Full Report - Evidence-based Dentistry

Transcription

Systematic Review and Meta-Analysis
on the Nonsurgical Treatment of
Chronic Periodontitis by Scaling and
Root Planing with or without Adjuncts
ABSTRACT
Background
A panel of experts convened by the American Dental Association (ADA) Council on Scientific Affairs
(CSA) presents a systematic review and meta-analysis on nonsurgical treatment of patients with chronic
periodontitis by scaling and root planing (SRP) with or without adjuncts.
Types of studies reviewed
The authors conducted a search of PubMed/MEDLINE and Embase for randomized controlled trials of SRP
with or without the use of adjunctive treatments with clinical attachment level (CAL) outcomes of trials at
least six months in duration and published in English through July 2014.
Results
The panel included 72 articles in its review and assessed the level of certainty in as well as efficacy of SRP
with or without systemic antimicrobials, a systemic host modulator (sub-antimicrobial dose doxycycline),
locally-delivered antimicrobials (chlorhexidine chips, doxycycline hyclate gel, and minocycline
microspheres), and a variety of lasers used nonsurgically (photodynamic therapy [PDT] with a diode laser,
a diode laser [non-PDT], Nd: YAG lasers, and erbium lasers). The panel also presents evidence on the
potential adverse events associated with each treatment.The panel makes recommendations for further
research.
Conclusions
The literature on randomized controlled trials of SRP versus no treatment or debridement is scant, but
confirmed the commonly reported result of approximately 0.5 mm improvement in CAL. The literature on
adjunctive therapies was varied providing only a moderate level of certainty on the benefits of the four
adjunctive therapies: systemic sub-antimicrobial dose doxycycline, systemic antimicrobials, chlorhexidine
chips, and photodynamic therapy with a diode laser. There was a low level of certainty on the benefits of
all other adjunctive therapies. The panel also assessed the balance between the benefits and potential for
adverse events and harms from each treatment. The panel makes specific recommendations for
additional research on the topic of nonsurgical treatment for chronic periodontal disease to fill the gaps in
knowledge and improve the evidence base.
Clinical implications
The associated Clinical Practice Guideline summarizes the clinical implications of this systematic review.
July 2015
Page 1
AUTHORS
Christopher J. Smiley, DDS; Sharon L. Tracy, PhD; Elliot Abt, DDS, MSc, MS; Bryan Michalowicz,
DDS; Mike T. John, Dr. med. dent., PhD, MPH; John (Jack) Gunsolley, DDS, MS; Charles M. Cobb,
DDS, PhD; Jeffrey Rossmann, DDS, MS; Stephen K. Harrel, DDS; Jane L. Forrest, EdD; Philippe P.
Hujoel, DDS, MSD, MS, PhD; Kirk W. Noraian, DDS, MS, MBA; Henry Greenwell, DMD, MSD; Julie
Frantsve-Hawley, PhD; Cameron Estrich, MPH; Nicholas (Buck) Hanson, MPH
AFFILIATIONS
Christopher J. Smiley is a dentist in private practice in Grand Rapids, MI. He was the chair of the panel.
Sharon L. Tracy is assistant director, Center for Evidence-Based Dentistry, Division of Science, American
Dental Association, Chicago, IL.
Elliot Abt is Attending Staff, Department of Dentistry, Advocate Illinois Masonic Medical Center, Chicago,
IL.
Bryan Michalowicz is Professor and Erwin Schaffer Chair in Periodontal Research, Division of
Periodontology, Department of Developmental and Surgical Sciences at the University of Minnesota.
Mike T. John is Associate Professor in the Division of TMD and Orofacial Pain, Department of Diagnostic
and Biological Sciences at the University of Minnesota.
John (Jack) Gunsolley is Professor of Periodontics at Virginia Commonwealth University.
Charles M. Cobb is Interim Director, Advanced Program, and Professor Emeritus, Department of
Periodontics at the University of Missouri-Kansas City in Kansas City, MO. He represented the American
Academy of Periodontology on the panel.
Jeffrey Rossmann is Professor and Chair of the Department of Periodontics at Texas A&M University
Baylor College of Dentistry, Dallas, TX.
Stephen K. Harrel is Adjunct Professor of Periodontology at Texas A&M University Baylor College of
Dentistry, Dallas, TX.
Jane L. Forrest is Director, National Center for Dental Hygiene Research & Practice, Ostrow School of
Dentistry, University of Southern California, Los Angeles, CA. She represented the American Dental
Hygiene Association on the panel.
Philippe P. Hujoel is Professor of Periodontics, Department of Oral Health Sciences, School of Dentistry,
and Adjunct Professor of Epidemiology, Department of Epidemiology, School of Public Health, University
of Washington, Seattle, WA.
Kirk W. Noraian is a periodontist in private practice in Bloomington and Urbana, IL.
Henry Greenwell is Professor and Director for Graduate Periodontics at the University of Louisville.
Julie Frantsve-Hawley was senior director, Center for Evidence-Based Dentistry, Division of Science,
American Dental Association, Chicago, IL when this document was written. She is now executive director,
American Association of Public Health Dentistry, Springfield, IL.
July 2015
Page 2
Cameron Estrich is a health science research analyst, Division of Science, American Dental Association,
Chicago, IL.
Nicholas (Buck) Hanson is previously a health science research analyst, Division of Science, American
Dental Association, Chicago, IL.
ACKNOWLEDGMENTS
The panel would like to acknowledge the efforts of the following individuals and their commitment in
helping complete this project.
Dr. Gina Thornton-Evans, a Dental Officer with the Surveillance, Investigations, and Research Team in
the Division of Oral Health, Centers for Disease Control and Prevention, Atlanta, GA participated in
reviewing evidence throughout the project.
Dr. Dave Preble and Dr. Krishna Aravamudhan, ADA Council on Dental Benefit Programs liasions; Dr.
Sheila Strock, ADA Council on Access, Prevention, and Interprofessional Relations liaison; Dr. Pam
Porembski, ADA Council on Dental Practice liaison; Ms. Malavika Tampi, research assistant, ADA; Ms.
Sharon Myaard, senior manager administrative services, ADA; Ms. Kathleen Alexandrakis, senior project
assistant; Ms. Kathleen Dennis, senior project assistant.
The panel would like to thank the following individuals and organizations whose valuable input during
external peer review helped improve this report:
Dr. David Sarrett, Virginia Commonwealth University, Richmond, VA; Dr. Robert W. Rives, ADA Council
on Dental Benefit Programs nominee, Jackson, MI; Dr. Linda Vidone, Dentaquest/Delta Dental of
Massachusettes, Boston, MA: Ashley C. Grill, RDH, BSDH, MPH, ADHA, New York, NY; ADA Council on
Dental Practice; Dr. Alpdogan Kantarci, Forsyth Institute and International Academy of Periodontology,
Cambridge, MA; Dr. Debora Matthews, Assistant Dean, Research Director Graduate Periodontics Faculty
of Dentistry, Dalhousie University, Halifax, Nova Scotia, Canada; Dr. Samantha Rutherford, Scottish
Dental Clinical Effectiveness Programme, NHS Education for Scotland, Dundee, Scotland, UK; Professor
Helen Worthington, University of Manchester and Cochrane Oral Health Group, Manchester, UK; Dr.
Jane C. Atkinson, Center for Clinical Research, NIDCR, Bethesda, MD; Dr. Donald J. DeNucci, Center for
Clinical Research, NIDCR, Bethesda, MD; Dr. Sally Hewett, Council on Communications, Bainbridge
Island, WA; Dr. Benjamin Youel, Academy of General Dentistry, Chicago, IL; Dr. Jennifer Bone, Academy
of General Dentistry, Chicago, IL; and the American Academy of Periodontology, Chicago, IL.
Disclosures
Dr. Michalowicz has received research support from Ora-Pharma and Atrix Laboratories in the past. Dr.
Cobb was the principal investigator of the University of Missouri-Kansas City site for a multicenter clinical
trial conducted by OraPharma (Arestin) and has been an unpaid consultant for Hu-Freidy and Livionex.
Dr. Hujoel is a national scientific advisor for Delta Dental Plans. Dr. Noraian is a certified instructor for the
Institute for Advanced Laser Dentistry. Dr. Greenwell was part of a multicenter study for Millennium
Dental Technologies and a laser study for American Dental Technologies. None of the other authors
reported any Disclosures.
Funding source: Funded by the American Dental Association
July 2015
Page 3
Contents
1
Introduction ............................................................................................................................................ 6
2
Methods ................................................................................................................................................. 7
2.1 Panel composition ............................................................................................................................... 7
2.2 Literature search strategy and screening ............................................................................................ 7
2.2.1 Literature search strategy ............................................................................................................. 7
2.2.2. Inclusion/exclusion criteria ........................................................................................................... 7
2.2.3 Definitions ..................................................................................................................................... 9
2.2.4 Grey literature ............................................................................................................................. 11
2.2.5 Electronic database search update ............................................................................................ 11
2.3 Data extraction .................................................................................................................................. 11
2.4 Critical appraisal process – individual studies ................................................................................... 12
2.5 Data synthesis and meta-analysis: Evaluating the effect of the intervention .................................... 12
2.5.1 Choice of outcomes measure, measurement issues, and issues with respect to data
adjustments .......................................................................................................................................... 12
2.5.2 Choice of summary effect estimate, meta-analysis model, meta-analysis procedures, and
generating forest plots ......................................................................................................................... 13
2.5.3 Sensitivity analyses .................................................................................................................... 14
2.5.4 Statistical heterogeneity .............................................................................................................. 14
2.5.5 Subgroup analysis ...................................................................................................................... 15
2.6 Interpreting CAL results in clinical context ........................................................................................ 15
2.7 Determining the level of certainty in the evidence ............................................................................. 15
2.8 Determining the net benefit rating ..................................................................................................... 18
3
Results ................................................................................................................................................. 18
3.1 Literature search and screening ........................................................................................................ 19
3.1.1 Literature search and screening results ..................................................................................... 19
3.1.2 Characteristics of excluded studies ............................................................................................ 20
3.2 Evidence summary ............................................................................................................................ 21
3.2.1
Scaling and root planing (SRP) ............................................................................................... 25
3.2.2
Systemic sub-antimicrobial dose doxycycline + SRP ............................................................. 29
3.2.3
Systemic antimicrobials + SRP ............................................................................................... 34
3.2.4
Locally-delivered antimicrobials + SRP ................................................................................... 42
3.2.5
Nonsurgical use of lasers + SRP ............................................................................................ 56
3.3
July 2015
Caries data .................................................................................................................................. 69
Page 4
3.4
Smokers versus non-smokers..................................................................................................... 70
4.
Discussion ............................................................................................................................................ 70
5.
Limitations ............................................................................................................................................ 72
5.1
Of the evidence ........................................................................................................................... 72
5.2
Of the systematic review ............................................................................................................. 73
6.
Future research .................................................................................................................................... 74
7.
Conclusions ......................................................................................................................................... 75
8.
References ........................................................................................................................................... 77
9.
Appendices .......................................................................................................................................... 88
Appendix 1 – Literature searches and results ......................................................................................... 88
Appendix 2 – Excluded studies and reasons for exclusion ..................................................................... 92
Appendix 3 – Study characteristics, outcomes data, and critical appraisals of individual trials ............ 124
Appendix 4 – Details on data analysis calculations .............................................................................. 175
Combining results stratified by pocket depth ..................................................................................... 175
Data adjustments for meta-analysis calculations .............................................................................. 175
Specific methods for standard error imputation when data not provided .......................................... 177
July 2015
Page 5
1
Introduction
Chronic periodontal disease is a prevalent condition, affecting 47.2% of the adult U.S.
population aged 30 and older.1 Chronic periodontal disease results in the loss of toothsupporting connective tissue and alveolar bone and, if untreated, is a major cause of tooth loss
in adults. Periodontal disease can be classified as slight, moderate, or severe; the prevalence of
moderate has been reported as 30.0% and severe as 8.5%.1 The definition of slight, moderate,
and severe for this systematic review is based on Armitage et al.2: Slight disease is defined as 1
or 2 mm of CAL (clinical attachment level) loss, moderate as 3 or 4 mm CAL loss; and severe
as greater than or equal to 5 mm CAL loss. There are several therapies available to treat
chronic periodontal disease ranging from scaling and root planing (SRP), SRP with adjunctive
treatments, to surgical interventions.
In 2011, the Council on Scientific Affairs (CSA) of the American Dental Association (ADA)
resolved to develop a clinical practice guideline for the nonsurgical treatment by scaling and root
planing (SRP) with or without adjuncts on patients with any severity of chronic periodontitis
based on an evidence-based systematic review of the literature. In this systematic review, the
authors evaluated the effect of SRP alone and in combination with adjuncts on a single clinical
outcome of periodontal disease, the change in clinical attachment level. The authors evaluated
the following professionally-applied or prescribed medical adjuncts: locally applied
antimicrobials (chlorhexidine chips, doxycycline hyclate gel and minocycline microspheres),
nonsurgical use of lasers (diode, both photodynamic and non-photodynamic therapies; Nd:YAG;
and erbium), systemic antimicrobials, and systemic sub-antimicrobial dose doxycycline.
Systemic antimicrobials were categorized separately from systemic sub-antimicrobial dose
doxycycline because the mechanisms of action are different. The mechanism of action for subantimicrobial dose doxycycline has been reported as inhibiting mammalian collagenase activity
(MMP-8) without a measureable antibiotic effect or development of antibiotic resistance.3, 4
Experimental adjuncts, adjuncts not currently available in the United States, non-prescription
(over-the-counter) adjuncts, or surgical treatments were not considered. This systematic review
provides the evidence base for the companion clinical practice guideline.5
The authors addressed two main clinical questions and two sub-questions. The main questions
are:
July 2015
Page 6
1. In patients with chronic periodontitis, does scaling and root planing (SRP) [hand and/or
ultrasonic] result in greater improvement of CAL when compared to a) no treatment; b)
supragingival scaling and polish (prophylaxis); or c) debridement?
2. In patients with chronic periodontitis, does the use of local antibiotics/antimicrobials,
systemic antibiotics, combinations of local and systemic antibiotics, agents for
biomodification or host modulation, or nonsurgical lasers with SRP compared to scaling
and root planing alone result in greater improvement of CAL?
The sub-questions are:
a. Is there a change in caries increment among the comparison groups?
(note: only use data if papers already included with CAL data)
b. Is there a difference between smokers and non-smokers?
2
Methods
2.1 Panel composition
The authors comprise a multidisciplinary panel of subject matter experts and ADA staff
methodologists convened by the American Dental Association (ADA) Council on Scientific
Affairs (CSA).
2.2 Literature search strategy and screening
2.2.1 Literature search strategy
The authors developed the search strategy as presented in Appendix 1. Two authors (NBH and
CE) used the strategy to search PubMed and Embase. In addition, one author (ST) handsearched references of relevant systematic reviews6-45 to find studies that might have been
missed through the electronic sources.
2.2.2. Inclusion/exclusion criteria
The authors developed inclusion/exclusion criteria through consensus. The criteria are
presented in Table 1. Most of the criteria were developed a priori; however, as typically occurs
during systematic reviews, criteria that were not considered a priori are identified during the
screening process. To minimize bias that may have affected inclusion/exclusion decisions, the
panel experts were presented with de-identified trial specifics by the authors involved in the
screening process, and decisions were made on inclusion or exclusion by other authors without
knowledge of the trial’s results.
July 2015
Page 7
Table 1. Inclusion/Exclusion criteria
Inclusion criteria:













Human trials
Studies with concurrent control
Studies with randomized controls – ONLY Randomized or quasi-randomized controlled trials
Prospective
Published in English language
After 1960
At least 6 months in duration
Studies that report on chronic adult periodontitis; progressive periodontitis; rapidly progressive
periodontitis; recurrent periodontitis; or refractory periodontitis; or periodontitis (unspecified)
Split-mouth and parallel-group trials
Must report CAL, relative attachment level/loss, probing attachment level/loss or attachment level/loss
data in full text to be included
Control can have an additional intervention (such as CHX irrigation if treatment arm has the same
additional intervention). Saline irrigation is acceptable as part of a control with SRP even if there is no
additional intervention.
Trials where selected failing pockets are reinstrumented with SRP periodically throughout the study
period
Medical/prescription adjuncts
Exclusion criteria:









Non-English
Studies that report on aggressive (early onset) periodontitis, aggressive periodontitis, localized
aggressive periodontitis, generalized aggressive periodontitis, juvenile periodontitis or “pre-pubertal”
periodontitis
Studies that do not report CAL or any related attachment level data
Anti-inflammatories, statins; other medications with mechanisms of action not related to altering the
biological environment; chlorhexidine rinse; experimental interventions; herbals, over-the-counter
Studies comparing different SRP delivery methods
Treatments (full products, not just active ingredients) that are not commercially available in the United
States [for example, Actisite (tetracycline fibers) and Elyzol (metronidazole), chlorhexidine varnish]
Trials that apply the first dose of adjunct after 1 week from SRP
Trials that reapply adjuncts at selected failing sites during the study (note: this does not apply to studies
on SRP alone because of ethical reasons and the standard of care)
No exclusions based on length of time that adjunct is administered
Although ideally there is no language restriction for systematic reviews, for practical reasons,
the panel limited the eligible studies to those available in English. The literature search strategy
included searching a primarily European electronic database (Embase) to help offset this
limitation by searching for articles of foreign origin. This database provided a source of English
language articles published outside the United States that may not be catalogued in Medline.
One result of these choices is that literature was retrieved on products available worldwide, but
that are not currently commercially available in the United States, such as Elyzol (a topical
metronidazole gel).
Cognizant of the limitations of split-mouth trials, the panel decided to include both split-mouth
and parallel-group trial designs as long as the resulting meta-analyses were presented sub-
July 2015
Page 8
grouped by trial design. One limitation to split-mouth trials is that the magnitude and direction of
bias are inestimable; however, a recent meta-epidemiological study46 provides some evidence
that there is no difference in intervention effect estimates derived from split-mouth and parallelarm RCTs.
Another choice the panel made was to include only trials of at least six months in duration.
There was concern regarding the volume of studies that would remain with this criterion;
however, the panel decided six months was the minimum amount of time that was necessary to
observe a lasting therapeutic effect. The panel also noted that this 6-month criterion is used for
FDA approval of drugs for treatment or prevention of gingivitis.47
The panel also considered the minimum number of sites measured per participant. It decided to
include studies that evaluated at least one site in each patient.
The type of probe used to obtain clinical measurements was considered by the panel. Various
manual and automated probes, with different incremental markings, were used in different
studies. While recognizing that this variability could be a concern, the panel also recognized
that skilled and standardized evaluators have been shown to be accurate with many types of
manual and automated probes.48 The panel thus elected to use measurements as reported by
the authors and to not exclude any type of probing method from consideration.
All full text articles were also screened independently and in duplicate by two of the authors (ST,
NBH, CE, or JFH) for inclusion. Articles where agreement could not be achieved were
presented to the panel for further discussion and a final decision.
2.2.3 Definitions
The panel found some variability with definitions in the literature related to periodontal disease,
which complicated efforts to screen studies to answer the clinical questions. Others have also
commented on the variability of periodontal disease definitions, disease classifications, and
measures used to quantify disease.49 The following are definitions that the panel used when
conducting this systematic review:
Scaling and root planing (SRP): Within this systematic review, “SRP” is defined as noted
within the Code on Dental Procedures and Nomenclature (CDT). These codes and their
associated nomenclature and descriptors serve to record and report care. SRP should be
differentiated from supra- or sub-gingival debridement as noted below from the CDT:
July 2015
Page 9

D4341, Periodontal Scaling and Root Planing/per Quad: “Root planing is the definitive
procedure designed for the removal of cementum and dentin that is rough and/or
permeated by calculus or contaminated with toxins or microorganisms...”

