase activities in the GCF. SDDcaused a 23% to 30% reduction in
neutral proteases, whereas a com-
bination of SDD and LDF produced
the greatest reduction (43% to
75%). This is the first study to de-
monstrate that a combination of
drugs may have a synergistic effect.
The mechanism for this synergistic
activity and its long-term effects are
unknown.
Periodontal diseases may addto the inflammatory burden of an
individual, which may have systemic
consequences. A 6-month study that
included 50 patients indicated that
SDD administration results in a sta-
tistically significant decrease in lev-
els of C-reactive protein, MMP-9,
and IL-6 among patients with acute
coronary syndromes (eg, myocardial
infarction, unstable angina).49 These
results suggest that SDD may reducesystemic markers of inflammation
and possibly the risk of myocardial
infarction. Additional studies are
needed to corroborate these pre-
liminary findings.
Pflug et al50 recently compared
the efficacy of scaling and root plan-
ing alone (n = 17) with scaling and
root planing plus systemically deliv-
ered azithromycin (500 mg a day
for 3 days; n = 15), metronidazole(250 mg, 3 times a day for 14 days;
n = 16), or SDD (20 mg, 2 times a
day for 3 months; n = 9) among
patients with chronic periodontitis.
The proportions of sites gaining
2 mm of clinical attachment in the
541
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