D4355, Full mouth debridement: “The gross removal of calculus that interferes with the
ability of the dentist to perform a comprehensive oral evaluation. This preliminary
procedure does not preclude the need for additional procedures.”
Debridement refers to the removal or disruption of dental biofilms and dental calculus from
supragingival tooth surfaces and subgingival root surfaces without the deliberate removal of
cementum as done in root planing. Thus, it was not considered as an active treatment in this
guideline.
Some researchers used the term “instrumentation” to describe the procedure performed in their
studies; however, this non-specific term was judged to be inconclusive. Similarly, some authors
stated that “ultrasonic scaling” or “sub-gingival scaling” was performed. These procedures were
often described as “debridement.” The panel decided that treatments that were not described
with the specific term “root planing” were excluded. Similarly, if the authors stated they
performed “scaling and root planing”, but described the use of ultrasonic instrumentation with no
mention of hand instrumentation, the treatment was included.
Diagnosis: The clinical questions specifiy a diagnosis of chronic periodontitis for inclusion. After
discussion, the panel also included the diagnoses “progressive periodontitis” and “rapidly
progressive periodontitis”, although the terms “aggressive periodontitis” and “rapidly aggressive
periodontitis” were excluded. The panel wanted to err on the side of inclusion rather than
exclusion, and was limited in their confidence that the diagnosis definitions and terminology
remained consistent over the years.
Disease severity: Many published papers did not define disease severity of the sample
population, but if they did, that nomenclature was recorded in the abstraction forms. The panel
refers to Armitage2 for standard definitions when severity was not named. Note that the
literature included in this review spans a time period wherein the disease severity classification
system and nomenclature were changing. The panel decided to include studies on patients with
“refractory periodontitis,” although the term is outmoded.
July 2015
Page 10
Site: Researchers’ use of the term “site” was often unclear and should be clarified in future
reporting. This term was used to indicate a measurement site (e.g. “CAL was measured at six
sites per tooth”) as well as a treatment site spanning multiple teeth (e.g. “one site received SRP
plus doxycycline hyclate gel”). This interchangability of terminology is particularly troublesome
when there is little description of how the mean CAL was calculated for each treatment. The
panel evaluated the use of “site” in each paper reviewed and made a determination of the
author’s meaning.
Attachment level: The clinical question uses the specific term “clinical attachment level.” Some
researchers used this term, while other used the terms: “attachment level”, “relative attachment
level”, and “probing attachment level.” Some authors specified the exact locations used for the
measurement of the attachment level. The panel decided to include all forms of attachment
level.
2.2.4 Grey literature
The expert panelists were asked whether or not they were aware of any unpublished or nonpeer-reviewed studies that should be considered for inclusion.
2.2.5 Electronic database search update
In July 2014, the electronic search strategy was rerun to collect any studies that had been
published between the time when the search had been conducted at the start of the project and
before completion of the manuscript. The literature was screened by in duplicate by two of three
authors (ST, CE, or JF).
2.3 Data extraction
A data extraction form was designed using Excel to capture information from each included
study with respect to study conduct, participants, disease severity, treatment, adverse events,
and CAL outcomes data. A priori rules for data extraction included the preference for 9-month
CAL results, and if that time period was not reported but both 6- and 12-month results were
reported, the 12-month results were extracted.
Two authors extracted data from each included study into the standardized form independently
and masked from each other’s work. The two data sets were then compared and adjudicated
by a third reviewer [one of four authors (ST, NH, CE, or JF), but different from the original
reviewers]. The data from the updated literature search was extracted by one of two authors (ST
or JF), and a second author reviewed the information. A summary of the extracted data is
July 2015
Page 11
presented in Appendix 3. During a three-day, face-to-face panel meeting, all panelists reviewed
and discussed results from each study.
2.4 Critical appraisal process – individual studies
The panel critically appraised each included study using Cochrane’s Risk of Bias tool.50 The tool
includes six domains for bias assessment: selection, performance, detection, attrition, reporting,
and other. The critical appraisal process assesses randomization; allocation concealment;
masking of participants, study personnel, and outcomes assessors; the interventions; and the
completeness of outcomes data and reporting. The tool requires evaluators to assess whether
there is low, unclear, or high risk of bias for that domain item as well as supporting information
for each assessment. The tool also provides concrete examples for each domain as to what is
considered low, unclear, and high risk methodologies to aid in decision-making.
All panel members participated in an orientation webinar to train them on the critical appraisal
process.
The studies were divided into categories by adjunct type, and two panel members were
assigned to each category. Each panel member received between 10-15 studies to review. The
panelists entered the appraisals into a standardized form.
Independent from the panel members, one of four authors (ST, NH, CE, or JF) duplicated the
critical appraisal of all included studies independently and masked from the panel’s review. The
two data sets were then compared and adjudicated by a third reviewer [one of four authors (ST,
NH, CE, or JF), but different from the original appraisers] to achieve consensus on the Risk of
Bias assessment for each domain. The data from the updated literature search was appraised
by one of two authors (ST or JF), and a second author reviewed the information. The critical
appraisal results are presented in Appendix 3.
2.5 Data synthesis and meta-analysis: Evaluating the effect of the
intervention
2.5.1 Choice of outcomes measure, measurement issues, and issues with respect to data
adjustments
A patient-centered outcome such as tooth loss or quality of life would provide the best evidence
on periodontal treatment effectiveness; however, periodontal researchers have mostly reported
on surrogate outcomes such as probing depth (PD) and CAL. PD is measured from the gingival
margin and the measurement is impacted by gingival recession or inflammation, but CAL is
July 2015
Page 12
measured from a fixed reference point (typically the cementoenamel junction) and is a more
valid metric and a more stable indicator of improvement in periodontal health. The panel voted
to use CAL as the primary outcome to be used on the assessment of periodontal therapies for
many reasons including 1) it is used to measure the clinical effect of SRP;36, 51 2) gains in clinical
attachment account for roughly 50% of probing depth reduction following SRP of periodontal
pockets with 4-6 mm and ≥ 7 mm probing depths;36, 51 3) Imrey et al.52 recommended that CAL
or alveolar bone support be used as a primary outcome in non-surgical interventional trials of
periodontitis, and they also advocated using CAL as an a priori secondary outcome in trials in
which bone loss was the primary outcome; and 4) the Food and Drug Administration (FDA) has
generally adopted these recommendations in their product/drug approval process for
adjuncts. Regardless of the debate regarding use of CAL vs. PD, the “gold standard” for
measuring stability or progression of periodontitis remains CAL.53, 54
Studies reported data in several formats, such as change in mean full-mouth CAL, change at
disease/study sites only, or changes stratified by baseline probing pocket depth, to facilitate
data aggregation and interpretation. The panel used a set of rules to maximize the uniformity of
the data abstraction and analysis processes. The rules include the choice of data presented by
disease/study site over that for full mouth or stratified by pocket depth. If the data were only
presented stratified by pocket depth, the data were combined as described in Appendix 4.
When there was no information on standard deviation or any way to impute from an inferential
statistic, the standard deviations of the other studies in its category were averaged55 in most
cases, and exceptions are noted in Appendix 4.
In some studies, there was one control arm and multiple treatment arms. If these treatments
appeared in the same meta-analysis, the number of subjects in the control group was divided by
the number of treatment arms for the purposes of the meta-analysis. This adjustment was made
to ensure that the control subjects were not over-represented.
2.5.2 Choice of summary effect estimate, meta-analysis model, meta-analysis procedures, and
generating forest plots
In assessing the efficacy of SRP, the panel compared mean change in CAL between SRP and
placebo groups. To assess adjuncts, the panel compared mean changes between groups
receiving SRP and those receiving SRP plus the adjunct. The authors used the generic inverse
variance method56 as contained in RevMan software57 to calculate the summary effect over all
included trials using the random effects model.
July 2015
Page 13
The random effects model was chosen because the authors could not assume that the studies
were conducted under similar conditions. Although it is possible that the effect size was similar
among the studies, the authors assumed the effect size varied among studies because of
differences in population age, comorbidities, socio-economic class, and/or clinician
experience.58
When interpreting the random effects-generated mean difference and confidence interval, it is
important to consider that the “summary effect estimate” is an estimate of a distribution of
effects, not a common effect.58 For example, although the 95% confidence interval of the mean
effect of a treatment may cross the line of no effect, there is the possibility that the treatment
varies by context, such as population age, comorbidities, socio-economic class, or clinician
experience.59
2.5.3 Sensitivity analyses
Correlation coefficients (designated as ), indicating within-patient correlation in split mouth
trials at a given time point or correlation between CAL measures over time, were required for
the statistical computations. The initial value of  was set at 0.25 following the protocol of a
related systematic review60.
Since the true value of  is unknown, the effect of that assumption on the results of the metaanalysis computations was tested by conducting a sensitivity analysis. The meta-analyses were
rerun by changing the value  to either -0.1 or 0.9 and observing the effect of the change on the
resulting values of the mean difference, 95% confidence interval, and heterogeneity statistics. A
similar analysis was conducted removing studies where no information regarding the standard
deviation (SD) was reported, which necessitated estimating the SD based on the reported
results of similar trials.
2.5.4 Statistical heterogeneity
Statistical heterogeneity was interpreted primarily using the tau-squared, p-value of tausquared, and I-squared statistics. The tau-squared statistic was interpreted as an estimate of
the between-study variance, the p-value of this statistic was interpreted as the statistical
significance of between-study variance, and the I-squared was interpreted as the percent of
total variance that is attributable to true between-study variance (as opposed to within-study
error variance).58
July 2015
Page 14
2.5.5 Subgroup analysis
The authors decided a priori to present the results of the meta-analyses in sub-groups based on
trial design.
2.6 Interpreting CAL results in clinical context
The panel reviewed the power calculations of included studies to determine the threshold that
the authors used to determine statistical significance. These CAL differences ranged from 0.25
mm61 to 1.8 mm62. Caution must be observed with respect to using power calculations as these
are not always performed a priori.
For the purposes of interpreting the results, the panel made the following clinical relevance
scale a priori to reviewing the results (Table 2):
Table 2. Clinical relevance scale for interpreting mean differences in CAL
CAL Difference Range (mm)
0 - 0.2
>0.2 – 0.4
>0.4 – 0.6
>0.6
Judged clinical relevance
Zero benefit
Small benefit
Moderate benefit
Substantial benefit
The panel notes that the literature is inconsistent on methodology regarding how many sites and
teeth are assessed and analyzed. In particular, some researchers study and analyze only
diseased sites, whereas other report whole mouth averages. Whole mouth measurements will
tend to underestimate the effect since healthy or less severe sites will be included with more
severe sites. Therefore, practitioners are cautioned when comparing average results to
individual tooth or tooth site results.
2.7 Determining the level of certainty in the evidence
After the data were collected, the authors reviewed the results to determine their level of
certainty in the evidence as high, moderate, or low. Several criteria were evaluated to make this
determination as follows:
1. The quantity of evidence (number and size of studies)
2. Risk of bias for each outcome (limitations of the evidence across domains and
studies)
3. Applicability of evidence
4. Consistency/inconsistency (or unexplained heterogeneity) of results
5. Precision/imprecision (narrow or wide confidence intervals)
July 2015
Page 15
6. Probability of publication bias
The revised Clinical Practice Guidelines Handbook63 gives more details on evaluating these
criteria. During a three-day, face-to-face panel meeting, and at follow up conference calls and
through email, all panelists reviewed and discussed results from each study individaully as well
as in aggregate on each treatment to arrive at consensus on the level of certainty in the
evidence.
Table 3 has been developed63 as a tool to aid in capturing the assessments, presenting the
assessments in a repeatable manner for each intervention evaluated, and facilitating consistent
judgments of evidence criteria to be made between multiple interventions in this systematic
review.
Table 3. Evidence profile reporting format
Therapy
aInterpreted
Quantity of evidence
No.
No.
Trials participants
Level of certainty assessment
Risk
ConsisAppliPreciof
tencya
cability
sion
bias
Publication
bias
Level of
Certainty
according to the Cochrane Handbook 55 section 9.5.2:
The results of the meta-analysis were entered into the evidence profile in the “Mean difference
(mm)” column to summarize the treatment effect. The number of studies and participants were
also input into the corresponding columns. The panel assessed the risk of bias by making an
overall assessment of the critical appraisal data for each domain of every study. The panel
judged the applicability of the evidence by assessing whether or not the results could be
generalized to a common population. Consistency was evaluated according to the I-squared
statistic provided in each meta-analysis according to Table 4.55 Note that when there are less
than 20 studies in a meta-analysis, consistency-related statistics have very low power.64, 65
Table 4. Consistency interpretation
I-squared
0-40%
30-60%
50-90%
75-100%
Interpretation
Might not be important
May represent moderate
heterogeneity*
May represent substantial
heterogeneity*
Considerable heterogeneity*
Nomenclature
Consistent
Moderate inconsistency
Substantial inconsistency
Inconsistent
*The importance of the observed value of I-squared depends on (i) magnitude and direction of effects and (ii)
strength of evidence for heterogeneity (e.g. p-value from the chi-square test, or a confidence interval for Isquared). Note that the thresholds overlap and are arbitrary and uncertain66; and also that there is a lot of
uncertainty around the I-squared statistic, especially when the number of studies is few (less than three).67
July 2015
Page 16
Mean
difference
(mm)
Precision is judged by the width of the 95% confidence intervals in relation to clinical relevance
of the treatment effect. Publication bias is assessed when there are at least 10 studies in an
analysis via Egger’s procedures using Stata.68
The panel reviewed all the information of the evidence profile to arrive at a summary level of
certainty in the effect estimate as shown in Table 5, which provides a description and types of
evidence for each level of certainty.
Table 5. Level of Certainty in the body of evidence included within the systematic review.
Level of
Certainty in
Effect Estimate
Description
High
The body of evidence usually includes consistent results from welldesigned, well-conducted studies in representative populations.
This conclusion is unlikely to be strongly affected by the results of
future studies.
This statement is strongly established by the best available evidence.
Moderate
As more information becomes available, the magnitude or direction
of the observed effect could change, and this change could be large
enough to alter the conclusion.
This statement is based on preliminary determination from the current
best available evidence, but confidence in the estimate is constrained by
one or more factors, such as:

the limited number or size of studies;

plausible bias that raises some doubt about the results;

inconsistency of findings across individual studies;

imprecision in the summary estimate;

limited applicability due to the populations of interest;

evidence of publication bias; or

lack of coherence in the chain of evidence.
Low
July 2015
More information could allow a reliable estimation of effects on
health outcomes.
The available evidence is insufficient to support the statement or the
statement is based on extrapolation from the best available evidence.
Evidence is insufficient or the reliability of estimated effects is limited by
factors such as:

the limited number or size of studies;

plausible bias that seriously weakens confidence in the results;

inconsistency of findings across individual studies;

imprecision in the summary estimate;

gaps in the chain of evidence;
Page 17



findings not applicable to the populations of interest;
evidence of publication bias; or
a lack of information on important health outcomes.
2.8 Determining the net benefit rating
This systematic review serves as the foundation for the companion evidence-based clinical
practice guideline.5 The methods require a determination of the net benefit rating for the
intervention in question. The net benefit rating is assessed by judging the balance between the
benefit (estimate of effect from the meta-analysis, which could actually be negative or no
benefit) and any potential harms that have been identified by the panel. For each treatment, the
panelists selected from one of three options: 1) the benefits clearly outweigh the harms; 2) the
benefits and harms are closely balanced, or there is uncertainty in the estimate of the balance;
or 3) the harms clearly outweigh the benefits. This determination involves an assessment of
several features of the evidence, the details of which are described in the following sections.
The panel reviewed the evidence of harms (or adverse events) for each treatment arising from
a) the included studies or b) commonly reported adverse events from sources such as the FDA.
During a three-day, face-to-face panel meeting, and at follow up conference calls and through
email, all panelists reviewed and discussed results from each study individually as well as in
aggregate on each treatment to arrive at consensus on the level of certainty in the evidence and
the net benefit rating.
3
Results
The authors conducted a comprehensive search of the biomedical literature, screened the
results of the search according to inclusion/exclusion criteria, critically appraised the included
studies, synthesized the data through meta-analyses where appropriate, and evaluated the level
of certainty in the evidence regarding the magnitude of the net benefit. A summary of the results
of these processes is presented in sections according to treatment. Each section begins with a
general description of the studies in terms of number of studies, study design, sample size,
country in which the study was conducted, and severity and smoking status of included
participants. Note that this information is descriptive, and at this time there were not enough
studies with any particular characteristic except study design that would allow a subgroup
analysis to be performed based on the characteristic. For example, studies with any severity
(slight through severe) of chronic periodontitis were included; however, there was not enough
information to differentiate results based on periodontitis severity.
July 2015
Page 18
The other subsections are critical appraisal, assessment of publication bias, results of
intervention, sensitivity analyses, evidence profile, adverse events assessment (potential for
harms), and balancing benefits with potential for harms. Note that translation of this information
into a clinical practice guideline is presented in the companion paper5. The supplemental
materials (Appendices 1-4) contain further detailed information for the interested reader as
follows: Appendix 1- search strategies and results; Appendix 2 - detailed list of excluded studies
with reasons; Appendix 3 – study characteristics, outcomes data, and authors’ judgments of
risks of bias; and Appendix 4 – details on data analysis calculations.
3.1 Literature search and screening
3.1.1 Literature search and screening results
Figure 1 shows the step-by-step results of the literature screening process. PubMed and
Embase were searched from 1966 through October 2012 resulting in 1681 records after
duplicates were removed. The updated literature search added 315 publications through July
2014, and after duplicates were removed, a total of 1944 records were screened by title and
abstract. At least two authors (ST, CE, JF, and NBH) independently screened the titles and
abstracts of all the retrieved articles according to the inclusion/exclusion criteria. Any article that
either screener selected was retrieved for full text review. There was 77% agreement of full text
retrieval by both parties, with the remaining selected by either party individually. Full texts of 440
records were retrieved and reviewed, with the final number of included studies being 72. No
citations were found through hand searching that met inclusion criteria.
July 2015
Page 19
Figure 1. PRISMA flow diagram of literature search and screening process
3.1.2 Characteristics of excluded studies
Appendix 2 lists the excluded studies with reasons for exclusion. The reasons were combined
into 12 larger groups to better understand the distribution of reasons for study exclusion. Table
6 lists the exclusion groups and the percentage of the total excluded studies in each group.
Note that studies on subgingival irrigation69-77 were identified in the literature search showing
July 2015
Page 20
varying effects; however, none of these studies met all the inclusion criteria, and therefore were
not eligible to be summarized in this systematic review.
Table 6. Categories of reasons for study exclusion after full text review with percentage
of studies in each category
Percent of excluded
Exclusion group
Details of studies excluded
studies in this
category
Design
Availability
Data
Publication
Duration
Adjunct
Not RCTs; not randomized; no control; no
passive control; head-to-head trials
Adjunct not commercially available
(compounded by author); adjunct not
commercially available in the U.S. for dental
applications (e.g. Elyzol, KTP laser,
compounded materials, Actisite);
experimental therapies (multiple
pharmacotherapies)
No CAL data; data in unusable format; data
not provided separately for treatment
Ineligible publication type
Less than 6 months in duration
Not medical adjunct as defined in inclusion
criteria (such as hyperbaric oxygen); therapy
not used as adjunct to SRP; insufficient
details about use (lasers); experimental
therapy
Duplicate
citation
Disease
SRP
Retreatment
Duplicate data
Erroneous duplicate citations
Aggressive periodontal disease; not chronic
periodontal disease; not periodontal disease
Not SRP procedure; debridement; SRP
methods comparisons; surgical treatment
Retreatment at failing sites
Data reported in another included publication
23
15
13
11
10
8
6
5
4
3
2
3.2 Evidence summary
The panel included 72 randomized clinical trials on nonsurgical treatments for chronic
periodontal disease. A summary of the evidence is presented in Table 7. All extracted data are
July 2015
Page 21
presented in three tables per each treatment in Appendix 3, one table each for study
characteristics, outcomes data, and the authors’ judgment of the risk of bias.
July 2015
Page 22
Table 7. EVIDENCE PROFILE SUMMARY TABLE
Level of certainty assessment criteria
Therapy
No.
No.
RCTs
participants
Risk of
bias
Consistency
Applicability
Precision
Publication
bias
Level of
Certainty
Benefit (Mean
difference in
CAL)
SRP
11
331
Unclear
Consistent
Yes
No serious
imprecision
None detected
p=0.707
Moderate
0.49 (0.36 to
0.62)
SRP+systemic
subantimicrobi
al dose
doxycycline
11
813
Unclear
Moderate
inconsistency
Yes
No serious
imprecision
None detected
p=0.121
Moderate
0.35 (0.15 to
0.56)
Yes
No serious
imprecision
None detected
p=0.803
Moderate
0.35 (0.20 to
0.51)
SRP+systemic
antimicrobials
24
1086
Unclear
Substanti
al
inconsistency
SRP+CHX
chip
6
316
Unclear
Consistent
Yes
No serious
imprecision
Too few
studies to
assess
Moderate
0.40 (0.24 to
0.56)
SRP+
doxycycline
hyclate gel
3
64
Unclear
Moderate
inconsistency
Yes
Serious
imprecision
Too few
studies to
assess
Low
0.64 (0.00 to
1.28)
SRP +
minocycline
microspheres
5
572
Unclear
Moderate
inconsistency
Yes
Serious
imprecision
Too few
studies to
assess
Low
0.24 (-0.06 to
0.55)
July 2015
Net benefit
rating
Moderate
benefit
outweighs
potential for
harms
Small benefit
outweighs
potential for
harms
Balance
between small
benefit and
potential harms
Balance
between
moderate
benefit and
potential harms
Uncertainty in
the balance
between
benefits and
harms because
benefits are
unclear
Uncertainty in
the balance
between
benefits and
harms because
Page 23
SRP + diode
laser (PDT)
SRP + diode
laser (nonPDT)
10
4
306
98
Low
Inconsistent
Yes
Serious
imprecision
None detected
(p=0.679)
Moderate
0.53 (0.06 to
1.00)
Unclear
Substanti
al
inconsistency
Yes
Serious
imprecision
Too few
studies to
assess
Low
0.21 (-0.23 to
0.64)
No evidence of
a benefit
Yes
Serious
imprecision
Too few studies to
assess; expert
knowledge of
unpublished
studies
Low
0.41 (-0.12 to
0.94)
No evidence of
a benefit
Yes
Serious
imprecision
Too few
studies to
assess
Low
0.18 (-0.63 to
0.98)
No evidence of
a benefit
SRP +
Nd:YAG laser
3
82
Unclear
Moderate
inconsistency
SRP+erbium
lasers
3
82
Low
Inconsistent
July 2015
benefits are
unclear
Uncertainty in
magnitude of
moderate
benefit balanced
with potential
harms
Page 24
3.2.1
Scaling and root planing (SRP)
General description of studies
Eleven studies met inclusion criteria reporting the effect of SRP compared to no treatment,
supragingival scaling, or debridement on chronic periodontitis.78-87 Six were split-mouth78-83 and
five were parallel-group84-88 trial designs. All studied small sample sizes (from 7 to 43 per
group). The studies were conducted worldwide, including Sweden, China, Germany, Italy, Brazil
and the U.S. from 1983 through 2014.
The severity of periodontal disease was described as moderate to advanced (severe) in five
studies79, 81, 83, 85, 87, advanced (severe) in three studies78, 80, 86, and not stated in two studies82,
but the probing pocket depth of included participants was described as ≥ 5 mm in one study and
attachment loss > 3 mm in another88. One study84 was exclusively on participants with Type 2
diabetes, and another88 exclusively on participants with chronic obstructive pulmonary disease.
One86 of the studies excluded smokers, three79, 82, 83 studies included smokers, but did not
perform a sub-group analysis reporting results by smoking status, and seven78, 80, 81, 84, 85, 87, 88
studies did not mention the smoking status of the participants.
Critical appraisal
Details for each domain and the support for each judgment for each individual study are
presented in Appendix 3. Slightly less than half the study arms were at a low risk of bias for
random sequence generation, one was inadequate, and the rest were unclear as to how
randomization was performed. Four studies reported an adequate concealment procedure for
allocation, two were inadequate, and the rest were unclear as to how allocation was concealed.
Only three studies masked participants, and two masked personnel. The panel noted that SRP
masking from either the participants or personnel would be extremely difficult, and did not weigh
this dimension highly. Most (73%) studies treated the groups the same except for the
intervention. Most studies (64%) masked the outcomes assessor and reported complete
outcomes data. There was no indication of selective reporting in 91% of the studies. The
judgments of high, unclear, or low risk for bias as a percentage of included studies in this
section are depicted by domain in Figure 2. The main issues for bias for this group of studies
were lack of adequate randomization procedures, allocation, and masking of personnel and
participants. The panel judged the overall risk of bias of the included studies as unclear.
July 2015
Page 25
Figure 2. Review authors’ judgment of each risk of bias item as low, unclear, or high as a percent of
included studies
Assessment of publication bias
Since there were over 10 studies included comparing SRP to no treatment, an assessment of
publication bias by visual inspection of the funnel plot as well as Egger’s test were undertaken.
Figure 3 shows the funnel plot with 11 studies and 13 arms. The panel found no evidence of
publication bias (Egger’s test result, p=0.707).
.2
.4
.6
SE Mean Difference
0
Funnel plot with pseudo 95% confidence limits
-1
0
1
2
Mean Difference
Figure 3. Funnel plot of studies on SRP
July 2015
Page 26
Results of intervention
Figure 4 shows the meta-analysis sub-grouped by study design comparing SRP to no
treatment. The overall group mean difference is 0.49 mm gain in clinical attachment level (i.e.,
improvement) with SRP treatment versus no treatment with a 95% CI from 0.36 to 0.62 mm.
Figure 4. Meta-analysis of studies on SRP sub-grouped by study design; mean difference
in units of millimeters.
Notes: Lindhe, used Kahl data for SE calculations, see Appendix for details; Neill, data in figure and text inconsistent, used figure
data; Ng, used final data since change not reported; Berglundh, used Kahl data for SE calculations, see Appendix for details;
Kahl, see details in Appendix for calculations; Rotundo, used final data since change not reported; Jones, Note that very small SE
impacts the weight; however, the data were extracted from the paper figure without adjustment; Van Dyke, used all treated site
change data although data available stratified by pocket depth; converted SE to SD for calculations; Riberio, combined change data
stratified by pocket depth; Chen, calculated change from baseline and final data; divided control "n" by 2 because two intervention
arms; Zhou, calculated change from baseline and final data; divided control "n" by 2 because two intervention arms.
Sensitivity analyses
Because assumptions were made with respect to choosing a correlation coefficient for the
statistical calculations, the sensitivity of the result to these assumptions was investigated. Table
8 shows the impact of changing the correlation coefficient from the initial value of 0.25 to both 0.1 and 0.9. At correlation coefficients of -0.1, the mean difference did not change; however, at
the correlation coefficient of 0.9, the mean difference increased by 0.10 mm. The heterogeneity
did not change at -0.1, and it increased substantially at 0.9. In three studies, problems were
July 2015
Page 27
identified with study methodology78-80, so the SEs were imputed (see Appendix for methods).
The results without these studies are shown in the third row of the table. Results without Jones
are shown in the final row.
Table 8. Summary of sensitivity analyses using the random effects model.
Treatment
SRP
SRP
Without study
with imputed
standard errors†
Without Jones
†
Hetero-
Mean
geneity p-
difference
(%)
value
(mm)
0
0.08
0
75
0.86
<0.00001
0.49
0.59
0.35, 0.62
0.40, 0.78
8
0
0
0.92
0.47
0.33, 0.60
10
0
0
0.62
0.48
0.24, 0.71
Correlation
# of
Hetero-
coefficient
studies
geneity 2
-0.1
0.9
11
11
0.25
0.25
Heterogeneity
I2
95% CI
Lindhe 1983, Berglundh 1998, Kahl 2007
Evidence profile
The summary of findings is summarized in Table 9. The panel judged the overall level of
certainty in the evidence to be moderate. Although there were 10 studies, the number of
participants was small. The panel reminds readers that the studies included in this analysis
randomized patients to receive SRP or no treatment. There are many other clinical studies that
did not meet inclusion criteria that use SRP as the positive control treatment.
Table 9. Evidence profile for SRP treatment versus no treatment.
Therapy
SRP vs. no
treatment
No.
No.
RCTs
participants
11
331
Risk of
bias
Consistency
Applicability
Precision
Publication
bias
Unclear
Consistent
Yes
No serious
imprecision
None
detected
p=0.707
Level of
Certainty
Moderate
*Interpreted as 0.49 mm mean gain in clinical attachment level with SRP treatment, with a 95% CI from 0.36 mm to 0.62 mm
improvement.
Adverse events assessment (potential for harms)
Any type of root planing, including hand and ultrasonic instrumentation, carries the risk of
damaging the root surface and potentially causing tooth/root sensitivity. Generally expected
post-SRP procedural adverse events include discomfort.
One study83 comparing SRP to supragingival debridement (with two other treatments including
lasers that are not described here) measured patient-reported pain, dental hypersensitivity, and
chewing discomfort according to a visual-analog scale. At the end of treatment, there was a
July 2015
Page 28
Mean
difference
in CAL
(mm)
0.49
higher
(0.36 to
0.62)*
statistically significant difference in pain (higher for SRP than supragingival debridement). After
one week, the only statistically significant difference was found in dental hypersensitivity, which
was higher with SRP than supragingival debridement. There were no statistically significant
differences in the three patient-reported indices at 3 or 6 months after treatment. Another
study86 also compared SRP to supragingival debridement, and reported no statistically
significant differences in pain, number of analgesics, fever, or oral ulceration the day of or the
next day after treatment. Two studies81, 84 reported that no adverse events (AEs) occurred, and
five78-80, 82, 85 did not solicit information or report on AEs. There is a report of an increase in
cytokine levels.89 Overall, the panel judged the potential for harms from SRP to be negligible.
Balancing benefits with potential for harms
The panel judged that the moderate benefit of SRP outweighed the potential for harms.
3.2.2
Systemic sub-antimicrobial dose doxycycline + SRP
Sub-antimicrobial dose doxycycline (SDD, Periostat®) treats periodontal disease by a
mechanism called host modulation, which refers to the concept of modulating the host’s
response to the presence of bacteria with methods such as inhibiting collagen-destructive
enzymes.42, 90 Eleven studies61, 62, 91-100 (in 12 publications) met inclusion criteria reporting the
effect of SRP plus LDD versus SRP alone. All were parallel-group trials. There was a varying
range of sample sizes from 7 to 133 per treatment group. The studies were conducted
worldwide including four in the U.S., four in Turkey (three from one author), and one each in the
U.K., India, and Saudi Arabia. The studies were published between 2000 and 2011.
With respect to populations, one study included only geriatric participants62 and two only
diabetics91, 93. The severity of periodontal disease was described as moderate-to-severe in five
of the studies61, 62, 94-97, severe in one study98, and not stated in five studies91-93, 99, 100, but in three
studies the probing pocket depth of included participants was described as > 4 mm99 or ≥ 5 mm
but less than or equal to 891 or 992 mm.
Of the sub-antimicrobial dose doxycycline studies, no other special populations were noted
except smoking status. One study100 included only smokers, seven61, 62, 92, 94-98 included smokers
but did not perform a sub-group analysis, and three91, 93, 99 did not describe the smoking status
of their participants.
July 2015
Page 29
Studies on other host modulators considered to be experimental were excluded from this
section: a study101 on another form of SDD that is administered as a single 40 mg dose
(Oracea®); two studies on bisphosphonates102, 103; and three on other anti-inflammatory
drugs104-106.
Critical appraisal
presented in Appendix 3. Eighty-two percent of the studies were at a low risk of bias for random
sequence generation. Only four studies reported an adequate concealment procedure for
allocation while the other studies did not provide a description. Most of the studies masked the
participants and personnel. All studies treated groups the same except for the intervention. Twothirds of the studies masked the outcomes assessor. Just under half had complete outcomes
data and were judged to be at low risk for attrition bias, while the same number had significant
loss of participants (over 20%) and were judged to be at high risk of attrition bias. No evidence
of selective reporting was found. The judgments of high, unclear, or low risk for bias as a
percentage of included studies in this section are depicted by domain in Figure 5. The main
issue for bias for this group of studies was incomplete outcomes data and the risk for attrition
bias. The panel judged the overall risk of bias of the included studies as unclear.
included studies.
July 2015
Page 30
Since there were over 10 studies included comparing systemic sub-antimicrobial dose
doxycycline plus SRP to SRP alone, an assessment of publication bias by visual inspection of
the funnel plot as well as Egger’s test were undertaken. Figure 6 shows the funnel plot with the
studies identified by their sub-group. The panel found no evidence for publication bias (Egger’s
test, p=0.121).
Figure 6. Funnel plot of studies on SRP plus SDD versus SRP alone.
.4
.6
1
.8
SE Mean Difference
.2
0
-2
-1
0
1
Mean Difference
2
3
Figure 7 shows the meta-analysis for the included studies comparing SRP to SRP plus SDD.
The overall group mean difference is 0.35 mm mean gain in clinical attachment level when SDD
was used adjunctively with SRP versus SRP alone with a 95% CI from 0.15 to 0.56 mm
improvement. One study62 on a population of geriatric participants appears to be primarily
responsible for the observed heterogeneity in these results.
July 2015
Page 31
Figure 7. Meta-analysis of studies on SRP plus SDD versus SRP alone; mean difference in units of
millimeters.
Notes: Caton, Mohammad, Preshaw, Combined change score data that were stratified by disease severity (pocket depth) and
converted SE to SD for calculation; Emingil (all three citations, 2004, 2008, 2011) and Gurkan, Study site data used in preference
to whole mouth or pocket-depth-stratified data; change scores calculated; Haffajee, Change score provided; SE converted to SD;
data estimated from figure; Needleman, ANCOVA results; 95% CI 0.64, 0.18; Al Mubarak, Calculated change from baseline and
final data; converted SE to SD; data from experimental sites only; Deo, Error in manuscript and stated change score SD judged to
be SE therefore converted;.
10 shows the impact of changing the correlation coefficient from the initial value of 0.25 to both 0.1 and 0.9. At both correlation coefficients -0.1 and 0.9, the mean difference and 95% CI did
not change appreciably from those found at the initial value of 0.25. At all correlation
coefficients, there is a very small amount of true between-study variation. The summary
estimate is judged not to be sensitive to the assumptions that were made.
Adjunctive
Treatment
Correlation
coefficient
N of
studies
Heterogeneity
2
Heterogeneity
I2 (%)
Heterogeneity
P-value
SRP+SDD
SRP+SDD
-0.1
0.9
11
11
0.04
0.04
43
51
0.06
0.03
July 2015
Mean
difference
(mm)
0.35
0.36
Page 32
95% CI
0.15, 0.56
0.18, 0.54
Evidence profile
The evidence profile is summarized in Table 11. The panel judged the overall level of certainty
in the evidence to be moderate based on the quantity of evidence, the overall risk of bias, the
consistency, applicability, and no evidence of publication bias.
Table 11. Evidence profile for SRP+systemic low dose doxycycline versus SRP alone.
Therapy
No.
No.
RCTs
participants
Risk of
bias
Consistency
Applicability
Precision
Publication
bias
Level of
Certainty
None
detected
Moderate
p=0.121
*Interpreted as 0.35 mm mean gain in clinical attachment level with systemic LDD adjunctive use with SRP versus SRP alone, with
SRP + SDD
vs. SRP
11
813
Unclear
Moderate
inconsistency
Yes
No serious
imprecision
a 95% CI from 0.15 mm to 0.56 mm improvement.
The studies reported that SDD was well tolerated92, 94-97 with no participants reporting AEs93-97 or
that the incidence of AEs was similar between the SDD and placebo groups92, 107. The AEs that
were judged to possibly be related to SDD were dizziness92, 99 and tachycardia99. In one study,
AEs were only reported in the placebo group100. Three studies did not report on AEs62, 91, 98.
The FDA label108 lists the following warnings for Periostat® (this is a partial list, and includes
warnings for the tetracycline class of drugs): May cause permanent discoloration of the teeth
during tooth development; enamel hypoplasia reported; special consideration should be given to
pregnant women; may cause an increase in BUN; photosensitivity manifested by sunburn
reaction has been observed, and patients are advised to avoid exposure to direct sunlight or
ultraviolet light.
The FDA label108 lists special precautions such as overgrowth of nonsusceptible
microorganisms including fungi, and caution is advised for those with a history of predisposition
to oral candidiasis.
The FDA label108 lists the most frequent adverse reactions that occurred during clinical trials as
headache, common cold, flu symptoms, and toothache. Other adverse reactions to tetracyclines
are listed.
The panel judged that antimicrobial resistance should not be a factor at sub-antimicrobial dose.
Overall, the panel judged the potential for harms from SDD was negligible.
July 2015
Page 33
Mean
difference in
CAL (mm)
0.35 higher
(0.15, 0.56)*
The panel judged the small benefit outweighs the potential for harms.
3.2.3
Systemic antimicrobials + SRP
Twenty-four studies78, 80, 82, 99, 109-128 met inclusion criteria reporting the effect of SRP plus a
systemic antimicrobial versus SRP alone. All were parallel-group trials. The sample sizes were
relatively small, ranging from 7 to 46 per treatment group. The studies were conducted
worldwide including three in the U.S.; three in Sweden and Brazil; two each in Switzerland,
Germany, , India, and Japan; one each in Canada, England, Greece, Norway, Spain, and
Turkey; and one in both the U.S. and Sweden. The studies were published between 1983 and
2014.
The panel decided to combine all antimicrobials into one treatment class for an overall analysis
and one evidence profile. The studies reported on five major groups of antimicrobials:
amoxicillin/metronidazole combination therapy78, 110, 111, 113, 121, 126, metronidazole99, 118, 127,
erythromycin analogues (azithromycin112, 115, 117, 122-125 and clarithromycin119), moxifloxacin114 (a
fourth generation fluoroquinolone antibacterial agent), and others, e.g., tetracycline80, 109, 120 and
doxycycline128 82, 114 (antimicrobial dose of doxycycline, not to be confused with sub-antimicrobial
dose, which is covered in a separate section).
One of the studies110 described the severity of the disease of included participants as slight,
one117 included only participants with moderate disease, seven113, 115, 116, 118, 119, 125, 128 included
participants with moderate-to-severe (or advanced) disease, nine78, 80, 109, 112, 114, 120-122 included
participants with severe/advanced disease, and six did not state the severity of disease, but
described the probing pocket depth as ≥4 mm99, 123, ≥5 mm82, 126, 127, or ≥ 6 mm111. Two studies
included only diabetics.126, 128
Seven112, 119, 121, 123-125, 128 of the studies excluded smokers, eight82, 99, 110, 113, 114, 116, 117, 120 included
smokers but did not perform a sub-group analysis reporting the results by smoking status, six78,
80, 109, 111, 126, 127
studies did not mention the smoking status of the participants, one115 study
included only smokers, and one118 study reported results sub-grouped by smoking status.
There was a variety of dosing regimens for each systemic antimicrobial drug. Table 12 lists the
dosing regimens by drug and study citation.
July 2015
Page 34
Table 12. Systemic antimicrobial dosing regimens used in research studies
Drug
Dose
Timing
Author/citation
AMX/MET
375 mg AMX+250 mg MET
tid for 14 days
Berglundh 1998
AMX/MET
tid for 7 days
Cionca 2009
AMX/MET
tid for 8 days
Flemmig 1998
AMX/MET
500 mg AMX bid + 250 mg MET tid for 14 days
Goodson 2012
AMX/MET
tid for 14 days
Miranda 2014
AMX/MET
375 mg AMX+ 250 mg MET
tid for 7 days
Mombelli 2005, Ribeiro
2009
Metronidazole
250 mg
tid for 14 days
Haffajee 2007
Metronidazole
200 mg
tid for 7 days
Palmer 1998, 1999
Metronidazole
400 mg
tid for 10 days
Preus 2013
Azithromycin
Dose not stated
qd 3 days prior to SRP
Gomi 2007
Azithromycin
500 mg
qd for 3 days
Haffajee 2007, Oteo
2010
Azithromycin
500 mg
qd for 3 days
Han 2012
Azithromycin
500 mg
qd for 3 days
Martande 2014
Azithromycin
250 mg bid first day / 250 mg qd following 4 days
Mascarenhas 2005
Azithromycin
500 mg
qd 5 days
Sampaio 2011
Azithromycin
500 mg
qd 3 days prior to SRP
Yashima 2009
Clarithromycin
500 mg
bid for 3 days
Pradeep 2011
Moxifloxacin
400 mg
qd for 7 days
Guentsch 2008
Tetracycline
250 mg
Every 6 hours for 14 days
Al-Joburi 1989
Tetracycline
Tetracycline
250 mg qid for 2 weeks / 250 mg qd for 48 weeks
250 mg
qid for 3 weeks
Lindhe 1983
Ramberg 2001
Doxycycline
200 mg first day / 100 mg per day for 9 days
Guentsch 2008
Doxycycline
200 mg first day / 100 mg per day for 6 weeks
Ng 1998
Doxycycline
200 mg loading dose, then
100 mg
qd for 20 days
Tsalikis 2014
Qd=once per day; bid=twice per day; tid=three times per day; qid=four times per day
Critical appraisal
presented in Appendix 3. Over half the studies were at a low risk of bias for random sequence
July 2015
Page 35
generation. Only six studies reported an adequate concealment procedure for allocation, one
reported a procedure at high risk of bias, while the other studies did not provide a description.
Half the studies did not mask the participants and personnel. Most studies (80%) treated groups
the same except for the intervention. Seventy percent masked the outcomes assessor. Almost
60% had complete outcomes data, and 67% were judged to be at low risk for selective reporting
bias. The judgments of high, unclear, or low risk for bias as a percentage of included studies in
this section are depicted by domain in Figure 8. The main issues for bias for this group of
studies were lack of masking of personnel and participants and unclear allocation concealment.
The panel judged the overall risk of bias of the included studies as unclear.
included studies.
Since there were over 10 studies included comparing systemic antimicrobials plus SRP to SRP
alone, an assessment of publication bias by visual inspection of the funnel plot as well as
Egger’s test were undertaken. Figure 9 shows the funnel plot with the studies identified by their
sub-group. The panel found no evidence for publication bias (Egger’s test, p=0.803).
July 2015
Page 36
Figure 9. Funnel plot of studies on SRP plus systemic antimicrobials.
1.5
1
Test SD
.5
0
-4
-2
0
Test Mean
2
4
Figure 10 shows the meta-analysis for the included studies comparing SRP to SRP plus
systemic antimicrobials sub-grouped by systemic antimicrobial type. The overall group mean
difference is 0.35 mm mean gain in clinical attachment level when systemic antimicrobials were
used adjunctively with SRP versus SRP alone with a 95% CI from 0.20 to 0.51 mm
improvement.
July 2015
Page 37
Figure 10. Meta-analysis of studies on SRP plus systemic antimicrobials versus SRP alone, subgrouped by antimicrobial type; mean difference in units of millimeters.
Notes: 1.1.1 - Berglundh, see appendix for SE calculations; Flemmig, stratified site data combined; SE averaged from other
studies in the subgroup; Mombelli, see appendix for MD and SE calculations; Riberio, stratified site data combined for mean and
SD of change score; Cionca, no adjustments necessary; Goodson, SE converted to SD to calculate SE of difference in change
July 2015
Page 38
score; Miranda, Stratified site data combined for mean and SD of change score; 1.1.2 - Palmer 1999, data are identical to Palmer
1998 where the population was combined; Haffajee, use change data, but figure SE unclear, but estimated at 0.1 mm then
calculated SE of difference; divide control group n by 2 since 2 test arms; used all site data although results for PD> 6 mm available;
Preus, Change score provided; converted 95% CI to SD; 1.1.3 - Mascarenhas, used all sites data although data stratified by PD
are available; although error data stated SE, it was judged to be SD; change score calculated with time correlation coefficient; Gomi
2007, change score means calculated from baseline and final results; Haffajee, see section 1.1.2; Yashima, used change score
data; divided control n by 2 since two test arms; calculated SE from SD of change score and n; Oteo 2010, converted SE to SD to
calculate difference SE; Sampaio, used full mouth change scores although stratified data available; Han, No adjustments
necessary; Martande, No adjustments necessary; 1.1.4 - Pradeep, change scores used at 9 months; 1.1.5 - Guentsch, used
change score data and calculated SE from SD in paper and divided control n by 2 since 2 treatment arms; 1.1.6 - Lindhe, see
appendix for SE calculations; Al-Joburi, calculated combined score from stratified data for baseline and final data, then used time
correlation coefficient for difference calculations; Ng, see appendix for SE calculations; Ramberg, used change score data and
calculated SE from SD in paper; number of participants at 1 year not reported so used conservative estimate of number at 13 years;
Guentsch, see 1.1.5; Tsalikis, Used change score data and calculated SE from SD in paper.
coefficients, there is a small amount of variation, the majority of which is due to true betweenstudy variation.
Three studies in the AMX/MET sub-group and two studies in the tetracycline sub-group did not
report standard deviations or standard errors, or there were concerns with the reported standard
deviations, so standard errors were estimated. The third row of the table (Systemic
antimicrobials, without studies with estimated standard errors) shows the mean difference and
95% CI with those studies excluded from the calculation; the results of which indicate that their
inclusion did not substantially impact the summary estimates of mean difference. The fourth row
(AMX/MET sub-group, without studies with estimated standard errors) shows the effect of
eliminating three studies from AMX/MET sub-group on the results. The mean difference has
increased from 0.39 to 0.46, and the 95% CI widens and the result becomes less precise.
One study119 on clarithromycin appears to be primarily responsible for the heterogeneity in the
results and the presence of sub-group differences. When this study is removed from the metaanalysis, the mean difference decreases and the overall heterogeneity decreases.
July 2015
Page 39
Adjunctive
Treatment
Systemic
antimicrobials
Systemic
antimicrobials
Systemic
antimicrobials,
without studies
with estimated
standard errors†
AMX/MET subgroup, without
studies with
estimated
standard errors††
Without
clarithromycin
(Pradeep)
Correlation
coefficient
# of
studies
Heterogeneity 2
Heterogeneity
I2 (%)
Heterogeneity
p-value
Mean
difference
(mm)
-0.1
24
0.11
75
<0.00001
0.35
0.19, 0.50
0.9
24
0.14
82
<0.00001
0.39
0.23, 0.55
0.25
19
0.11
78
<0.00001
0.33
0.16, 0.49
0.25
3
0.25
83
0.0004
0.46
-0.09, 1.01
0.25
23
0.04
51
0.001
0.29
0.17, 0.41
95% CI
†
Ng 2008, Berglundh 1998, Flemmig 1998, Lindhe 1983, and Mombelli 2005
††
Berglundh 1998, Flemmig 1998, and Mombelli 2005
Evidence profile
in the evidence to be moderate based on the quantity of evidence, the overall risk of bias, the
consistency, applicability, and lack of evidence of publication bias.
Table 14. Evidence profile for SRP+systemic antimicrobials versus SRP alone.
Therapy
No.
No.
RCTs
participants
Risk of
bias
Consistency
Applicability
Precision
Publication
bias
Level of
Certainty
SRP+systemic
None
Substantial
No serious
antimicrobials
24
1086
Unclear
Yes
detected
Moderate
inconsistency
imprecision
vs. SRP alone
p=0.803
*Interpreted as 0.35 mm mean gain in clinical attachment level with SRP plus systemic antimicrobial adjunctive use versus SRP
alone, with a 95% CI from 0.20 mm to 0.51 mm improvement.
In the amoxicillin/metronidazole sub-group of studies, gastrointestinal problems such as
diarrhea and cramps were observed more often in the test group than the placebo group110, 111,
126
; as well as nausea/vomiting, headache, and metallic taste126; however, there were no
statistically significant differences compared to placebo126. One study113 reported no serious
July 2015
Page 40
Mean
difference in
CAL (mm)
0.35 higher
(0.20 to
0.51)*
adverse events associated with any of the treatments, but one participant dropped out of the
test group because of nausea and vomiting and another developed candidiasis. One study121
reported no acute problems such as periodontal abscesses during the study period. The
study121 also reported nausea and diarrhea in four test and three control participants. Two
studies78, 116 did not report on adverse events.
In the metronidazole sub-group of studies, two adverse events were reported in one study99 in
the test group: dizziness and diarrhea. One study reported diarrhea, nausea/headache, feeling
unwell, metallic taste, and dizziness, occurring more often with metronidazole, but the
differences compared to placebo were not statistically significant127. The other study118 did not
report on adverse events.
In the azithromycin sub-group of studies, these events were possibly associated with the use of
the drug: diarrhea112, 117, 122, 123, allergic reaction99, and difficulty swallowing the tablets99. One
study124 reported no adverse events, and two studies115, 125 did not report on adverse events.
With respect to clarithromycin, no adverse reactions or discomfort were reported by the test
group, except for unpalatable taste and mild gastric intolerance.119
With respect to moxifloxacin, no adverse events were reported.114 However, the FDA issued a
box warning for this drug as being associated with increased risk of tendinitis and tendon
rupture, exacerbation of muscle weakness in persons with myasthenia gravis and associated
breathing problems.
With respect to tetracycline, one study reported a case of severe diarrhea109. Two studies did
not report on adverse events.80, 120
For doxycycline, one study reported no adverse events114 and the other two did not report on
adverse events.82, 128
Antimicrobials as a class of drugs are well known to cause allergic reactions in some people.
Other adverse effects are commonly reported (this list is not exhaustive) such as rash, diarrhea,
abdominal pain, and/or nausea/vomiting. Additionally, the overuse of antimicrobials promotes
the development of resistant strains of bacteria, which are a risk to the population. In general,
this class of drugs should be reserved for short-term (less than 21 days) use only, although
lower doses may be acceptable over a longer time period.
July 2015
Page 41
Lastly, if antimicrobials are overused or misused, there is the risk of the development of
antimicrobial-resistant bacteria.129
The panel judged the small benefit is likely to be balanced with the potential for harms.
3.2.4
Locally-delivered antimicrobials + SRP
Three therapies are included in this section on locally-delivered antimicrobials as adjuncts to
SRP: chlorhexidine (CHX) chips, doxycycline hyclate gel, and minocycline microspheres.
Several studies were excluded from this section because the local antimicrobial products were
used as stand-alone applications and not as adjuncts to SRP.130-132 Another category causing
exclusion is lack of commercial availability of the product in the U.S., such as tetracycline fibers
(“Actisite”) or strips133-143, minocycline gel144-147, metronidazole gel (“Elyzol”)148-155, clarithromycin
gel156, 157, azithromycin gel158, CHX varnish,159-161 CHX gel,162-166 and other researcher-prepared
gels such as EDTA gel167 and chitosan gel168.
3.2.4.1 CHX chip + SRP
Six studies compared the effects of SRP plus the local delivery of chlorhexidine chips to SRP
alone on chronic periodontitis.169-174 Four were split-mouth169, 171-173 and two were parallelgroup170, 175 trial designs. All but two172, 173 had small sample sizes (ranging from 12 to 25
participants per group); the larger studies included between 82 and 116 participants per
treatment arm. The studies were conducted in Turkey, Greece, the U.K., Italy, and Germany
from 2001 through 2011.
All studies included participants with moderate-to-severe (or advanced) chronic periodontitis as
described by the authors or assessed from their inclusion criteria.
Four studies170-173 excluded smokers (one170 excluded “heavy” smokers, defined as smoking
more than 10 cigarettes per day), one175 included smokers but did not separate the results by
smoking status, and one169 did not report smoking status. Because of the variety of smoking
inclusion/exclusion criteria, we were unable to determine if the treatment effects differed in
smokers and non-smokers.
The extracted data are presented in two tables in Appendix 3, one table each for study
characteristics and CAL data.
July 2015
Page 42
Several studies were excluded from this category for the following reasons. In several CHX chip
studies (Grisi et al.176, Jeffcoat et al.177, Jeffcoat et al.178, Mizrak et al.179, Soskolne et al.180) sites
with CAL greater than or equal to 5 mm that remained after the baseline chip placement were
retreated with new CHX chips. The panel excluded these studies from the analysis because the
control subjects with failing sites were not retreated in any manner, leading to a design bias in
favor of the CHX chip. Another study (Rodrigues et al. 181) placed the chip three months after
SRP, which the panel judged to be part of maintenance therapy and not adjunctive to SRP.
Critical appraisal
Details for each domain are presented in Appendix 3. Half the studies reported an adequate
method of randomization, while half did not describe the randomization method. No studies
reported methods for allocation concealment. In all studies, either the participant or the clinician
was unmasked or their masking was unclear. In all studies but one173, the groups were treated
the same except for the intervention. The outcomes assessor was masked in five studies, but in
one169 the masking was unclear. Three of the studies had less than 10% drop-outs, one had
11%, and two did not report this information. There was some indication of selective reporting in
two studies172, 173 where mistakes in reporting were noted as omissions in data reporting. The
judgments of high, unclear, or low risk for bias in this section are depicted by domain in Figure
11. Because many domains of the included studies were judged to have unclear and/or high risk
of bias, the panel judged the risk of bias from this body of evidence as unclear.
July 2015
Page 43
included studies.
chlorhexidine chips sub-grouped by study design. The overall group mean difference is 0.40
mm mean gain (95% CI: 0.24 to 0.56 mm) in clinical attachment level (i.e., improvement) when
chlorhexidine chips were used adjunctively with SRP treatment versus SRP alone. There was
no statistically significant difference between the group means according to study design.
July 2015
Page 44
Figure 12. Meta-analysis of studies on SRP plus CHX chip versus SRP alone, sub-grouped by
study design; mean difference in units of millimeters.
Notes: Heasman, CAL change score reported and used; 2002, CAL change score provided in graphical form (endpoint data not
reported); converted SE to SD; Azmak, CAL change score provided in graphical form (endpoint data not reported); converted SE to
SD; Paolantonio (A), "all site" RAL change score estimated from Figure 4a in publication and converted SE to SD; Paolantonio
(B), final data used; Dimitra, CAL change score calculated; Gonzales, mean CAL gain reported but no SD, averaged SDs from 4
other studies to impute the SD.
The split-mouth trials showed a statistically significant effect with chlorhexidine chip use,
whereas the parallel-group trials did not; however, subgroup analysis indicated no difference
between the subgroups.
15 shows the impact of changing the correlation coefficient from the initial value of 0.25 to both 0.1 and 0.9. At a correlation coefficient of -0.1, neither the mean difference nor the
heterogeneity statistics changed substantially. At a correlation coefficient of 0.9, the mean
difference remains statistically significant favoring adjunctive CHX chip use, but the magnitude
of the mean difference has decreased. The amount of between study variation is small and a
large proportion of it is true and not due to random error. One study170 did not report an SD, so it
was imputed by averaging the SDs from the other studies in this category. The results without
this study are shown in the final row of the table. The results remain similar to those including
the study, although I2 increased slightly.
July 2015
Page 45
Mean
Correlation
N of
Heterogeneity
Heterogeneity
Heterogeneity
coefficient
studies
2
I2 (%)
P-value
CHX chip
-0.1
6
0.00
0
0.54
0.41
CHX chip
0.9
6
0.04
81
<0.0001
0.32
CHX chip
without
Gonzales
0.25
5
0.01
28
0.24
0.39
Treatment
95%
difference
CI
(mm)
0.25,
0.58
0.15,
0.50
0.21,
0.58
Evidence profile
The summary of findings is shown in Table 16. The panel judged the overall level of certainty in
the evidence to be moderate based on the quantity of evidence, the overall risk of bias, the
consistency, and applicability of the data to U.S. populations.
Table 16. Evidence profile for SRP+CHX chip versus SRP alone
Mean
difference
in CAL
Precision
(mm)
Too few
0.40 higher
SRP+CHX
No serious
6
316
Unclear
Consistent
Yes
studies to
Moderate
(0.24 to
chip vs. SRP
imprecision
assess
0.56)*
*Interpreted as 0.40 mm mean gain in clinical attachment level with SRP plus chlorhexidine chip use versus SRP alone, with a 95%
Therapy
No.
No.
RCTs
participants
Risk of
bias
Consistency
Applicability
Publication
bias
Level of
Certainty
CI from 0.24 mm to 0.56 mm improvement.
Two of the six included studies assessed and reported about adverse events. Dimitra et al.174
reported there were no patient-reported adverse effects, such as discomfort, pain or swelling,
resulting from chlorhexidine chip placement. Heasman et al.171 reported one non-treatmentrelated aphthae on the buccal mucosa. According to FDA prescribing information, the most
frequently observed adverse events were toothache, upper respiratory tract infection, and
headache.182 The only adverse event with frequency of occurrence that was statistically
significantly higher than the placebo group was toothache. Oral pain or sensitivity may occur
during the first week after SRP and chip placement, although in some cases it may occur later,
but it is typically mild to moderate in severity and is expected to resolve within days.
Postmarketing surveillance reports that anaphylaxis, as well as serious allergic reactions, have
occurred with dental products containing chlorhexidine.182
July 2015
Page 46
The panel notes that the products should be applied according to the manufacturers’ general
instructions.
The panel judged that there is a balance between a moderate benefit and potential harms.
3.2.4.2 Doxycycline Hyclate Gel + SRP
Three small studies met inclusion criteria reporting the effect of SRP plus the local delivery of
doxycycline hyclate gel compared to SRP alone.183-185 Two studies184, 186 reported on the same
participants and are included as one set of data with preference given to the 6-month study184
results because more participants were included. Two124, 126 were split-mouth183, 185 and one184
was a parallel-group trial. The sample sizes ranged from 10 to 22 participants per group. One
study was conducted in Turkey183 and the other two in Brazil.184, 185 The studies were conducted
between 2004 and 2006. All participants in the Martorelli de Lima et al. study185 had Type I
diabetes mellitus.
The participants in two183, 185 of the studies were diagnosed with advanced chronic periodontitis,
whereas the disease severity in the participants in the other study184 was not reported.
Machion et al.184 included only smokers, whereas Agan et al.183 and Martorelli de Lima et al.185
did not describe the smoking status of the participants. Because of the variety of smoking
inclusion/exclusion criteria, no further sub-analyses determined if the results were different for
smokers versus non-smokers.
One study was excluded because the concentration of doxycycline hyclate (14%) in the product
is not commercially available in the U.S.187 One study188 reported on the effects of doxycycline
hyclate gel in smokers, but the study was excluded because 1) it combined subpopulations from
two randomized studies and an open label study with no control arm; and 2) the patients were
included in other unpublished trials189 included in the analysis.
Critical appraisal
presented in Appendix 3. Only one study183 reported an adequate method of randomization,
while the others did not describe the specific randomization method used. No studies reported
methods for allocation concealment. In only one study185 were both the participants and
clinicians masked; in one study183 it was unclear if both were masked; and in one study184 the
July 2015
Page 47
clinicians were masked but not the participants. In all three studies the groups were treated the
same except for the intervention. In one study184 the outcomes assessor was masked, whereas
in the other two studies their masking was unclear. All studies had low risk of attrition bias.
There was low risk of selective reporting bias. The judgments of high, unclear, or low risk for
bias as a percentage of included studies in this section are depicted by domain in Figure 13.
Because all domains of the studies are at low or unclear risk of bias, and the impact of those
domains judged to be at unclear risk of bias on the summary estimate of effect is not known, the
overall assessment for the risk of bias for this body of evidence was judged to be unclear.
included studies (there were 3 studies).
doxycycline hyclate gel sub-grouped by study design. The overall group mean difference is 0.64
mm (95% CI, 0.00 to 1.28) mean gain in clinical attachment level (i.e., improvement) when
doxycycline hyclate gel was used adjunctively with SRP versus SRP alone. Since there are only
three trials with wide and overlapping confidence intervals, the effect of study design was not
statistically significant (p=0.80).
July 2015
Page 48
Figure 14. Meta-analysis of studies on SRP plus doxycycline hyclate gel versus SRP alone, subgrouped by study design; mean difference in units of millimeters.
Notes: Martorelli de Lima, used endpoint data, and SE converted to SD for data adjustments; Agan, CAL gain reported but not SD,
SE imputed by averaging SEs from the other two studies; Machion, used Machion (2004) 6-month data over Machion (2006) 12month data because n is higher for the earlier study, also used all pocket data over pocket-depth-stratified data; reported the mean
difference and SD between baseline and final CAL so no r adjustment necessary.
17 shows the impact of changing the correlation coefficient from the initial value of 0.25 to both 0.1 and 0.9. At a correlation coefficient of -0.1, the mean difference decreased slightly from
0.64 mm to 0.60 mm and no longer touched the line of no effect and statistical heterogeneity
decreased. At a correlation of 0.9, the mean difference increased to 0.76 mm, but became more
imprecise, crossing the line of no effect. Statistical heterogeneity also increased. One study
(insert Agan) did not report an SD, so it was imputed. The results without this study are shown
in the final row of the table. In this case, the mean difference increased to 0.93 mm and barely
crossed the line of no effect. The mean difference is judged to be somewhat sensitive to the
assumptions that were made.
July 2015
Page 49
Treatment
Hetero-
Mean
geneity P-
difference
(%)
value
(mm)
0.08
26
0.26
0.60
0.03, 1.17
3
0.44
86
0.001
0.76
-0.05, 1.57
2
0.28
55
0.14
0.93
-0.01, 1.86
Correlation
N of
Hetero-
coefficient
studies
geneity 2
-0.1
3
0.9
0.25
Doxycycline
hyclate gel
Doxycycline
hyclate gel
Doxycycline
hyclate gel
without
Agan et al.
Heterogeneity
I2
95% CI
Evidence profile
Table 18 summarizes the evidence profile for SRP + doxycycline hyclate gel versus SRP alone.
The panel judged the overall level of certainty in the evidence to be low based on the quantity of
evidence, the overall risk of bias, the consistency, and applicability of the data to U.S.
populations.
Table 18. Evidence profile for SRP+doxycycline hyclate gel versus SRP alone.
Therapy
No.
No.
RCTs
participants
Risk of
bias
Consistency
Applicability
Precision
Publication
bias
Level of
Certainty
SRP+
Serious
Too few
doxycycline
Moderate
3
64
Unclear
Yes
imprecisio
studies to
Low
hyclate gel vs.
inconsistency
n
assess
SRP
*Interpreted as 0.64 mm mean gain in clinical attachment level with SRP plus doxycycline hyclate gel versus SRP alone, with a 95%
CI from 0.00 mm to 1.28 mm improvement.
Adverse events were recorded from 1) included articles; 2) articles where the product was used
for at least six months, but not as an adjunct to SRP; 3) articles without CAL data but with
adverse event information; and 4) adverse events available from the FDA.
From the included studies, adverse events either were not described by the authors or none
were reported by the participants. Two excluded studies reported adverse reactions as follows:
Wennstrom et al.190 reported that 34% of participants reported adverse events after the initial
phase of treatment, but that there was no difference in the frequency of adverse events between
the experimental and control arms of the trial. The majority of the reported events was related to
July 2015
Page 50
Mean
difference
in CAL
(mm)
0.64 higher
(0.00 to
1.28)
mild or moderate gingival soreness and thermal tooth sensitivity following treatment. Garrett et
al.191 reported that a large majority of adverse events that were probably or possibly related to
treatment were related to moderate gingival soreness following treatment, and that no subjects
withdrew from the trial who were in the doxycycline hyclate gel arm. The authors noted that no
subjects experienced oral candidiasis.
The FDA label192 lists the following warnings for Atridox® (this is a partial list): May cause
permanent discoloration of the teeth during tooth development (pregnant women, infancy, or
childhood to age eight); Enamel hypoplasia reported; Photosensitivity manifested by sunburn
reaction has been observed; avoid exposure to direct sunlight or ultraviolet light; May result in
overgrowth of nonsusceptible microorganisms including fungi; Caution with a history of
predisposition to oral candidiasis; other potential adverse reactions: headache, gum discomfort
(pain/soreness), toothache, periodontal (abscess, exudate, infection, drainage, extreme
mobility, suppuration), thermal tooth sensitivity, sore mouth, premenstrual tension syndrome,
muscle aches, common cold, respiratory flu, stuffy head, post nasal drip, congestion, sore
throat. The FDA label192 lists these adverse reactions from clinical trials of over 1,400
participants: 1.6% of participants on Atridox® reported “unspecified essential hypertension”,
while only 0.2% in the vehicle control arm and none in either the SRP or oral hygiene instruction
arms reported this adverse event. There is no known association of oral doxycycline hyclate use
with essential hypertension. Two participants in the placebo group and none in the Atridox®
group reported localized allergic response.
This product has not been clinically tested in pregnant women or immunocompromised
participants.192
Since the benefits are unclear, the panel judged that there is uncertainty in the balance between
benefits and harms.
3.2.4.3 Minocycline Microspheres + SRP
Three small87, 193, 194 and two relatively large and unpublished new drug application (NDA)
studies (“Study 103A” and “Study 103B” available in one document189) met inclusion criteria
reporting the effect of SRP plus the local delivery of minocycline microspheres compared to
SRP alone. The sample sizes in the small studies ranged from 10-15 participants per group,
July 2015
Page 51
whereas the unpublished study sample sizes ranged from 121-128 per group. One study was a
split-mouth design,193 whereas the others were parallel-group. One study was conducted in New
Zealand193, one in Slovenia194, and the others in the U.S. in the time period between 2000 and
2004. The severity of periodontitis was moderate to severe (or “advanced”) for all studies except
one194, for which disease severity was not reported. Four studies included smokers but did not
perform sub-analysis189, 193, 194; and one87 did not indicate the smoking status of the participants.
All participants in Skaleric et al.194 had Type I diabetes.
Critical appraisal
presented in Appendix 3. None of the studies described the specific randomization method used
or methods for allocation concealment. None of the studies masked the personnel, and only one
clearly masked the participants. In all studies the groups were treated the same except for the
intervention. In four of the five studies the outcomes assessor was masked, whereas in the
other studies it was unclear. All studies had low risk of attrition bias due to less than 10% lost to
follow-up, except one,87 in which case the risk to bias was judged to be unclear because of up to
20% lost to follow-up. There was uncertainty in the risk of selective reporting bias in two
unpublished studies189 because CAL data were not included in the study publication195;
however, CAL was not listed as the studies' primary outcome measure. Note that the critical
appraisals for the two unpublished data sets189 are based on Williams et al.,195 since it contains
methodological details that are not available in the unpublished source. The judgments of high,
unclear, or low risk for bias as a percentage of included studies in this section are depicted by
domain in Figure 15. Because most of the studies are at low or unclear risk of bias, and the
impact of the lack of masking of participants and personnel on the summary estimate of effect,
the overall assessment for the risk of bias for this body of evidence was judged to be unclear.
July 2015
Page 52
included studies. Note: Williams served as proxy for evaluating the methodology of two unpublished NDA
reports (four studies in this assessment).
minocycline microspheres sub-grouped by study design. The overall group mean difference is
0.24 mm mean gain in clinical attachment level (i.e., improvement) when minocycline
microspheres were used adjunctively with SRP versus SRP alone with a 95% CI from -0.06 to
0.55 mm. The effect of study design was not shown to be statistically significant.
With respect to split-mouth trials, there can be concern about a carryover effect between treated
and untreated sites in the same mouth, which would create a bias toward the null (a
conservative bias). Henderson et al.193, however, compared the effect of minocycline on
adjacent and remote sites, and concluded there was no carryover effect.
July 2015
Page 53
Figure 16. Meta-analysis of studies on SRP plus minocycline microspheres versus SRP alone,
sub-grouped by study design; mean difference in units of millimeters.
Notes: Henderson, used n at baseline (final n not reported), and combined control groups (adjacent and remote sites); Studies
103A and 103B reported the mean difference and SD between baseline and final CAL so no  adjustment necessary; Van Dyke,
used all treated sites data although data stratified by pocket depth are available, and also converted SE to SD, reported the mean
difference and SD between baseline and final CAL so no  adjustment necessary; Skaleric, change score and time correlation
calculated.
19 shows the impact of changing the correlation coefficient from the initial value of 0.25 to both 0.1 and 0.9. At a correlation of -0.1, the mean difference decreased from 0.24 mm to 0.16 mm
and still crossed the line of no effect. At a correlation coefficient of 0.9, the mean difference
increased to 0.49 mm, and no longer crossed the line of no effect. The mean difference is
judged to be sensitive to the assumptions that were made, contributing to the low level of
certainty in the evidence.
Treatment
Minocycline
microspheres
Minocycline
microspheres
July 2015
Correlation
coefficient
N of
studies
Heterogeneity
2
Heterogeneity
I2 (%)
Heterogeneity
P-value
Mean
difference
(mm)
-0.1
5
0.01
14
0.32
0.16
0.9
5
0.20
83
<0.0001
0.49
95%
CI
-0.08,
0.41
0.05,
0.93
Page 54
Evidence profile
Table 20 summarizes the panel's findings. The panel judged the overall level of certainty in the
evidence to be low based on the quantity of evidence, the overall risk of bias, the consistency,
and applicability of the data to U.S. populations.
Table 20. Evidence profile for SRP+minocycline microspheres versus SRP alone.
Therapy
No.
No.
RCTs
participants
Risk of
bias
Consistency
Applicability
Precision
Level of
Certainty
Publication
bias
SRP + minoToo few
cycline
Moderate
Serious
5
572
Unclear
Yes
studies to
Low
microspheres
inconsistency
imprecision
assess
vs. SRP
*Interpreted as 0.24 mm mean gain in clinical attachment level with SRP plus minocycline microspheres versus SRP alone, with a
95% CI from 0.06 mm worsening to 0.55 mm improvement.
Adverse events were recorded from 1) included articles; 2) articles where the product was used
for at least six months, but not as an adjunct to SRP; 3) articles without CAL data, but with
adverse event information; and 4) adverse events available from the FDA.
From the included studies, Van Dyke et al.87 reported one adverse event (black hairy tongue)
that was ruled to be possibly drug-related. Other adverse events were reported but judged not
to be related to study medication. There was no significant difference in intensity and extent of
tooth staining at any assessment point between groups that received or did not receive
minocycline. There were no abnormal clinical chemistry or haematological results observed in
the study for any of the groups.
Williams et al.195 (the CAL data from which are included in Studies 103A189 and 103B189)
reported no dramatic differences between groups. Adverse events were reported by 62.4% and
68.3% of participants in control and combination therapy groups respectively. The incidence of
adverse events was similar among treatment groups. The most common adverse events
included headache, dental infection, increased periodontitis, tooth sensitivity, tooth caries,
dental pain, gingivitis, and stomatitis. No clinically significant changes in vital signs or oral hard
or soft tissues were noted in these studies.
The FDA label196 lists the following warnings for Arestin® (this is a partial list, and includes
warnings for the tetracycline class of drugs): May cause permanent discoloration of the teeth
July 2015
Page 55
Mean
difference in
CAL (mm)
0.24 higher
(-0.06 to
0.55)*
during tooth development; enamel hypoplasia reported; special consideration should be given to
pregnant women; photosensitivity manifested by sunburn reaction has been observed, avoid
exposure to direct sunlight or ultraviolet light. Special precautions include hypersensitivity
reactions not limited to anaphylaxis and serious skin reactions, such as Stevens Johnson
syndrome (SJS) and erythema multiforme reported; associated with development of
autoimmune syndromes including a lupus-like syndrome. Not recommended in an acutely
abscessed periodontal pocket. May result in overgrowth of nonsusceptible microorganisms
including fungi; caution is advised for those with a history of predisposition to oral candidiasis.
The FDA label196 lists the following most frequently reported adverse events in three multicenter
U.S. trials: headache, infection, flu syndrome, and pain.
The panel notes that the products should be applied according to the manufacturers’
instructions.
Since the benefits are unclear, the panel judged that there is uncertainty in the balance between
benefits and harms.
3.2.5
Nonsurgical use of lasers + SRP
The panel of experts analyzed all studies that met the inclusion criteria of nonsurgical
application of a laser (pocket disinfection) and did not consider studies using lasers for
alternative surgical therapy. There are several lasers used nonsurgically as adjunctive
treatments with SRP. The lasers are categorized primarily by the wavelength of the emitted
light. Five categories of lasers are included and described below. One laser type was not
available in the U.S. (potassium titanyl phosphate, KTP) 197 and not included. The panel notes
that there are no standard operating protocols (such as power intensity/density, power, spot
size, energy, repetition rate, tip size, pulsing vs. continuous mode, mean energy loss, or time of
application) for the lasers.
3.2.5.1 PDT diode laser + SRP
Ten studies198-207 met inclusion criteria reporting the effect of SRP plus a photodynamic-therapy
(PDT) diode laser (wavelength 660-810 nm) versus SRP alone. Six198, 201-204, 206 were split-mouth
trials, and four199, 200, 205, 207 were parallel-group. The sample sizes were relatively small, ranging
from 12 to 44 per treatment group. The studies were conducted worldwide including three in
July 2015
Page 56
Brazil, two in the Netherlands, and one each in Germany, India, Italy, Jordan, and Turkey. The
studies were published between 2008 and 2014.
Two of the studies201, 202 described the severity of disease of included participants as moderateto-severe, seven197-200, 204, 205, 207 did not describe the severity except by probing pocket depth
and bleeding on probing inclusion criteria, and one study203 reported on slight-to-moderate
periodontitis in participants with HIV.
Five studies excluded smokers,197, 198, 202, 205, 207 four199-201, 203 included smokers, but did not
perform a sub-group analysis reporting the results by smoking status, and one did not mention
smoking status.204 It is noted that Theodoro only included one site per treatment. Two arms of
two studies were excluded: the toluidine blue O (TBO)-only arm of Theodoro et al.202 and the
KTP laser arm of Dilsiz et al.197
Critical appraisal
presented in Appendix 3. Nine of ten studies were at a low risk of bias for random sequence
generation, and identical treatment of groups except for the intervention; and all ten studies
were at a low risk of bias for masking of outcomes assessment and detection of selective
reporting. The judgments of high, unclear, or low risk for bias as a percentage of included
studies in this section are depicted by domain in Figure 17. The main issues for bias for this
group of studies were lack of masking of personnel and participants, which may have been
difficult to obtain due to the nature of the intervention. The risk of bias for these two domains
were judged as not being as significant as outcomes assessment masking. The panel judged
the overall risk of bias of the included studies as low.
July 2015
Page 57
included studies.
Since there were 10 studies included comparing PDT lasers plus SRP to SRP alone, an
assessment of publication bias by visual inspection of the funnel plot as well as Egger’s test
were undertaken. Figure 18 shows the funnel plot with the studies identified by their sub-group.
The panel found no evidence for publication bias (Egger’s test, p=0.679).
Figure 18. Funnel plot of studies on SRP plus PDT lasers.
.2
.3
.5
.4
SE Mean Difference
.1
0
-1
0
1
2
Mean Difference
July 2015
Page 58
Figure 19 shows the meta-analysis for the included studies comparing SRP to SRP plus PDT
diode laser. The overall group mean difference is 0.53 mm mean gain in clinical attachment
level (i.e., improvement) when a PDT diode laser was used adjunctively with SRP versus SRP
alone with a 95% CI from 0.06 mm to 1.00 mm improvement. The subgroup analysis indicated
that the results were not statistically significantly different with respect to study design.
Figure 19 (updated). Meta-analysis of studies on SRP plus PDT diode laser versus SRP alone, subgrouped by study design; mean difference in units of millimeters.
Notes: Gianelli, final data used; Berakdar, mean CAL gains visually estimated from publication figure and SD estimated by dividing
range by 2; Filho, final data used (change score not provided); Theodoro, final data used (change score not provided); Dilsiz,
change data used; Betsy, SE estimated by averaging since only intraquartile range reported; Alwaeli, Christodoulides,
Chondros, and Luchesi, no adjustments necessary.
coefficients, there is true between-study variation. The summary estimate is judged to not be
sensitive to the assumptions that were made.
July 2015
Page 59
Hetero-
Mean
geneity p-
difference
(%)
value
(mm)
0.49
84
<0.00001
0.52
0.03, 1.02
10
0.46
95
<0.00001
0.53
0.09, 0.97
9
0.51
87
<0.00001
0.47
-0.04,
0.99
Adjunctive
Correlation
# of
Hetero-
Treatment
coefficient
studies
geneity 2
-0.1
10
0.9
0.25
PDT diode
laser
PDT diode
laser
Without
Betsy
(estimated
SE)
Heterogeneity
I2
95% CI
Evidence profile
in the evidence to be low based on inconsistency and imprecision.
Table 22. Evidence profile for SRP+PDT diode laser versus SRP alone.
Therapy
No.
No.
RCTs
participants
Risk of
bias
Consistency
Applicability
Precision
Publication
bias
Level of
Certainty
SRP+ PDT
None
Serious
diode laser
10
306
Low
Inconsistent
Yes
detected
Moderate
imprecision
vs. SRP
(p=0.679)
*Interpreted as 0.48 mm mean gain in clinical attachment level with PDT diode laser adjunctive use with SRP versus SRP alone,
with a 95% CI from 0.05 mm to 0.92 mm improvement.
Several studies reported no adverse events: therapies were well tolerated198, healing was
uneventful with no pain or discomfort reported199, no burning sensation or pain with laser
treatment200, 205, no major periodontal inflammatory symptoms after instrumentation during the
entire study or complications such as infections, suppuration, or abscesses were observed197,
204
, and no complications201-203 or adverse effects207.
Uncertainty in magnitude of moderate benefit balanced with potential harms.
July 2015
Page 60
Mean
difference in
CAL
(mm)
0.53 higher
(0.06 to
1.00)*
3.2.5.2 Non-PDT diode laser + SRP
Four studies208-211 met inclusion criteria reporting the effect of SRP plus a non-photodynamictherapy (non-PDT) diode laser (wavelength 808 to 980 nm). Three were split-mouth, and one209
was a parallel group study. In Euzebio Alves et al.208 only one site per mouth was tested with
each treatment. The sample sizes were relatively small, between 13 and 36. The studies were
conducted in Brazil,208 Italy,211 and Turkey,209, 210 and published in 2008 through 2014.
One208 of the studies described the severity of disease of the included participants (severe
chronic periodontitis), while the others were judged to include moderate severity based on the
probing pocket depth inclusion criteria.
Three of the studies excluded smokers while Caruso et al.211 did not describe the smoking
status of their participants. Because of the variety of smoking inclusion/exclusion criteria, no
further sub-analyses to determine if the results were different for smokers versus non-smokers
were attempted.
Critical appraisal
presented in Appendix 3. Euzebio Alves et al.208 was at a low risk of bias for all dimensions. The
judgments of high, unclear, or low risk for bias as a percentage of included studies in this
section are depicted by domain in Figure 20. Because both allocation concealment and
participant, personnel, and outcomes assessment masking were unclear for one211 of the
studies, the fact that only one site was treated in each arm of Alves et al.208, and the lack of
participant and personnel masking in two studies209, 210, the panel judged the risk of bias for the
two studies as a whole as unclear.
July 2015
Page 61
included studies.
Figure 21 shows the meta-analysis for the included studies comparing SRP to SRP plus nonPDT diode laser. The overall group mean difference is 0.21 mm mean gain in clinical
attachment level when a non-PDT laser was used adjunctively with SRP treatment versus SRP
alone with a 95% CI from 0.23 mm worse to 0.64 mm improvement. Because the 95% CI
crosses the line of no effect, this result is interpreted as no statistically significant difference
between the two treatments.
Figure 21. Meta-analysis of studies on SRP plus non-PDT laser versus SRP alone; mean difference
July 2015
Page 62
Notes: Caruso, final values were used (not change over time); Alves, CAL gain was reported as well as SD; Ustun, final values
used; Saglam, change score calculated.
23 shows the impact of changing the correlation coefficient from the initial value of 0.25 to both 0.1 and 0.9. At a correlation of -0.1 and 0.9, the mean difference still indicates no statistically
significant effect from adding the adjunctive treatment.
Treatment
Correlation
coefficient
# of
studies
Heterogeneity 2
Heterogeneity
I2 (%)
Heterogeneity
p-value
Mean
difference
(mm)
-0.1
4
0.06
33
0.21
0.21
0.9
4
0.19
93
<0.00001
Non-PDT
diode laser
Non-PDT
diode laser
95% CI
-0.22,
0.64
-0.25,
0.63
0.19
Evidence profile
in the evidence to be low based on the small quantity of evidence, the unclear risk of bias, the
substantial inconsistency, and serious imprecision.
Table 24. Evidence profile for SRP+non-PDT laser versus SRP alone.
Therapy
No.
No.
RCTs
participants
Risk of
bias
Consistency
Applicability
Precision
Publication
bias
Level of
Certainty
SRP+nonSubstantial
Too few
Serious
PDT diode
4
98
Unclear
inconsisten
Yes
studies to
Low
imprecision
laser vs. SRP
cy
assess
*Interpreted as 0.21 mm mean gain in clinical attachment level with non-PDT diode laser adjunctive use with SRP versus SRP
Mean
difference in
CAL (mm)
0.21 (-0.23 to
0.64)*
alone, with a 95% CI from 0.23 mm worse to 0.64 mm improvement.
Two studies reported no adverse events such as discomfort,
burning sensation, dentin hypersensitivity, or pain related to non-PDT laser irradiation. .
There was no evidence of a benefit.
July 2015
Page 63
3.2.5.3 Nd:YAG laser + SRP
Three studies81, 212, 213 met inclusion criteria reporting the effect of SRP plus an Nd:YAG laser
(wavelength 1064 nm). All were split-mouth studies with small sample sizes (10 to 26
participants). One was conducted in the U.S. in 1997 on participants with moderate-to-severe
periodontitis81, while another was conducted in Turkey in 2012 on participants with moderate
periodontitis212. Neither of these studies mentioned the smoking status of the included
participants. One study213 compared the effects of the addition of Nd:YAG lasers to SRP on
smokers versus nonsmokers in two arms of the study.
Critical appraisal
presented in Appendix 3. The judgments of high, unclear, or low risk for bias as a percentage of
included studies in this section are depicted by domain in Figure 22. The main issues for bias
for this group of studies were lack of or unclear masking of personnel, participants, and
outcomes assessors. The panel judged the overall risk of bias of the included studies as
unclear.
included studies.
Nd:YAG laser. The overall group mean difference is 0.41 mm mean gain in clinical attachment
July 2015
Page 64
level when an Nd:YAG laser was used adjunctively with SRP treatment versus SRP alone with
a 95% CI from 0.12 mm worsening to 0.94 mm improvement.
Figure 23. Meta-analysis of studies on SRP plus Nd:YAG laser versus SRP alone; mean difference
Notes: Neill, used data from text, which appears to be inconsistent from publication Figure 4; Eltas A and B, final data used
(change score not provided).
25 shows the impact of changing the correlation coefficient from the initial value of 0.25 to both 0.1 and 0.9. At a correlation coefficient of -0.1 the mean difference and 95% CI did not change
from the original value, and at a correlation coefficient of 0.9, the mean difference and 95% CI
decreased slightly. Since there were only three studies, one of which had two arms,
heterogeneity statistics are less meaningful. However, the trend is for heterogeneity to increase
with increasing correlation coefficient values. The summary estimate is judged to not be
Adjunctive
Treatment
Correlation
coefficient
# of
studies
Heterogeneity 2
Heterogeneity I2
(%)
Heterogeneity
p-value
Mean
difference
(mm)
Nd:YAG laser
-0.1
3
0.13
46
0.13
0.41
Nd:YAG laser
0.9
3
0.27
95
<0.00001
0.40
July 2015
Page 65
95% CI
-0.12,
0.94
-0.12,
0.93
Evidence profile
in the evidence to be low based on the small quantity of evidence, the unclear risk of bias, and
inconsistent results.
Table 26. Evidence profile for SRP+Nd:YAG laser versus SRP alone.
Therapy
No.
No.
Studies
participants
Risk of
bias
Consistency
Applicability
Precision
Publication
bias
Level of
Certainty
Too few
studies to
Moderate
Serious
assess; expert
3
82
Unclear
Yes
Low
inconsistency
imprecision
knowledge of
unpublished
studies
*Interpreted as 0.41 mm mean gain in clinical attachment level with Nd:YAG laser adjunctive use with SRP versus SRP alone, with
SRP+
Nd:YAG
laser vs. SRP
a 95% CI from 0.12 mm worsening to 0.94 mm improvement.
One study stated that there were no adverse events reported as well as minimal pain81, the
other two studies212, 213 did not include adverse event reporting.
3.2.5.4 Erbium laser + SRP
Three studies83, 214, 215 met inclusion criteria reporting the effect of SRP plus an erbium laser
(either Er,Cr:YSGG214 or Er:YAG83, 215, wavelengths 2.79 and 2.94 m, respectively). All were
split-mouth studies with small sample sizes (19-33 participants). Each study was conducted in a
different country: Lithuania214, Brazil215, and Italy83, and published between 2010 and 2011.
Two of the studies83, 215 described the severity of disease of included participants as moderateto-severe, and one214 was early-to-moderate.
Two of the studies214, 215 excluded smokers, and one83 included smokers but did not perform a
sub-group analysis reporting the results by smoking status.
July 2015
Page 66
Mean
difference
in CAL
(mm)
0.41 higher
(-0.12 to
0.94)*
Critical appraisal
presented in Appendix 3. All studies were at low risk of bias for random sequence generation.
One83 was at low risk of bias for allocation concealment, while the others did not report details
about their methods in this area. Masking of participants and personnel was either unclear or
not performed; however, in all studies the outcomes assessor was masked. There was low risk
of bias for all studies with respect to identical treatment of groups except for the intervention,
selective reporting, and complete outcomes data, except for one study214 where there was an
unclear risk of bias concerning incomplete outcomes data. The judgments of high, unclear, or
low risk for bias as a percentage of included studies in this section are depicted by domain in
Figure 24. The main issues for bias for this group of studies were lack of masking of personnel
and participants, which may have been difficult to obtain due to the nature of the intervention.
This risk of bias was judged as not being as significant as outcomes assessment masking. The
panel judged the overall risk of bias of the included studies as low.
included studies.
Figure 25 shows the meta-analysis for the included studies comparing SRP to SRP plus an
erbium laser. The overall group mean difference is 0.18 mm mean gain in clinical attachment
level (i.e., improvement) when an erbium laser was used adjunctively with SRP versus SRP
alone with a 95% CI from 0.63 mm worsening to 0.98 mm improvement. These results are
July 2015
Page 67
interpreted as a non-statistically-significant difference from SRP with the addition of an erbium
laser.
Figure 25. Meta-analysis of studies on SRP plus erbium laser versus SRP alone; mean difference
Notes: Rotundo, final data used (change score not provided); Lopes, final data used (change score not provided); Kelbauskiene,
change scores provided and used.
not change appreciably from those found at the initial value of 0.25. There is less statistical
heterogeneity at the smaller correlation coefficient. The summary estimate is judged to not be
Adjunctive
Treatment
Correlation
coefficient
# of
studies
Heterogeneity 2
Erbium laser
Erbium laser
-0.1
0.9
3
3
0.32
0.47
Heterogeneity I2
(%)
64
96
Heterogeneity pvalue
0.06
<0.00001
Mean
difference
(mm)
0.20
0.13
95% CI
-0.61, 1.01
-0.66, 0.92
Evidence profile
in the evidence to be low based on the small quantity of evidence, inconsistent results, and
evidence of no effect.
July 2015
Page 68
Table 28. Evidence profile for SRP+erbium laser versus SRP alone.
Therapy
No.
No.
RCTs
participants
Risk
ConsistAppliof
Precision
ency
cability
bias
Publication
bias
Level of
Certainty
Mean
difference in
CAL (mm)
Too few
0.18 higher
studies to
Low
(-0.63 to
assess
0.98)*
*Interpreted as 0.18 mm mean gain in clinical attachment level with SRP plus erbium laser adjunctive use versus SRP alone, with a
SRP+ erbium
laser vs. SRP
3
82
Low
Inconsistent
Yes
Serious
imprecision
95% CI from 0.63 mm worsening to 0.98 mm improvement.
One study83 reported the occurrence of abscesses, three in the control group and two in the
laser group. There was one patient who reported fever in the week following treatment, but the
treatment group was not identified. 83 The other two studies214, 215 did not report on adverse
events.
3.2.5.5 Summary statements on non-surgical use of lasers
Lasers, unlike other instrumentation, have no defined and accepted protocols for standard
usage. Since every operator determines their own protocol based on anecdotal rules or
experiences, the potential for harms to the tooth and patient is higher than other local delivery
systems. Also, every laser wavelength is different and affects the hard and soft tissues
differently, making comparisons between lasers unpredictable and often incorrect. Common
protocols are needed for each laser used in nonsurgical therapy of chronic periodontitis to allow
for repeatable results and comparisons among studies in the literature. The wide ranges found
in the few studies considered for CAL gain/loss demonstrates the need for larger sample sizes
and additional studies to properly evaluate the potential benefits of laser use as an adjunct to
SRP. At this time, based on the criteria set in this systematic review there is insufficient
evidence with any laser wavelength except PDT diode lasers to accurately define the benefits
for adjunctive nonsurgical therapy of periodontitis with evidence-based literature.
3.3
Caries data
Although the panel was interested in the effect that nonsurgical treatments for chronic
periodontal disease have on caries, no data were found on this topic to answer the question.
July 2015
Page 69
3.4
Smokers versus non-smokers
Although some studies included only smokers or non-smokers or did post-hoc analyses
comparing smokers to non-smokers, the panel was unable to make any general conclusions
regarding the effect of any of the treatments on smokers versus non-smokers.
4.
Discussion
SRP is considered the gold standard for nonsurgical periodontal therapy. Because of SRP’s
status, many clinical trials use SRP as an “active” control. This approach often leads to a clinical
trial that compares the results from SRP to the results of a studied experimental therapeutic
approach. Because there are very few trials that compare SRP to no treatment, the panel was
limited in their ability to determine the level of certainty above the level of “moderate”.
The panel found multiple trials for sub-antimicrobial dose doxycycline. By definition, subantimicrobial dose doxycycline is prescribed at a dosage that does not show antimicrobial effect
and is therefore not considered a systemic antibiotic. Sub-antimicrobial dose doxycycline
showed a small and statistically significant adjunctive benefit. Since the dose is low, the panel
judged that the small benefit outweighs the potential for harms.
The panel found a variety of systemic antimicrobials and regimens used in periodontal treatment
trials. Overall, the panel found a statistically significant but small benefit based on the class of
antibiotics with variation between the subclasses of antibiotics. Since there is wide reporting of
adverse events associated with systemic antibiotic use, the panel judged that the small benefit
is balanced with the potential for harms.
The panel observed a statistically significant, moderate benefit with the adjunctive use of CHX
chips; however, the panel judged that these benefits were balanced with the potential for harms.
The panel observed a substantial adjunctive benefit for doxycycline hyclate gel (DH); however,
because of wide confidence interval around the estimated benefit, the data were also
compatible with no benefit. It is important to note that DH was developed, originally tested, and
FDA approved as a stand-alone product (i.e., used without scaling and root planing). Garret et
al.132, 216 does address the use of DH as an independent therapy without SRP. Although there
may be benefit for this independent approach, it was not a consideration for this systematic
review, which addresses the benefit of DH as an adjunct to SRP versus SRP alone. Garret et
al.132, 216 reported results from two large multi-center trials in which DH alone resulted in a 0.3 to
July 2015
Page 70
0.5 mm gain in CAL [each study reported different results] when compared to no treatment,
which was statistically significantly better than no treatment. They also presented results
comparing DH to SRP, which indicated these treatments were not statistically significantly
different from each other.
The panel also observed a small adjunctive benefit for minocycline microspheres. Again, based
on the confidence interval, the data for the microspheres also were compatible with no benefit.
Additionally, minocycline microspheres were approved by the FDA for their beneficial effect on
pocket depth (PD), not CAL. The panel did not assess PD change in this meta-analysis,
although this measure may be of importance for some practitioners and patients.
Overall, the small number of studies on both DH and minocycline microspheres limited the
assessment of the consistency of studies, the usefulness of the sensitivity analyses, and the
ability to assess publication bias. In addition, the risk of bias for both adjuncts was judged to be
unclear. These factors add to the uncertainty of the estimated benefit for DH and minocycline
microspheres. Clinicians should bear in mind the ambiguity of the adjunctive benefits of these
products, represented by the wide confidence intervals, before recommending their use as part
of the nonsurgical treatment of periodontitis.
Lastly, lasers, unlike other instrumentation, have no defined and accepted protocols for
standard usage. Since every operator determines their own protocol based on anecdotal rules
or experiences, the potential for harms to the tooth and patient is higher than for other
adjunctive treatment systems. Also, every laser type and wavelength is different and affects the
hard and soft tissues differently, making comparisons between lasers unpredictable and
potentially incorrect. Common protocols are needed for each laser used in nonsurgical therapy
of chronic periodontitis to allow for repeatable results and valid comparisons among studies in
the literature. The wide ranges found in the few studies considered for CAL gain/loss
demonstrates the need for larger sample sizes and additional studies to properly evaluate the
potential benefits of laser use as an adjunct to SRP. At this time, based on the criteria set in this
systematic review, there is low certainty in the evidence for any laser type or wavelength except
PDT diode lasers to accurately define the benefits of adjunctive nonsurgical therapy of
periodontitis with evidence-based literature. Since there was imprecision in the magnitude of the
benefit of PDT diode lasers, the panel judged there was a balance between the benefit and
harm.
July 2015
Page 71
5.
Limitations
5.1
Of the evidence
The amount of published material on the nonsurgical treatment of periodontitis is voluminous.
However, this systematic review was limited by the number of studies that could be included in
the review. Much of this limitation was due to the ambiguity inherent in many of the studies. As
mentioned before, there were multiple studies that did not clearly specify that root planing was
performed. Various descriptions were used such as debridement that may have been used
interchangeably with root planing but the panel felt that the non-specificity of these terms had to
preclude the inclusion of these studies. The literature is also inconsistent on what is a clinically
relevant outcome: the value of the clinically relevant difference in attachment gain varied
between 0.2 and greater than 1.0 mm.
Another limiting factor was the description of the periodontal disease state of the patients. Part
of this ambiguity was due to the fact that in the last several decades the description of the
degree of periodontal disease has undergone several revisions. The panel made several
exceptions to the description of chronic periodontal disease. However, many studies used
outmoded or unconventional descriptions of the disease level of the patients included in these
studies. The panel felt that the use of terms such as aggressive periodontitis was sufficiently at
variance to the term chronic periodontitis that studies using this description could not be
included. Also, many studies did not include any description of the disease state of the patients
treated. In the future, the panel strongly urges researchers to include a standardized
description of the level of disease being treated.
Many otherwise rigorous studies reported their results in terms of pocket depth and not
attachment levels. While pocket depths are the routine clinical measure used in most day-today treatment of patients, pocket depths do not recognize the role of recession in the treatment
of periodontal diseases. Impressive reductions in pocket depth can be obtained through
treatment-induced recession. With the use of CAL the reader can get a true measure of exactly
how much the improvement was due to gain in attachment to the root surface as opposed to a
reduction in pocket depth due to recession. Since the panel chose to rely on CAL, studies that
only provide results in terms of pocket depth were excluded from this systematic review.
Most of the included studies were small in terms of the number of participants. Small studies
can have a problem with low statistical power. Several of the included studies tested only one
July 2015
Page 72
site per patient per treatment. This procedure does not allow an adequate assessment of
variation within a patient.
A major concern in judging the reliability of the results of a study is the extent of patients that
start the study and are retained to the end of the study. If a large number of patients drop out of
a study before the final data is collected, this attrition can greatly influence the reliability of the
results. Many studies did not include data about the retention of test subjects and this ambiguity
in turn influenced the panel’s ability to judge the strength of the study’s findings.
Although we intended to study the effect of these treatments on caries risk, we were unable to
do so because few if any studies assessed this outcome. Also, issues regarding safety and/or
adverse events were not often reported.
The methodology in the literature on adjunctive use of lasers has generally been poorly reported
and has not been standardized. The energy densities (i.e. dose of energy) were not
standardized so methodological heterogeneity is introduced that complicates analysis and
interpretation of the data. Techniques of application were also underreported.
5.2
Of the systematic review
For this systematic review, only English language databases were searched and only articles in
English were included in the review. These choices could lead to bias in the results and
interpretations if significant studies published in languages other than English exist since they
were not captured.
In addition, by screening the literature according to inclusion/exclusion criteria, by definition
studies were excluded that could provide additional information related to the topic, although the
impact of these a priori decisions on the results is unknown. For example, many studies were
excluded for being less than 6 months in duration or for reporting PD in preference to CAL.
Although the disease severity information was captured during the data abstraction process, this
systematic review did not assess the results subgrouped by disease severity.
The competitive environment in which clinical trials are financed and conducted, as well as the
non-reporting of negative results by some investigators or publications, fosters publication
bias.217 Ten or more studies were identified in only three treatments in this systematic review
allowing investigation of publication bias, so for the other treatments, the presence of publication
bias is unknown.
July 2015
Page 73
6.
Future research
The panel noted the need for further well designed studies that evaluate all types of adjunctive
therapy. Many studies had specific design flaws, and many were inadequately powered. Poor
methodology left the panel in the position of evaluating a particular adjunctive treatment from a
minimum number of papers. This shortcoming can only be overcome by further well designed
and powered studies in all areas of adjunctive treatment. The panel makes the following specific
recommendations regarding the methodology of future trials:

Methodology and reporting of future clinical trials should conform to current standards for
human clinical trials. In part this protocol involves registering trials with clinicaltrials.gov
and conforming to the CONSORT statement for human trials.218 These protocols
generally ensure a minimum power to the study as well as speaking to treatment
allocation, concealment (blinding) of evaluators and patients, bias in detection of
outcomes, as well as attrition bias and reporting bias.

To minimize attrition bias, researchers should focus more heavily on retaining enrolled
participants and providing adequate personnel and resources to ensure that the primary
outcome is assessed.

Conduct larger, multi-center studies

Test more than one site in a patient’s mouth

Follow up patients at least 6 months

Clearly define and describe endpoints that are reproducible

Report mean CAL and variance, preferable in tables and not figures, and include
baseline and final measurements or changes; consider additional summary statistics
such as distributions or percent of sites improving

Use parallel group trial design if at all possible. Only in specific circumstances would
split-mouth trials be recommended

Use appropriate statistical tests including checking for normal distribution of data and
transforming skewed data

Report details regarding statistical analysis methods and reasoning

Report on tooth loss as well as post-treatment morbidity and recession

Report on patient-centered outcomes (e.g., discomfort, oral health-related quality of life,
satisfaction) and costs

Use standardized protocols for handling failing sites and report the number of failing or
retreated sites
July 2015
Page 74

Evaluate safety or adverse events of treatments

For laser studies, completely report or otherwise calculate all parameters/settings used
such as energy density, duration of exposure, surface area of exposure, wavelength,
frequency, time, hard/soft tissue, pulse and all other relevant techniques of application
The panel also identified many topics for future studies related to nonsurgical treatment of
chronic periodontitis:

Studies comparing treatment results in smokers versus non-smokers

Studies reporting effect of periodontal treatment on caries

Studying the effect of irrigants without retreating failing sites with the test treatment
during the trial

Studies on special populations such as diabetics

Studies investigating mechanisms of action of lasers to determine the relative
importance of de-epithialization, antibacterial activity, or biostimulation

Studies on CO2 lasers not delivered through fiber optic and KTP lasers that are not
currently available in the U.S.

Systematically reviewing the evidence on stand-alone treatments such as doxycycline
hyclate gel in comparison to mechanical therapies such as SRP and not strictly as
adjuncts to SRP

Studying the effect of treatments on patients with varying severity of periodontitis to
allow for more individualized care

Systematically reviewing the evidence on debridement (scaling without root planing) on
chronic periodontitis
7.
Conclusions
A total of 72 RCTs have been critically appraised and summarized on 10 forms of nonsurgical
treatment for chronic periodontitis. The literature on SRP versus no treatment or debridement is
scant, but confirmed the commonly reported36, 51 result of approximately 0.5 mm improvement in
CAL. The literature on adjunctive therapies was varied providing only a moderate level of
certainty on the benefits of the four adjunctive therapies: systemic sub-antimicrobial dose
doxycycline, systemic antimicrobials, chlorhexidine chips, and photodynamic therapy with a
diode laser. There was a low level of certainty on the benefits of all other adjunctive therapies.
The panel also assessed the balance between the benefits and potential for adverse events and
July 2015
Page 75
harms from each treatment. The panel makes specific recommendations for additional research
on the topic of nonsurgical treatment for chronic periodontal disease to fill the gaps in
knowledge and improve the evidence base. The panel makes clinical recommendations in a
companion clinical practice guideline.
July 2015
Page 76
8.
References
1.
Thornton-Evans G, Eke P, Wei L, et al. Periodontitis among adults aged >/=30 years - United
States, 2009-2010. MMWR Surveill Summ 2013;62 Suppl 3:129-35.
Armitage G. Development of a Classification System for Periodontal Diseases and Conditions.
Ann Periodontol 1999;4:1-6.
Golub LM, Wolff M, Lee HM, et al. Further evidence that tetracyclines inhibit collagenase activity
in human crevicular fluid and from other mammalian sources. J Periodontal Res 1985;20:12–23.
Golub LM, Ciancio S, Ramamurthy NS, Leung M, McNamara TF. Low-dose doxycycline therapy:
Effect on gingival and crevicular fluid collagenase activity in humans. J Periodontal Res
1990;25:321–30.
Smiley C, et al. Evidence-Based Clinical Practice Guideline on the Nonsurgical Treatment of
Chronic Periodontal Disease. J Am Dent Assoc 2014;x(x):xx-xx.
Sgolastra F, Petrucci A, Severino M, et al. Adjunctive photodynamic therapy to non-surgical
treatment of chronic periodontitis: a systematic review and meta-analysis. J Clin Perio
2013;40(5):514-26.
Sanz I, Alonso B, Carasol M, Herrera D, Sanz M. Nonsurgical treatment of periodontitis. J Evid
Based Dent Pract 2012;12(3 Suppl):76-86.
Matesanz-Perez P, Garcia-Gargallo M, Figuero E, et al. A systematic review on the effects of
local antimicrobials as adjuncts to subgingival debridement, compared with subgingival
debridement alone, in the treatment of chronic periodontitis. J Clin Periodontol 2013;40(3):22741.
Herrara D, Matesanz P, Bascones-Martinez A, Sanz M. Local and systemic antimicrobial therapy
in periodontics. J Evid Based Dent Pract 2012;S1:50-60.
Worthington H, Needleman I. Evidence-based periodontal disease prevention and treatment:
introduction. Periodontol 2000 2005;37:9-11.
Angaji M, Gelskey S, Nogueira-Filho G, Brothwell D. A systematic review of clinical efficacy of
adjunctive antibiotics in the treatment of smokers with periodontitis. J Periodontol
2010;81(11):1518-28.
Atieh MA. Photodynamic therapy as an adjunctive treatment for chronic periodontitis: a metaanalysis. Lasers Med Sci 2010;25(4):605-13.
Azarpazhooh A, Shah PS, Tenenbaum HC, Goldberg MB. The effect of photodynamic therapy for
periodontitis: a systematic review and meta-analysis. J Periodontol 2010;81(1):4-14.
Beirne P, Worthington HV, Clarkson JE. Routine scale and polish for periodontal health in adults.
Cochrane Database Syst Rev 2007(4):CD004625.
Berkey CS, Antczak-Bouckoms A, Hoaglin DC, Mosteller F, Pihlstrom BL. Multiple-outcomes
meta-analysis of treatments for periodontal disease. J Dent Res 1995;74(4):1030-9.
Cosyn J, Wyn I. A systematic review on the effects of the chlorhexidine chip when used as an
adjunct to scaling and root planing in the treatment of chronic periodontitis. J Periodontol
2006;77(2):257-64.
Eberhard J, Jepsen S, Jervoe-Storm PM, Needleman I, Worthington HV. Full-mouth disinfection
for the treatment of adult chronic periodontitis. Cochrane Database Syst Rev 2008(1):CD004622.
Eberhard J, Jervoe-Storm PM, Needleman I, Worthington H, Jepsen S. Full-mouth treatment
concepts for chronic periodontitis: a systematic review. J Clin Periodontol 2008;35(7):591-604.
Elter JR, Lawrence HP, Offenbacher S, Beck JD. Meta-analysis of the effect of systemic
metronidazole as an adjunct to scaling and root planing for adult periodontitis. J Periodontal Res
1997;32(6):487-96.
Haffajee AD, Patel M, Socransky SS. Microbiological changes associated with four different
periodontal therapies for the treatment of chronic periodontitis. Oral Microbiol Immunol
2008;23(2):148-57.
Hallmon WW, Rees TD. Local anti-infective therapy: mechanical and physical approaches. A
systematic review. Ann Periodontol 2003;8(1):99-114.
Heasman PA, McCracken GI, Steen N. Supportive periodontal care: the effect of periodic
subgingival debridement compared with supragingival prophylaxis with respect to clinical
outcomes. J Clin Periodontol 2002;29 Suppl 3:163-72; discussion 95-6.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
July 2015
Page 77
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
Hung HC, Douglass CW. Meta-analysis of the effect of scaling and root planing, surgical
treatment and antibiotic therapies on periodontal probing depth and attachment loss. J Clin
Periodontol 2002;29(11):975-86.
Lang NP, Tan WC, Krahenmann MA, Zwahlen M. A systematic review of the effects of full-mouth
debridement with and without antiseptics in patients with chronic periodontitis. J Clin Periodontol
2008;35(8 Suppl):8-21.
Muller HP. A bivariate multi-level model, which avoids mathematical coupling in the study of
change and initial periodontal attachment level after therapy. Clin Oral Investig 2007;11(3):30710.
Pavia M, Nobile CG, Bianco A, Angelillo IF. Meta-analysis of local metronidazole in the treatment
of chronic periodontitis. J Periodontol 2004;75(6):830-8.
Pihlstrom BL, McHugh RB, Oliphant TH, Ortiz-Campos C. Comparison of surgical and
nonsurgical treatment of periodontal disease. A review of current studies and additional results
after 61/2 years. J Clin Periodontol 1983;10(5):524-41.
Sgolastra F, Gatto R, Petrucci A, Monaco A. Effectiveness of systemic amoxicillin/metronidazole
as adjunctive therapy to scaling and root planing in the treatment of chronic periodontitis: a
systematic review and meta-analysis. J Periodontol 2012;83(10):1257-69.
Sgolastra F, Petrucci A, Gatto R, Marzo G, Monaco A. Photodynamic therapy in the treatment of
chronic periodontitis: a systematic review and meta-analysis. Lasers Med Sci 2011.
Slot DE, Koster TJ, Paraskevas S, Van der Weijden GA. The effect of the Vector scaler system
on human teeth: a systematic review. Int J Dent Hyg 2008;6(3):154-65.
Slot DE, Kranendonk AA, Paraskevas S, Van der Weijden F. The effect of a pulsed Nd:YAG laser
in non-surgical periodontal therapy. J Periodontol 2009;80(7):1041-56.
Tunkel J, Heinecke A, Flemmig TF. A systematic review of efficacy of machine-driven and
manual subgingival debridement in the treatment of chronic periodontitis. J Clin Periodontol
2002;29 Suppl 3:72-81; discussion 90-1.
Van der Weijden GA, Timmerman MF. A systematic review on the clinical efficacy of subgingival
debridement in the treatment of chronic periodontitis. J Clin Periodontol 2002;29 Suppl 3:55-71;
discussion 90-1.
Bonito AJ, Lux L, Lohr KN. Impact of local adjuncts to scaling and root planing in periodontal
disease therapy: a systematic review. J Periodontol 2005;76(8):1227-36.
Bono A, Brunotto M. Amoxicillin/metronidazole or scaling and root planing in the treatment of
chronic periodontitis. Acta Odontol Latinoam 2010;23(3):196-203.
Cobb CM. Clinical significance of non-surgical periodontal therapy: an evidence-based
perspective of scaling and root planing. J Clin Periodontol 2002;29 Suppl 2:6-16.
Cobb CM. Lasers in periodontics: a review of the literature. J Periodontol 2006;77(4):545-64.
Hanes PJ, Purvis JP. Local anti-infective therapy: pharmacological agents. A systematic review.
Ann Periodontol 2003;8(1):79-98.
Herrera D, Sanz M, Jepsen S, Needleman I, Roldan S. A systematic review on the effect of
systemic antimicrobials as an adjunct to scaling and root planing in periodontitis patients. J Clin
Periodontol 2002;29 Suppl 3:136-59; discussion 60-2.
Pavia M, Nobile CG, Angelillo IF. Meta-analysis of local tetracycline in treating chronic
periodontitis. J Periodontol 2003;74(6):916-32.
Preshaw PM, Hefti AF, Bradshaw MH. Adjunctive subantimicrobial dose doxycycline in smokers
and non-smokers with chronic periodontitis. J Clin Periodontol 2005;32(6):610-6.
Reddy MS, Geurs NC, Gunsolley JC. Periodontal host modulation with antiproteinase, antiinflammatory, and bone-sparing agents. A systematic review. Ann Periodontol 2003;8(1):12-37.
Sahrmann P, Puhan MA, Attin T, Schmidlin PR. Systematic review on the effect of rinsing with
povidone-iodine during nonsurgical periodontal therapy. J Periodontal Res 2010;45(2):153-64.
Sgolastra F, Petrucci A, Gatto R, Giannoni M, Monaco A. Long-term efficacy of subantimicrobialdose doxycycline as an adjunctive treatment to scaling and root planing: a systematic review and
meta-analysis. J Periodontol 2011;82(11):1570-81.
Zandbergen D, Slot DE, Cobb CM, Van der Weijden FA. The Clinical Effect of Scaling and Root
Planing and The Concomitant Administration of Systemic Amoxicillin and Metronidazole: A
Systematic Review. J Periodontol 2012.
July 2015
Page 78
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
Smail-Faugeron V, Fron-Chabouis H, Courson F, Durieux P. Comparison of intervention effects in
split-mouth and parallel-arm randomized controlled trials: a meta-epidemiological study. BMC
Med Res Methodol 2014;14:64.
U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug
Evaluation and Research (CDER). Guidance for Industry - Gingivitis: Development and
Evaluation of Drugs for Treatment or Prevention (Draft). Available at:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm07
1693.pdf; accessed January 13, 2014.; 2005.
Reddy MS, Palcanis KG, Geurs NC. A comparison of manual and controlled-force attachmentlevel measurements. J Clin Periodontol 1997;24(12):920-6.
Worthington HV, Clarkson JE, Bryan G, Beirne PV. Routine scale and polish for periodontal
health in adults. Cochrane Database of Systematic Reviews: John Wiley & Sons, Ltd; 2013.
Higgins JPT, Altman DG, Sterne JAC, Cochrane Statistical Methods Group and the Cochrane
Bias Methods Group. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT,
Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0
The Cochrane Collaboration; updated March 2011.
Cobb CM. Non-surgical pocket therapy: mechanical. Ann Periodontol 1996;1(1):443-90.
Imrey PB, Chilton NW, Pihlstrom B, et al. Proposed guidelines for American Dental Association
acceptance of products for professional, non-surgical treatment of adult periodontitis: Task Force
on Design and Analysis of Dental and Oral Research. J Periodontal Res 1994;29(5):348-60.
Ronderos M, Michalowicz BS. Epidemiology of periodontal diseases and risk factors. In: Rose LF,
Mealey BL, Genco RJ, Cohen DW, editors. Periodontics: Medicine, Surgery and Implants.
Philadelphia, PA: Elsevier Mosby; 2004. p. 39, 302.
Armitage G. Manual periodontal probing in supportive periodontal therapy. Periodontol 2000
1996;12:33-39.
Higgins JPT, Green S, (editors). Cochrane Handbook for Systematic Reviews of Interventions
Version 5.1.0: The Cochrane Collaboration. Available from www.cochrane-handbook.org;
updated March 2011.
Cochrane Cystic Fibrosis and Genetic Disorders Group. The generic inverse variance method.
Available at:
http://cfgd.cochrane.org/sites/cfgd.cochrane.org/files/uploads/Generic%20Inverse%20Variance%
20method.doc; updated 7 Feb 2013.
The Nordic Cochrane Centre. The Cochrane Collaboration. Review Manager (RevMan)
[Computer program]. Version 5.2. Copenhagen; 2012.
Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. A basic introduction to fixed-effect and
random-effects models for meta-analysis. Res Syn Meth 2010;1:97-111.
Riley RD, Higgins JPT, Deeks JJ. Interpretation of random effects meta-analysis. BMJ
2011;342:964-7.
Needleman IG, Worthington H, Giedrys-Leeper E, Tucker R. Guided tissue regeneration for
periodontal infra-bony defects. Cochrane Database of Systematic Reviews 2006;Apr
19(2):CD001724.
Preshaw PM, Hefti AF, Novak MJ, et al. Subantimicrobial dose doxycycline enhances the efficacy
of scaling and root planing in chronic periodontitis: a multicenter trial. J Periodontol
2004;75(8):1068-76.
Mohammad AR, Preshaw PM, Bradshaw MH, et al. Adjunctive subantimicrobial dose doxycycline
in the management of institutionalised geriatric patients with chronic periodontitis. Gerodontology
2005;22(1):37-43.
American Dental Association. ADA Clinical Practice Guideline Handbook - 2013 Update.
Chicago, IL.
Takkouche B, Cadarso-Suarez C, Spiegelman D. Evaluation of old and new tests of
heterogeneity in epidemiologic meta-analysis. Am J Epidemiol 1999;150(2):206-15.
Huedo-Medina T, Sanchez-Meca J, Marin-Martinez F, Botella J. Assessing heterogeneity in
meta-analysis: Q statistic or I2 index?". CHIP Documents, Paper 19 available at
http://digitalcommons.uconn.edu/chip_docs/19 2006.
Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 7. Rating the quality of evidence inconsistency. J Clin Epidemiol 2011;64:1294-302.
July 2015
Page 79
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
Ioannidis JPA. Interpretation of tests of heterogeneity and bias in meta-analysis. J Eval Clin Pract
2008;14:951-7.
StataCorp. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP; 2011.
Feng HS, Bernardo CC, Sonoda LL, et al. Subgingival ultrasonic instrumentation of residual
pockets irrigated with essential oils: a randomized controlled trial. J Clin Periodontol
2011;38(7):637-43.
Schlagenhauf U, Stellwag P, Fiedler A. Subgingival irrigation in the maintenance phase of
periodontal therapy. J Clin Periodontol 1990;17(9):650-3.
Wennstrom JL, Heijl L, Dahlen G, Grondahl K. Periodic subgingival antimicrobial irrigation of
periodontal pockets (I). Clinical observations. J Clin Periodontol 1987;14(9):541-50.
Del Peloso Ribeiro E, Bittencourt S, Ambrosano GM, et al. Povidone-iodine used as an adjunct to
non-surgical treatment of furcation involvements. J Periodontol 2006;77(2):211-7.
Ribeiro Edel P, Bittencourt S, Sallum EA, et al. Non-surgical instrumentation associated with
povidone-iodine in the treatment of interproximal furcation involvements. J Appl Oral Sci
2010;18(6):599-606.
Rosling B, Hellstrom MK, Ramberg P, Socransky SS, Lindhe J. The use of PVP-iodine as an
adjunct to non-surgical treatment of chronic periodontitis. J Clin Periodontol 2001;28(11):1023-31.
Braatz L, Garrett S, Claffey N, Egelberg J. Antimicrobial irrigation of deep pockets to supplement
non-surgical periodontal therapy. II. Daily irrigation. J Clin Periodontol 1985;12(8):630-8.
Leonhardt A, Bergstrom C, Krok L, Cardaropoli G. Healing following ultrasonic debridement and
PVP-iodine in individuals with severe chronic periodontal disease: a randomized, controlled
clinical study. Acta Odontol Scand 2006;64(5):262-6.
MacAlpine R, Magnusson I, Kiger R, et al. Antimicrobial irrigation of deep pockets to supplement
oral hygiene instruction and root debridement. I. Bi-weekly irrigation. J Clin Periodontol
1985;12(7):568-77.
Berglundh T, Krok L, Liljenberg B, et al. The use of metronidazole and amoxicillin in the treatment
of advanced periodontal disease. A prospective, controlled clinical trial. J Clin Periodontol
1998;25(5):354-62.
Kahl M, Haase E, Kocher T, Ruhling A. Clinical effects after subgingival polishing with a nonaggressive ultrasonic device in initial therapy. J Clin Periodontol 2007;34(4):318-24.
Lindhe J, Liljenberg B, Adielsson B. Effect of long-term tetracycline therapy on human periodontal
disease. J Clin Periodontol 1983;10(6):590-601.
Neill ME, Mellonig JT. Clinical efficacy of the Nd:YAG laser for combination periodontitis therapy.
Pract Periodontics Aesthet Dent 1997;9(6 Suppl):1-5.
Ng VW, Bissada NF. Clinical evaluation of systemic doxycycline and ibuprofen administration as
an adjunctive treatment for adult periodontitis. J Periodontol 1998;69(7):772-6.
Rotundo R, Nieri M, Cairo F, et al. Lack of adjunctive benefit of Er:YAG laser in non-surgical
periodontal treatment: a randomized split-mouth clinical trial. J Clin Periodontol 2010;37(6):52633.
Chen L, Luo G, Xuan D, et al. Effects of non-surgical periodontal treatment on clinical response,
serum inflammatory parameters, and metabolic control in patients with type 2 diabetes: a
randomized study. J Periodontol 2012;83(4):435-43.
Jones AA, Kornman KS, Newbold DA, Manwell MA. Clinical and microbiological effects of
controlled-release locally delivered minocycline in periodontitis. J Periodontol 1994;65(11):105866.
Ribeiro IW, Sbrana MC, Esper LA, Almeida AL. Evaluation of the effect of the GaAlAs laser on
subgingival scaling and root planing. Photomed Laser Surg 2008;26(4):387-91.
Van Dyke TE, Offenbacher S, Braswell L, Lessem J. Enhancing the value of scaling and rootplaning: Arestin clinical trial results. J Int Acad Periodontol 2002;4(3):72-6.
Zhou X, Han J, Liu Z, et al. Effects of periodontal treatment on lung function and exacerbation
frequency in patients with chronic obstructive pulmonary disease and chronic periodontitis: a 2year pilot randomized controlled trial. J Clin Periodontol 2014;41(6):564-72.
Ide M, Jagdev D, Coward PY, et al. The short-term effects of treatment of chronic periodontitis on
circulating levels of endotoxin, C-reactive protein, tumor necrosis factor-alpha, and interleukin-6. J
Periodontol 2004;75(3):420-8.
July 2015
Page 80
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
Gu Y, Walker C, Ryan ME, Payne JB, Golub LM. Non-antibacterial tetracycline formulations:
clinical applications in dentistry and medicine. J Oral Microbiol 2012;4:19227
Al Mubarak S, Abou Rass M, Alsuwyed A, et al. A new paradigm between mechanical scaling
and root planing combined with adjunctive chemotherapy for glycated hemoglobin improvement
in diabetics. Intl J Diabetes Mellit 2010;2(3):158-64.
Caton JG, Ciancio SG, Blieden TM, et al. Treatment with subantimicrobial dose doxycycline
improves the efficacy of scaling and root planing in patients with adult periodontitis. J Periodontol
2000;71(4):521-32.
Deo V, Gupta S, Bhongade ML, Jaiswal R. Evaluation of subantimicrobial dose doxycycline as an
adjunct to scaling and root planing in chronic periodontitis patients with diabetes: a randomized,
placebo-controlled clinical trial. J Contemp Dent Pract 2010;11(3):009-16.
Emingil G, Atilla G, Sorsa T, et al. The effect of adjunctive low-dose doxycycline therapy on
clinical parameters and gingival crevicular fluid matrix metalloproteinase-8 levels in chronic
Emingil G, Atilla G, Sorsa T, Savolainen P, Baylas H. Effectiveness of adjunctive low-dose
doxycycline therapy on clinical parameters and gingival crevicular fluid laminin-5 gamma2 chain
levels in chronic periodontitis. J Periodontol 2004;75(10):1387-96.
Emingil G, Atilla G, Sorsa T, Tervahartiala T. The effect of adjunctive subantimicrobial dose
doxycycline therapy on GCF EMMPRIN levels in chronic periodontitis. J Periodontol
2008;79(3):469-76.
Emingil G, Gurkan A, Atilla G, Kantarci A. Subantimicrobial-dose doxycycline and cytokinechemokine levels in gingival crevicular fluid. J Periodontol 2011;82(3):452-61.
Gurkan A, Emingil G, Cinarcik S, Berdeli A. Post-treatment effects of subantimicrobial dose
doxycycline on clinical parameters and gingival crevicular fluid transforming growth factor-beta1
in severe, generalized chronic periodontitis. Int J Dent Hyg 2008;6(2):84-92.
Haffajee AD, Torresyap G, Socransky SS. Clinical changes following four different periodontal
therapies for the treatment of chronic periodontitis: 1-year results. J Clin Periodontol
2007;34(3):243-53.
Needleman I, Suvan J, Gilthorpe MS, et al. A randomized-controlled trial of low-dose doxycycline
for periodontitis in smokers. J Clin Periodontol 2007;34(4):325-33.
Preshaw PM, Novak MJ, Mellonig J, et al. Modified-release subantimicrobial dose doxycycline
enhances scaling and root planing in subjects with periodontal disease. J Periodontol
2008;79(3):440-52.
El-Shinnawi UM, El-Tantawy SI. The effect of alendronate sodium on alveolar bone loss in
periodontitis (clinical trial). J Int Acad Periodontol 2003;5(1):5-10.
Lane N, Armitage GC, Loomer P, et al. Bisphosphonate therapy improves the outcome of
conventional periodontal treatment: results of a 12-month, randomized, placebo-controlled study.
J Periodontol 2005;76(7):1113-22.
El-Sharkawy H, Aboelsaad N, Eliwa M, et al. Adjunctive treatment of chronic periodontitis with
daily dietary supplementation with omega-3 Fatty acids and low-dose aspirin. J Periodontol
2010;81(11):1635-43.
Reddy MS, Palcanis KG, Barnett ML, et al. Efficacy of meclofenamate sodium (Meclomen) in the
treatment of rapidly progressive periodontitis. J Clin Periodontol 1993;20(9):635-40.
Yen CA, Damoulis PD, Stark PC, et al. The effect of a selective cyclooxygenase-2 inhibitor
(celecoxib) on chronic periodontitis. J Periodontol 2008;79(1):104-13.
Preshaw PM, Hefti AF, Jepsen S, et al. Subantimicrobial dose doxycycline as adjunctive
treatment for periodontitis. A review. J Clin Periodontol 2004;31(9):697-707.
FDA Approved Drug Products. Periostat (doxycycline hyclate tablets) 20 mg label information.
Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/50783slr002_periostat_lbl.pdf.
Accessed January 14, 2014. 2004.
Al-Joburi W, Quee TC, Lautar C, et al. Effects of adjunctive treatment of periodontitis with
tetracycline and spiramycin. J Periodontol 1989;60(10):533-9.
Cionca N, Giannopoulou C, Ugolotti G, Mombelli A. Amoxicillin and metronidazole as an adjunct
to full-mouth scaling and root planing of chronic periodontitis. J Periodontol 2009;80(3):364-71.
July 2015
Page 81
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
Flemmig TF, Milian E, Karch H, Klaiber B. Differential clinical treatment outcome after systemic
metronidazole and amoxicillin in patients harboring Actinobacillus actinomycetemcomitans and/or
Porphyromonas gingivalis. J Clin Periodontol 1998;25(5):380-7.
Gomi K, Yashima A, Nagano T, et al. Effects of full-mouth scaling and root planing in conjunction
with systemically administered azithromycin. J Periodontol 2007;78(3):422-9.
Goodson JM, Haffajee AD, Socransky SS, et al. Control of periodontal infections: a randomized
controlled trial I. The primary outcome attachment gain and pocket depth reduction at treated
sites. J Clin Periodontol 2012;39(6):526-36.
Guentsch A, Jentsch H, Pfister W, Hoffmann T, Eick S. Moxifloxacin as an adjunctive antibiotic in
the treatment of severe chronic periodontitis. J Periodontol 2008;79(10):1894-903.
Mascarenhas P, Gapski R, Al-Shammari K, et al. Clinical response of azithromycin as an adjunct
to non-surgical periodontal therapy in smokers. J Periodontol 2005;76(3):426-36.
Mombelli A, Brochut P, Plagnat D, Casagni F, Giannopoulou C. Enamel matrix proteins and
systemic antibiotics as adjuncts to non-surgical periodontal treatment: clinical effects. J Clin
Periodontol 2005;32(3):225-30.
Oteo A, Herrera D, Figuero E, et al. Azithromycin as an adjunct to scaling and root planing in the
treatment of Porphyromonas gingivalis-associated periodontitis: a pilot study. J Clin Periodontol
2010;37(11):1005-15.
Palmer RM, Matthews JP, Wilson RF. Non-surgical periodontal treatment with and without
adjunctive metronidazole in smokers and non-smokers. J Clin Periodontol 1999;26(3):158-63.
Pradeep AR, Kathariya R. Clarithromycin, as an adjunct to non surgical periodontal therapy for
chronic periodontitis: a double blinded, placebo controlled, randomized clinical trial. Arch Oral Biol
2011;56(10):1112-9.
Ramberg P, Rosling B, Serino G, et al. The long-term effect of systemic tetracycline used as an
adjunct to non-surgical treatment of advanced periodontitis. J Clin Periodontol 2001;28(5):446-52.
Ribeiro Edel P, Bittencourt S, Zanin IC, et al. Full-mouth ultrasonic debridement associated with
amoxicillin and metronidazole in the treatment of severe chronic periodontitis. J Periodontol
2009;80(8):1254-64.
Sampaio E, Rocha M, Figueiredo LC, et al. Clinical and microbiological effects of azithromycin in
the treatment of generalized chronic periodontitis: a randomized placebo-controlled clinical trial. J
Clin Periodontol 2011;38(9):838-46.
Yashima A, Gomi K, Maeda N, Arai T. One-stage full-mouth versus partial-mouth scaling and root
planing during the effective half-life of systemically administered azithromycin. J Periodontol
2009;80(9):1406-13.
Han B, Emingil G, Ozdemir G, et al. Azithromycin as an adjunctive treatment of generalized
severe chronic periodontitis: clinical, microbiologic, and biochemical parameters. J Periodontol
2012;83(12):1480-91.
Martande SS, Pradeep AR, Singh SP, et al. Clinical and microbiological effects of systemic
azithromycin in adjunct to nonsurgical periodontal therapy in treatment of Aggregatibacter
actinomycetemcomitans associated periodontitis: a randomized placebo-controlled clinical trial. J
Investig Clin Dent 2014.
Miranda TS, Feres M, Perez-Chaparro PJ, et al. Metronidazole and amoxicillin as adjuncts to
scaling and root planing for the treatment of type 2 diabetic subjects with periodontitis: 1-year
outcomes of a randomized placebo-controlled clinical trial. J Clin Periodontol 2014.
Preus HR, Gunleiksrud TM, Sandvik L, Gjermo P, Baelum V. A randomized, double-masked
clinical trial comparing four periodontitis treatment strategies: 1-year clinical results. J Periodontol
2013;84(8):1075-86.
Tsalikis L, Sakellari D, Dagkalis P, Boura P, Konstantinidis A. Effects of doxycycline on clinical,
microbiological and immunological parameters in well-controlled diabetes type- 2 patients with
periodontal disease. A randomized controlled clinical trial. J Clin Periodontol 2014.
Center for Disease Control and Prevention. Antibiotic Resistance Threats in the United States,
2013: U. S. Department of Health and Human Services.
Eickholz P, Kim TS, Schacher B, et al. Subgingival topical doxycycline versus mechanical
debridement for supportive periodontal therapy: a single blind randomized controlled two-center
study. Am J Dent 2005;18(6):341-6.
July 2015
Page 82
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
Ryder MI, Pons B, Adams D, et al. Effects of smoking on local delivery of controlled-release
doxycycline as compared to scaling and root planing. J Clin Periodontol 1999;26(10):683-91.
Garrett S, Johnson L, Drisko CH, et al. Two multi-center studies evaluating locally delivered
doxycycline hyclate, placebo control, oral hygiene, and scaling and root planing in the treatment
of periodontitis. J Periodontol 1999;70(5):490-503.
Aimetti M, Romano F, Torta I, et al. Debridement and local application of tetracycline-loaded
fibres in the management of persistent periodontitis: results after 12 months. J Clin Periodontol
2004;31(3):166-72.
Drisko CL, Cobb CM, Killoy WJ, et al. Evaluation of periodontal treatments using controlledrelease tetracycline fibers: clinical response. J Periodontol 1995;66(8):692-9.
Friesen LR, Williams KB, Krause LS, Killoy WJ. Controlled local delivery of tetracycline with
polymer strips in the treatment of periodontitis. J Periodontol 2002;73(1):13-9.
Maze GI, Reinhardt RA, Agarwal RK, et al. Response to intracrevicular controlled delivery of 25%
tetracycline from poly(lactide/glycolide) film strips in SPT patients. J Clin Periodontol
1995;22(11):860-7.
Michalowicz BS, Pihlstrom BL, Drisko CL, et al. Evaluation of periodontal treatments using
controlled-release tetracycline fibers: Maintenance response. J Periodontol 1995;66(8):708-15.
Mombelli A, Lehmann B, Tonetti M, Lang NP. Clinical response to local delivery of tetracycline in
relation to overall and local periodontal conditions. J Clin Periodontol 1997;24(7):470-7.
Newman MG, Kornman KS, Doherty FM. A 6-month multi-center evaluation of adjunctive
tetracycline fiber therapy used in conjunction with scaling and root planing in maintenance
patients: clinical results. J Periodontol 1994;65(7):685-91.
Romano F, Torta I, Debernardi C, Aimetti M. Debridement and local application of tetracycline in
the management of persistent periodontitis. Clinical and microbiological results after 12 months.
Minerva Stomatol 2005;54(1-2):43-51.
Tonetti MS, Cortellini P, Carnevale G, et al. A controlled multicenter study of adjunctive use of
tetracycline periodontal fibers in mandibular class II furcations with persistent bleeding. J Clin
Periodontol 1998;25(9):728-36.
Wilson TG, Jr., McGuire MK, Greenstein G, Nunn M. Tetracycline fibers plus scaling and root
planing versus scaling and root planing alone: Similar results after 5 years. J Periodontol
1997;68(11):1029-32.
Wong MY, Lu CL, Liu CM, Hou LT, Chang WK. Clinical response of localized recurrent
periodontitis treated with scaling, root planing, and tetracycline fiber. J Formos Med Assoc
1998;97(7):490-7.
Jain R, Mohamed F, Hemalatha M. Minocycline containing local drug delivery system in the
management of chronic periodontitis: A randomized controlled trial. J Indian Soc Periodontol
2012;16(2):179-83.
Lin SJ, Tu YK, Tsai SC, Lai SM, Lu HK. Non-surgical periodontal therapy with and without
subgingival minocycline administration in patients with poorly controlled type II diabetes: a
randomized controlled clinical trial. Clin Oral Investig 2012;16(2):599-609.
Timmerman MF, van der Weijden GA, van Steenbergen TJ, et al. Evaluation of the long-term
efficacy and safety of locally-applied minocycline in adult periodontitis patients. J Clin Periodontol
1996;23(8):707-16.
van Steenberghe D, Rosling B, Soder PO, et al. A 15-month evaluation of the effects of repeated
subgingival minocycline in chronic adult periodontitis. J Periodontol 1999;70(6):657-67.
Buduneli E, Tunger A, Evrenosoglu E, Bilgic A. Comparative clinical and microbiological effects of
subgingival metronidazole application in adult periodontitis; 12-months results. J Int Acad
Periodontol 2001;3(4):81-6.
Griffiths GS, Smart GJ, Bulman JS, et al. Comparison of clinical outcomes following treatment of
chronic adult periodontitis with subgingival scaling or subgingival scaling plus metronidazole gel.
J Clin Periodontol 2000;27(12):910-7.
Knofler G, Purschwitz R, Jentsch H, Birkenmeier G, Schmidt H. Gingival crevicular fluid levels of
aspartate aminotransferase and alpha2-macroglobulin before and after topical application of
metronidazole or scaling and root planing. Quintessence Int 2008;39(5):381-9.
July 2015
Page 83
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
168.
169.
170.
Leiknes T, Leknes KN, Boe OE, Skavland RJ, Lie T. Topical use of a metronidazole gel in the
treatment of sites with symptoms of recurring chronic inflammation. J Periodontol
2007;78(8):1538-44.
Lie T, Bruun G, Boe OE. Effects of topical metronidazole and tetracycline in treatment of adult
Pedrazzoli V, Kilian M, Karring T. Comparative clinical and microbiological effects of topical
subgingival application of metronidazole 25% dental gel and scaling in the treatment of adult
periodontitis. J Clin Periodontol 1992;19(9 Pt 2):715-22.
Rudhart A, Purucker P, Kage A, Hopfenmuller W, Bernimoulin JP. Local metronidazole
application in maintenance patients. Clinical and microbiological evaluation. J Periodontol
1998;69(10):1148-54.
Stelzel M, Flores-de-Jacoby L. Topical metronidazole application as an adjunct to scaling and
root planing. J Clin Periodontol 2000;27(6):447-52.
Agarwal E, Pradeep AR, Bajaj P, Naik SB. Efficacy of local drug delivery of 0.5% clarithromycin
gel as an adjunct to non-surgical periodontal therapy in the treatment of current smokers with
chronic periodontitis: a randomized controlled clinical trial. J Periodontol 2012;83(9):1155-63.
Bajaj P, Pradeep AR, Agarwal E, Kumari M, Naik SB. Locally delivered 0.5% clarithromycin, as
an adjunct to nonsurgical treatment in chronic periodontitis with well-controlled type 2 diabetes: a
randomized controlled clinical trial. J Investig Clin Dent 2012.
Agarwal E, Bajaj P, Naik SB, Pradeep AR. Locally Delivered 0.5% Azithromycin, as an Adjunct to
Non Surgical Treatment in Chronic Periodontitis With Type 2 Diabetes: A Randomized Controlled
Clinical Trial. J Periodontol 2012.
Cosyn J, Sabzevar MM. Subgingival chlorhexidine varnish administration as an adjunct to sameday full-mouth root planing. II. Microbiological observations. J Periodontol 2007;78(3):438-45.
Cosyn J, Wyn I, De Rouck T, Sabzevar MM. Clinical benefits of subgingival chlorhexidine varnish
application as an adjunct to same-day full-mouth root planing: a pilot study. J Periodontol
2006;77(6):1074-9.
Cosyn J, Wyn I, De Rouck T, Sabzevar MM. Long-term clinical effects of a chlorhexidine varnish
implemented treatment strategy for chronic periodontitis. J Periodontol 2006;77(3):406-15.
Knofler GU, Purschwitz RE, Eick S, et al. Microbiologic findings 1 year after partial- and fullmouth scaling in the treatment of moderate chronic periodontitis. Quintessence Int
2011;42(9):e107-17.
Matesanz P, Herrera D, Echeverria A, et al. A randomized clinical trial on the clinical and
microbiological efficacy of a xanthan gel with chlorhexidine for subgingival use. Clin Oral Investig
2012.
Mongardini C, van Steenberghe D, Dekeyser C, Quirynen M. One stage full- versus partial-mouth
disinfection in the treatment of chronic adult or generalized early-onset periodontitis. I. Long-term
clinical observations. J Periodontol 1999;70(6):632-45.
Paolantonio M, D'Ercole S, Pilloni A, et al. Clinical, microbiologic, and biochemical effects of
subgingival administration of a Xanthan-based chlorhexidine gel in the treatment of periodontitis:
a randomized multicenter trial. J Periodontol 2009;80(9):1479-92.
Perinetti G, Paolantonio M, Cordella C, et al. Clinical and microbiological effects of subgingival
administration of two active gels on persistent pockets of chronic periodontitis patients. J Clin
Periodontol 2004;31(4):273-81.
Blomlof L, Bergman E, Forsgardh A, et al. A clinical study of root surface conditioning with an
EDTA gel. I. Nonsurgical periodontal treatment. Int J Periodontics Restorative Dent
2000;20(6):560-5.
Akncbay H, Senel S, Ay ZY. Application of chitosan gel in the treatment of chronic periodontitis. J
Biomed Mater Res B Appl Biomater 2007;80(2):290-6.
Azmak N, Atilla G, Luoto H, Sorsa T. The effect of subgingival controlled-release delivery of
chlorhexidine chip on clinical parameters and matrix metalloproteinase-8 levels in gingival
crevicular fluid. J Periodontol 2002;73(6):608-15.
Gonzales JR, Harnack L, Schmitt-Corsitto G, et al. A novel approach to the use of subgingival
controlled-release chlorhexidine delivery in chronic periodontitis: a randomized clinical trial. J
Periodontol 2011;82(8):1131-9.
July 2015
Page 84
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
Heasman PA, Heasman L, Stacey F, McCracken GI. Local delivery of chlorhexidine gluconate
(PerioChip) in periodontal maintenance patients. J Clin Periodontol 2001;28(1):90-5.
Paolantonio M, D'Angelo M, Grassi RF, et al. Clinical and microbiologic effects of subgingival
controlled-release delivery of chlorhexidine chip in the treatment of periodontitis: a multicenter
study. J Periodontol 2008;79(2):271-82.
Paolantonio M, Dolci M, Perfetti G, et al. Effect of a subgingival chlorhexidine chip on the clinical
parameters and the levels of alkaline phosphatase activity in gingival crevicular fluid during the
non-surgical treatment of periodontitis. J Biol Regul Homeost Agents 2008;22(1):63-72.
Sakellari D, Ioannidis I, Antoniadou M, Slini T, Konstantinidis A. Clinical and microbiological
effects of adjunctive, locally delivered chlorhexidine on patients with chronic periodontitis. J Int
Acad Periodontol 2010;12(1):20-6.
Dimitra S, Loannis L, Malama A, Theodora S, Antonis K. Clinical and microbiological effects of
adjunctive, locally delivered chlorhexidine on patients with chronic periodontitis. J Int Acad
Periodontol 2010;12(1):20-26.
Grisi DC, Salvador SL, Figueiredo LC, et al. Effect of a controlled-release chlorhexidine chip on
clinical and microbiological parameters of periodontal syndrome. J Clin Periodontol
2002;29(10):875-81.
Jeffcoat MK, Bray KS, Ciancio SG, et al. Adjunctive use of a subgingival controlled-release
chlorhexidine chip reduces probing depth and improves attachment level compared with scaling
and root planing alone. J Periodontol 1998;69(9):989-97.
Jeffcoat MK, Palcanis KG, Weatherford TW, et al. Use of a biodegradable chlorhexidine chip in
the treatment of adult periodontitis: clinical and radiographic findings. J Periodontol
2000;71(2):256-62.
Mizrak T, Guncu GN, Caglayan F, et al. Effect of a controlled-release chlorhexidine chip on
clinical and microbiological parameters and prostaglandin E2 levels in gingival crevicular fluid. J
Periodontol 2006;77(3):437-43.
Soskolne WA, Heasman PA, Stabholz A, et al. Sustained local delivery of chlorhexidine in the
treatment of periodontitis: a multi-center study. J Periodontol 1997;68(1):32-8.
Rodrigues IF, Machion L, Casati MZ, et al. Clinical evaluation of the use of locally delivered
chlorhexidine in periodontal maintenance therapy. J Periodontol 2007;78(4):624-8.
FDA U. S. Food and Drug Administration Safety Information - PerioChip (chlorhexidine
gluconate); available at http://www.fda.gov/safety/medwatch/safetyinformation/ucm330906.htm.
2012. Accessed 12 30 2013.
Agan S, Sonmez S, Serdar M. The effect of topical doxycycline usage on gingival crevicular fluid
MMP-8 levels of chronic and aggressive periodontitis patients: a pilot study. Int J Dent Hyg
2006;4(3):114-21.
Machion L, Andia DC, Benatti BB, et al. Locally delivered doxycycline as an adjunctive therapy to
scaling and root planing in the treatment of smokers: a clinical study. J Periodontol
2004;75(3):464-9.
Martorelli de Lima AF, Cury CC, Palioto DB, et al. Therapy with adjunctive doxycycline local
delivery in patients with type 1 diabetes mellitus and periodontitis. J Clin Periodontol
2004;31(8):648-53.
Machion L, Andia DC, Lecio G, et al. Locally delivered doxycycline as an adjunctive therapy to
scaling and root planing in the treatment of smokers: a 2-year follow-up. J Periodontol
2006;77(4):606-13.
Tonetti MS, Lang NP, Cortellini P, et al. Effects of a single topical doxycycline administration
adjunctive to mechanical debridement in patients with persistent/recurrent periodontitis but
acceptable oral hygiene during supportive periodontal therapy. J Clin Periodontol 2012;39(5):47582.
Oringer RJ, Van Dyke TE, Lessem J. The challenge of treating periodontal patients who smoke-the efficacy of Arestin. J Int Acad Periodontol 2002;4(3):89-94.
FDA Center for Drug Application Reviews. Statistical Review and Evaluation, Application Number
NDA 50-781. available at: www.fda.gov; 2000.
Wennstrom JL, Newman HN, MacNeill SR, et al. Utilisation of locally delivered doxycycline in
non-surgical treatment of chronic periodontitis. A comparative multi-centre trial of 2 treatment
approaches. J Clin Periodontol 2001;28(8):753-61.
July 2015
Page 85
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
207.
208.
209.
210.
Garrett S. Local delivery of doxycycline for the treatment of periodontitis. Compend Contin Educ
Dent 1999;20(5):437-40, 42, 44 passim; quiz 48.
FDA Approved Drug Products. Atridox (doxycycline hyclate) 10% label information. Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.
Accessed on January 14, 2014.; 2011.
Henderson RJ, Boyens JV, Holborow DW, Pack AR. Scaling and root-planing treatment with
adjunctive subgingival minocycline. A clinical pilot study over six months, of sites adjacent to and
remote from the antibiotic application. J Int Acad Periodontol 2002;4(3):77-87.
Skaleric U, Schara R, Medvescek M, et al. Periodontal treatment by Arestin and its effects on
glycemic control in type 1 diabetes patients. J Int Acad Periodontol 2004;6(4 Suppl):160-5.
Williams RC, Paquette DW, Offenbacher S, et al. Treatment of periodontitis by local
administration of minocycline microspheres: a controlled trial. J Periodontol 2001;72(11):1535-44.
FDA Approved Drug Products. Arestin (minocycline hydrochloride) Microspheres, 1 mg label
information. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050781s019lbl.pdf. Accessed on
January 14, 2014. 2012.
Dilsiz A, Canakci V, Aydin T. Clinical Effects of KTP Laser and Photodynamic Therapy on
Outcomes of Treatment of Chronic Periodontitis: A Randomized Controlled Clinical Trial. J
Periodontol 2012.
Berakdar M, Callaway A, Eddin MF, Ross A, Willershausen B. Comparison between scaling-rootplaning (SRP) and SRP/photodynamic therapy: six-month study. Head Face Med 2012;8:12.
Chondros P, Nikolidakis D, Christodoulides N, et al. Photodynamic therapy as adjunct to nonsurgical periodontal treatment in patients on periodontal maintenance: a randomized controlled
clinical trial. Lasers Med Sci 2009;24(5):681-8.
Christodoulides N, Nikolidakis D, Chondros P, et al. Photodynamic therapy as an adjunct to nonsurgical periodontal treatment: a randomized, controlled clinical trial. J Periodontol
2008;79(9):1638-44.
Giannelli M, Formigli L, Lorenzini L, Bani D. Combined photoablative and photodynamic diode
laser therapy as an adjunct to non-surgical periodontal treatment. A randomized split-mouth
clinical trial. J Clin Periodontol 2012;39(10):962-70.
Theodoro LH, Silva SP, Pires JR, et al. Clinical and microbiological effects of photodynamic
therapy associated with nonsurgical periodontal treatment. A 6-month follow-up. Lasers Med Sci
2012;27(4):687-93.
Filho GAN, Casarin RC, Casati MZ, Giovani EM. PDT in non-surgical treatment of periodontitis in
HIV patients: a split-mouth, randomized clinical trial. Lasers Surg Med 2012;44(4):296-302.
Alwaeli HA, Al-Khateeb SN, Al-Sadi A. Long-term clinical effect of adjunctive antimicrobial
photodynamic therapy in periodontal treatment: a randomized clinical trial. Lasers Med Sci 2013.
Betsy J, Prasanth CS, Baiju KV, Prasanthila J, Subhash N. Efficacy of antimicrobial
photodynamic therapy in the management of chronic periodontitis: a randomized controlled
clinical trial. J Clin Periodontol 2014;41(6):573-81.
Dilsiz A, Canakci V, Aydin T. Clinical effects of potassium-titanyl-phosphate laser and
photodynamic therapy on outcomes of treatment of chronic periodontitis: a randomized controlled
clinical trial. J Periodontol 2013;84(3):278-86.
Luchesi VH, Pimentel SP, Kolbe MF, et al. Photodynamic therapy in the treatment of class II
furcation: a randomized controlled clinical trial. J Clin Periodontol 2013;40(8):781-8.
Euzebio Alves VT, de Andrade AK, Toaliar JM, et al. Clinical and microbiological evaluation of
high intensity diode laser adjutant to non-surgical periodontal treatment: a 6-month clinical trial.
Clin Oral Investig 2013;17(1):87-95.
Saglam M, Kantarci A, Dundar N, Hakki SS. Clinical and biochemical effects of diode laser as an
adjunct to nonsurgical treatment of chronic periodontitis: a randomized, controlled clinical trial.
Lasers Med Sci 2014;29(1):37-46.
Ustun K, Erciyas K, Sezer U, et al. Clinical and biochemical effects of 810 nm diode laser as an
adjunct to periodontal therapy: a randomized split-mouth clinical trial. Photomed Laser Surg
2014;32(2):61-6.
July 2015
Page 86
211.
212.
213.
214.
215.
216.
217.
218.
Caruso U, Nastri L, Piccolomini R, et al. Use of diode laser 980 nm as adjunctive therapy in the
treatment of chronic periodontitis. A randomized controlled clinical trial. New Microbiol
2008;31(4):513-8.
Eltas A, Orbak R. Effect of 1,064-nm Nd:YAG laser therapy on GCF IL-1beta and MMP-8 levels
in patients with chronic periodontitis. Lasers Med Sci 2012;27(3):543-50.
Eltas A, Orbak R. Clinical effects of Nd:YAG laser applications during nonsurgical periodontal
treatment in smoking and nonsmoking patients with chronic periodontitis. Photomed Laser Surg
2012;30(7):360-6.
Kelbauskiene S, Baseviciene N, Goharkhay K, Moritz A, Machiulskiene V. One-year clinical
results of Er,Cr:YSGG laser application in addition to scaling and root planing in patients with
early to moderate periodontitis. Lasers Med Sci 2011;26(4):445-52.
Lopes BM, Theodoro LH, Melo RF, Thompson GM, Marcantonio RA. Clinical and microbiologic
follow-up evaluations after non-surgical periodontal treatment with erbium:YAG laser and scaling
and root planing. J Periodontol 2010;81(5):682-91.
Garrett S, Adams DF, Bogle G, et al. The effect of locally delivered controlled-release doxycycline
or scaling and root planing on periodontal maintenance patients over 9 months. J Periodontol
2000;71(1):22-30.
Scholey JM, Harrison JE. Delay and failure to publish dental research. Evid Based Dent
2005;6(3):58-61.
Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 statement: updated
guidelines for reporting parallel group randomized trials. Ann Intern Med 2010;152(11):726-32.
July 2015
Page 87
9.
Appendices
Appendix 1 – Literature searches and results
The panel decided to use two strategies for the literature search to be inclusive as well as pragmatic. The
first specified clinical attachment level, but did not filter by study design. The second used a filter for
randomized controlled trials (RCTs), but did not specify the outcome (clinical attachment level). The
purpose of the first search design was to retrieve all articles specifying clinical attachment level in the title
or abstract, and the purpose of the second was to retrieve all RCTs with the keywords on periodontal
disease, which could be hand-screened for applicability. Although the panel only included articles with
data on clinical attachment level, they were not confident that the authors would always mention that data
in the abstract.
Primary Search Strategy: Hits shown for PubMed/MEDLINE
Search
number
#1
Topic
Chronic
Periodontitis
#2
Scaling and Root
Planing
#3
#6
#4
Clinical Attachment
Level
#1 AND #2 AND #3
Exclusions/Limits
#5
#7
#8
#6 NOT #4
#7 AND #5
Syntax
(((((periodontal disease [mesh]) NOT gingival diseases
[mesh]) NOT peri-implantitis [mesh]) NOT periapical
diseases [mesh]) NOT periodontal cyst [mesh]) OR
periodontal disease [tw] OR periodontitis
dental scaling [mesh] OR dental scaling [tw] OR dental
prophylaxis [mesh] OR dental prophylaxis [tw] OR root
planing [mesh] OR root planing [tw] OR dental cleaning
OR scaling root planing OR root planing OR scaling
planing OR ultrasonic therapy [mesh] OR ultrasonic
therapy [tw] OR ultrasonic surgical procedures [mesh]
OR ultrasonic surgical procedures [tw] OR ultrasonic
scaling
attachment OR periodontal atrophy [mesh] OR
periodontal atrophy [tw]
(animal[mh] NOT human[mh]) OR cadaver[mh] OR
cadaver*[titl] OR ((comment[pt] OR editorial[pt] OR
letter[pt] OR "historical article"[pt]) NOT "clinical trial"[pt])
OR addresses[pt] OR news[pt] OR "newspaper
article"[pt] OR pmcbook
english [lang]
Hits
52861
31299
85302
1405
5336240
17861430
1325
1128
abstracts
399
RCTs
Secondary Search Strategy: same as primary except CAL replaced by RCT filter: (randomized
controlled trial[Publication Type] OR (randomized[Title/Abstract] AND controlled[Title/Abstract]
AND trial[Title/Abstract])) with approximately 600 records found.
July 2015
Page 88
Primary Search Strategy: Hits shown for Embase (10-31-12)
Topic
Search #
#1
Syntax
periodontal AND 'disease'/exp AND
Hits
50,794
[humans]/lim AND [english]/lim
#2
'periodontitis'/exp AND 'disease'/exp AND
18,648
#3
Chronic
Periodontitis
'peri implantitis'/exp AND [humans]/lim AND
136
[english]/lim
#4
periapical AND 'diseases'/exp AND
4,486
#5
periodontal AND 'cyst'/exp AND [humans]/lim
693
AND [english]/lim
#6
#3 OR #4 OR #5
5,028
#7
#1 OR #2
50,794
#8
#7 NOT #6
#9
dental AND scaling AND [humans]/lim AND
46,747
1,854
[english]/lim
#10
dental AND 'prophylaxis'/exp AND
9,799
#11
root AND planing AND [humans]/lim AND
1,285
[english]/lim
#12
dental AND 'cleaning'/exp AND [humans]/lim
150
AND [english]/lim
#13
Scaling and Root
Planing
scaling AND root AND planing AND
1,099
#14
scaling AND planing AND [humans]/lim AND
1,100
[english]/lim
#15
'ultrasonic'/exp AND 'therapy'/exp AND
18,369
#16
'ultrasonic'/exp AND surgical AND
11,979
'procedures'/exp AND [humans]/lim AND
[english]/lim
#17
'ultrasonic'/exp AND scaling AND
66
#18
#9 OR #10 OR #11 OR #12 OR #13 OR #14
35,909
OR #15 OR #16 OR #17
Combined
RCT
July 2015
#19
#20
#8 AND #18
2,229
#19 AND 'randomized controlled trial'/de
526
Page 89
Secondary Search Strategy: Hits shown for Embase (10-25-12)
Topic
Search #
#1
Syntax
periodontal AND 'disease'/exp AND
Hits
50,769
Chronic
Periodontitis
#2
gingival AND 'diseases'/exp
18,203
#3
'peri implantitis'/exp
176
#4
periapical AND 'diseases'/exp
6,753
#5
periodontal AND 'cyst'/exp
1,020
#6
'periodontitis'/exp
28,928
#7
#2 OR #3 OR #4 OR #5
25,441
#8
#1 OR #6
#9
#10
#8 NOT #7
61,059
44,716
dental AND scaling AND [humans]/lim AND
1,855
[english]/lim
#11
dental AND 'prophylaxis'/exp AND
9,790
#12
#13
root AND planing
1,554
dental AND 'cleaning'/exp AND [humans]/lim
150
AND [english]/lim
#14
Scaling and Root
Planing
scaling AND root AND planing AND
1,100
#15
scaling AND planing
1,276
#16
'ultrasonic'/exp AND 'therapy'/exp AND
18,274
#17
'ultrasonic'/exp AND surgical AND
11,920
'procedures'/exp AND [humans]/lim AND
[english]/lim
#18
'ultrasonic'/exp AND scaling AND
66
#19
#10 OR #11 OR #12 OR #13 OR #14 OR #15
36,071
OR #16 OR #17 OR #18
#20
attachment AND [humans]/lim AND
74,675
[english]/lim
#21
Clinical
attachment level
attachment AND level AND [humans]/lim AND
9,491
[english]/lim
#22
attachment AND loss AND [humans]/lim AND
6,053
[english]/lim
#23
periodontal AND 'atrophy'/exp AND
377
Combined
July 2015
#24
#25
#20 OR #21 OR #22 OR #23
75,040
#9 AND #19 AND #24
374
Page 90
#26
#9 AND #19 AND #24 AND [humans]/lim AND
374
[english]/lim
#27
preventative AND 'dentistry'/exp AND
15
#28
#1 OR #6 OR #27
61,071
#29
#30
#28 NOT #7
44,727
#19 AND #24 AND #29
374
1654 articles captured from Medline and Embase via primary and secondary searches with duplicates
removed.
442 abstracts recalled for full text
July 2015
Page 91
Appendix 2 – Excluded studies and reasons for exclusion
Author
Year
Abou Sulaiman, A. E. and R. M.
Shehadeh
2010
Agarwal, E., A. R. Pradeep, P.
Bajaj and S. B. Naik
2012
Agarwal, E., P. Bajaj, S. B. Naik
and A. R. Pradeep
2012
Ah, M. K., G. K. Johnson, W. B.
Kaldahl, K. D. Patil and K. L.
Kalkwarf
1994
Aimetti, M., F. Romano, I. Torta,
D. Cirillo, P. Caposio and R.
Romagnoli
2004
Aimetti, M., F. Romano, N. Guzzi
and G. Carnevale
2011
Aitken, S., P. Birek, G. V.
Kulkarni, W. L. Lee and C. A.
McCulloch
Akalin, F. A., E. Baltacioglu, D.
Sengun, S. Hekimoglu, M.
Taskin, I. Etikan and I. Fisenk
Akncbay, H., S. Senel and Z. Y.
Ay
Alec Yen, C., P. D. Damoulis, P.
C. Stark, P. L. Hibberd, M. Singh
and A. S. Papas
July 2015
1992
2004
2007
2008
Title
Assessment of total antioxidant capacity and
the use of vitamin C in the treatment of nonsmokers with chronic periodontitis
Efficacy of local drug delivery of 0.5%
clarithromycin gel as an adjunct to nonsurgical periodontal therapy in the treatment
of current smokers with chronic periodontitis:
a randomized controlled clinical trial
Locally Delivered 0.5% Azithromycin, as an
Adjunct to Non Surgical Treatment in Chronic
Periodontitis With Type 2 Diabetes: A
Randomized Controlled Clinical Trial
The effect of smoking on the response to
periodontal therapy
Debridement and local application of
tetracycline-loaded fibres in the management
of persistent periodontitis: results after 12
months
One-stage full-mouth disinfection as a
therapeutic approach for generalized
aggressive periodontitis
Serial doxycycline and metronidazole in
prevention of recurrent periodontitis in highrisk patients
A comparative evaluation of the clinical effects
of systemic and local doxycycline in the
treatment of chronic periodontitis
Application of chitosan gel in the treatment of
The effect of a selective cyclooxygenase-2
inhibitor (celecoxib) on chronic periodontitis
Journal
Volume
Issue
Page
J Periodontol
81
11
1547-54
Not 6 month study - too
short
J Periodontol
83
9
1155-63
Not commercially available
J Periodontol
Reason if Exclude
J Clin Periodontol
21
2
91-7
Paper does not present
nonsurgical data separate
from all data
J Clin Periodontol
31
3
166-72
J Periodontol
82
6
845-53
Aggressive perio
J Periodontol
63
2
87-92
Study evaluated use of
metronidazol for recurrent
perio within 7 months of
SRP plus placebo or SRP
plus doxycycline. This study
is really assessing the
impact that placebo vs
doxycycline pre tx has on
subsequent metronidazol
use. No comparison to SRP
alone vs metronidazol.
J Oral Sci
46
1
25-35
short
J Biomed Mater Res B
Appl Biomater
80
2
290-6
J Periodontol
79
1
104-113
Duplicate citation YEN
excluded anti inflammatory
Page 92
Al Mubarak, S., M. Abou Rass, A.
Alsuwyed, K. Al-Zoman, A. Al
Sohail, S. Sobki, M. Tariq, A.
Alwin Robert, S. Ciancio and P.
Dandona
Al-Mubarak, S., S. Ciancio, A.
Aljada, P. Mohanty, C. Ross and
P. Dandona
Al-Katma, M. K., N. F. Bissada, J.
M. Bordeaux, J. Sue and A. D.
Askari
2010
A new paradigm between mechanical scaling
and root planing combined with adjunctive
chemotherapy for glycated hemoglobin
improvement in diabetics
International Journal of
Diabetes Mellitus
2
3
158-164
Wrong intervention
2002
Comparative evaluation of adjunctive oral
irrigation in diabetics
J Clin Periodontol
29
4
295-300
Only 12 weeks in duration
2007
Control of periodontal infection reduces the
severity of active rheumatoid arthritis
J Clin Rheumatol
13
3
134-7
short
Alptekin, N. O., F. Kurtoglu, B.
Serpek, I. Duran and M. Gozlu
2000
Effects on the clinical indices and gingival
crevicular fluid enzyme activities of the cyclical
regimen of low-dose doxycycline therapy for
adult periodontitis
J Int Acad Periodontol
2
1
8-Mar
Not RCT
Alves, R. V., L. Machion, M. Z.
Casati, F. H. Nociti Jr, E. A.
Sallum and A. W. Sallum
2005
Clinical attachment loss produced by curettes
and ultrasonic scalers
J Clin Periodontol
32
7
691-694
No passive control
Angaji, M., S. Gelskey, G.
Nogueira-Filho and D. Brothwell
2010
A systematic review of clinical efficacy of
adjunctive antibiotics in the treatment of
smokers with periodontitis
J Periodontol
81
11
1518-28
Review
Angelov, N., S. Pesevska, M.
Nakova, I. Gjorgoski, K.
Ivanovski, D. Angelova, O.
Hoffmann and S. Andreana
2009
Periodontal treatment with a low-level diode
laser: clinical findings
Gen Dent
57
5
510-3
short
Apatzidou, D. A. and D. F. Kinane
2004
J Clin Periodontol
31
2
132-40
Comparison of 2 types of
SRP
Apatzidou, D. A., M. P. Riggio
and D. F. Kinane
2004
J Clin Periodontol
31
2
141-8
No CAL data
Aras, H., F. Caglayan, G. N.
Guncu, A. Berberoglu and K.
Kilinc
2007
J Periodontol
78
5
868-73
No CAL data
Ashley, R. A.
1999
Ann N Y Acad Sci
878
335-46
Duplicate to Caton 2000
data
Atieh, M. A.
2010
Lasers Med Sci
25
605-13
Review
Auyeung, L., P. W. Wang, R. T.
Lin, C. J. Hsieh, P. Y. Lee, R. Y.
Zhuang and H. W. Chang
Aykol, G., U. Baser, I. Maden, Z.
Kazak, U. Onan, S. Tanrikulu-
July 2015
Quadrant root planing versus same-day fullmouth root planing. I. Clinical findings
Quadrant root planing versus same-day fullmouth root planing. II. Microbiological findings
Effect of systemically administered naproxen
sodium on clinical parameters and
myeloperoxidase and elastase-like activity
levels in gingival crevicular fluid
Clinical trials of a matrix metalloproteinase
inhibitor in human periodontal disease. SDD
Clinical Research Team
Photodynamic therapy as an adjunctive
treatment for chronic periodontitis: a metaanalysis
4
2012
Evaluation of periodontal status and
effectiveness of non-surgical treatment in
patients with type 2 diabetes mellitus in
Taiwan for a 1-year period
J Periodontol
83
5
621-8
Not RCT. This study
compared SRP among
patients with diabetes.
There was no placebo group
that did not receive S&RP.
There was no randomization
because the same tx (SRP)
was provided to both groups
2011
The effect of low-level laser therapy as an
adjunct to non-surgical periodontal treatment
J Periodontol
82
3
481-8
Experimental therapy
(biostimulation)
Page 93
Kucuk, E. Ademoglu, H. Issever
and F. Yalcin
Azarpazhooh, A., P. S. Shah, H.
C. Tenenbaum and M. B.
Goldberg
Badersten, A., R. Nilveus and J.
Egelberg
Egelberg
Egelberg
2010
1981
1984
1984
Egelberg
1985
Bain, C. A., G. S. Beagrie, J.
Bourgoin, F. Delorme, A.
Holthuis, R. G. Landry, S. Roy, P.
Schuller, D. Singer and R.
Turnbull
1994
Bajaj, P., A. R. Pradeep, E.
Agarwal, M. Kumari and S. B.
Naik
2012
Beikler, T., H. Karch, B. Ehmke,
B. Klaiber and T. F. Flemmig
1999
Beirne, P., A. Forgie, H. V.
Worthington and J. E. Clarkson
Beirne, P., H. V. Worthington and
J. E. Clarkson
Berglundh, T., B. Liljenberg and
J. Lindhe
Berkey, C. S., A. AntczakBouckoms, D. C. Hoaglin, F.
Mosteller and B. L. Pihlstrom
Blomlof, L., E. Bergman, A.
Forsgardh, L. Foss, A. Larsson,
B. Sjoberg, L. Uhlander, B.
Jonsson, J. Blomlof and S.
Lindskog
Bogren, A., R. P. Teles, G.
Torresyap, A. D. Haffajee, S. S.
Socransky and J. L. Wennstrom
Bogren, A., R. Teles, G.
Torresyap, A. D. Haffajee, S. S.
Socransky, J. Lindhe and J. L.
Wennstrom
July 2015
2005
2007
1999
The effect of photodynamic therapy for
periodontitis: a systematic review and metaanalysis
Effect of nonsurgical periodontal therapy. I.
Moderately advanced periodontitis
Effect of nonsurgical periodontal therapy. II.
Severely advanced periodontitis
Effect of nonsurgical periodontal therapy. III.
Single versus repeated instrumentation
Effect of nonsurgical periodontal therapy. V.
Patterns of probing attachment loss in nonresponding sites
The effects of spiramycin and/or scaling on
advanced periodontitis in humans
Locally delivered 0.5% clarithromycin, as an
adjunct to nonsurgical treatment in chronic
periodontitis with well-controlled type 2
diabetes: a randomized controlled clinical trial
Protective effect of serum antibodies against a
110-kilodalton protein of Actinobacillus
actinomycetemcomitans following periodontal
therapy
Routine scale and polish for periodontal health
in adults
Routine scale and polish for periodontal health
in adults
Some effects of periodontal therapy on local
and systemic immunological parameters
J Periodontol
81
1
14-Apr
Review
J Clin Periodontol
8
1
57-72
No passive control
J Clin Periodontol
11
1
63-76
No passive control
J Clin Periodontol
11
2
114-24
No passive control
J Clin Periodontol
12
4
270-82
No passive control
J Can Dent Assoc
60
3
209, 212-7
J Investig Clin Dent
Oral Microbiol Immunol
Spiramycin not available in
USA
14
Cochrane Database Syst
Rev
Rev
5
281-7
1
CD004625
Review
4
CD004625
Review
J Clin Periodontol
26
2
91-8
No CAL data
No passive control
1995
Multiple-outcomes meta-analysis of
treatments for periodontal disease
J Dent Res
74
4
1030-9
Review
2000
A clinical study of root surface conditioning
with an EDTA gel. I. Nonsurgical periodontal
treatment
Int J Periodontics
Restorative Dent
20
6
560-5
24% EDTA gel. Not
commercially available in
US. Only 17% is available
2008
Locally delivered doxycycline during
supportive periodontal therapy: a 3-year study
J Periodontol
79
5
827-35
Doxycycline was provided
annually after SRP
2007
A three-year prospective study of adult
subjects with gingivitis. I: clinical periodontal
parameters
J Clin Periodontol
34
1
6-Jan
No CAL data
Page 94
Bonito, A. J., L. Lux and K. N.
Lohr
2005
Bono, A. and M. Brunotto
2010
Borrajo, J. L., L. G. Varela, G. L.
Castro, I. Rodriguez-Nunez and
M. G. Torreira
Bosco, J. M., B. M. Lopes, A. F.
Bosco, D. M. Spolidorio and R. A.
Marcantonio
2004
2009
Impact of local adjuncts to scaling and root
planing in periodontal disease therapy: a
systematic review
Amoxicillin/metronidazole or scaling and root
planing in the treatment of chronic
periodontitis
Diode laser (980 nm) as adjunct to scaling
and root planing
Local application of tetracycline solution with a
microbrush: an alternative treatment for
persistent periodontitis
Antimicrobial irrigation of deep pockets to
supplement non-surgical periodontal therapy.
II. Daily irrigation
Comparative clinical and microbiological
effects of subgingival metronidazole
application in adult periodontitis; 12-months
results
Clinical and microbiological effects of an
essential-oil-containing mouth rinse applied in
the "one-stage full-mouth disinfection"
protocol--a randomized doubled-blinded
preliminary study
Treatment of residual pockets with
photodynamic therapy, diode laser, or deep
scaling. A randomized, split-mouth controlled
clinical trial
Evaluation of the effect of subgingival
placement of chlorhexidine chips as an
adjunct to scaling and root planing
J Periodontol
76
8
1227-36
Review
Acta Odontol Latinoam
23
3
196-203
Review
Photomed Laser Surg
22
6
509-12
short
Quintessence Int
40
1
29-40
J Clin Periodontol
12
8
630-8
Debridement not SRP
3
4
81-6
Clin Oral Investig
13
2
189-94
No CAL data
Lasers Med Sci
27
5
979-986
Not adjuncts and no control
J Periodontol
78
6
997-1001
retx with CHX chip
J Clin Periodontol
28
8
782-9
Doubling Caton 2000 data
Braatz, L., S. Garrett, N. Claffey
and J. Egelberg
1985
Buduneli, E., A. Tunger, E.
Evrenosoglu and A. Bilgic
2001
Cavalca Cortelli, S., F. Cavallini,
M. F. Regueira Alves, A. Alves
Bezerra, Jr., C. S. Queiroz and J.
R. Cortelli
2009
Cappuyns, I., N. Cionca, P. Wick,
C. Giannopoulou and A. Mombelli
2012
Carvalho, J., M. J. Novak and L.
F. Mota
2007
Caton, J. G., S. G. Ciancio, T. M.
Blieden, M. Bradshaw, R. J.
Crout, A. F. Hefti, J. M. Massaro,
A. M. Polson, J. Thomas and C.
Walker
2001
Subantimicrobial dose doxycycline as an
adjunct to scaling and root planing: posttreatment effects
Cercek, J. F., R. D. Kiger, S.
Garrett and J. Egelberg
1983
Relative effects of plaque control and
instrumentation on the clinical parameters of
human periodontal disease
J Clin Periodontol
10
1
46-56
Not a randomized trial.
There were three sequential
treatments, but no control
group.
Chapple, I. L., A. D. Walmsley, M.
S. Saxby and H. Moscrop
1992
Effect of subgingival irrigation with
chlorhexidine during ultrasonic scaling
J Periodontol
63
10
812-6
Compares 2 types of scalers
Chapple, I. L., A. D. Walmsley, M.
S. Saxby and H. Moscrop
1995
Effect of instrument power setting during
ultrasonic scaling upon treatment outcome
J Periodontol
66
9
756-60
No control group; measured
power levels of ultrasonic
scalers
Chapple, I. L., M. R. Milward, N.
Ling-Mountford, P. Weston, K.
Carter, K. Askey, G. E. Dallal, S.
2012
Adjunctive daily supplementation with
encapsulated fruit, vegetable and berry juice
powder concentrates and clinical periodontal
outcomes: a double-blind RCT
J Clin Periodontol
39
1
62-72
Not adjunct of interest
July 2015
Page 95
De Spirt, H. Sies, D. Patel and J.
B. Matthews
Chaves, E. S., M. K. Jeffcoat, C.
C. Ryerson and B. Snyder
Chee, H. K., L. P. Lim, F. Tay, A.
C. Thai and C. F. Sum
Chen, T., Y. Zhou, J. Liu, B. Xu,
Z. Wu and D. Li
Chin Quee, T., W. Al-Joburi, C.
Lautar-Lemay, E. C. Chan, I.
Iugovaz, J. Bourgouin and F.
Delorme
Christgau, M., T. Manner, S.
Beuer, K. A. Hiller and G.
Schmalz
2000
2008
2002
1988
2007
Christie, P., N. Claffey and S.
Renvert
1998
Cionca, N., C. Giannopoulou, G.
Ugolotti and A. Mombelli
2010
Claffey, N., A. Kelly, J. Bergquist
and J. Egelberg
1996
Clark, D. C., S. Shenker, P.
Stulginski and S. Schwartz
1983
Cobb, C. M.
2002
Cobb, C. M.
2006
Copulos, T. A., S. B. Low, C. B.
Walker, Y. Y. Trebilcock and A. F.
Hefti
1993
Correa, F. O., D. Goncalves, C.
M. Figueredo, A. Gustafsson and
S. R. Orrico
2008
Corsair, A.
1994
July 2015
Persistent bacterial colonization of
Porphyromonas gingivalis, Prevotella
intermedia, and Actinobacillus
actinomycetemcomitans in periodontitis and
its association with alveolar bone loss after 6
months of therapy
Non-surgical periodontal treatment and lipid
levels in diabetic patients
Biological effects of hyperbaric oxygen on
human severe periodontitis
Comparison of spiramycin and tetracycline
used adjunctively in the treatment of
advanced chronic periodontitis
Periodontal healing after non-surgical therapy
with a new ultrasonic device: a randomized
controlled clinical trial
The use of 0.2% chlorhexidine in the absence
of a structured mechanical regimen of oral
hygiene following the non-surgical treatment
of periodontitis
Microbiologic testing and outcomes of fullmouth scaling and root planing with or without
amoxicillin/metronidazole in chronic
periodontitis
Patterns of attachment loss in advanced
periodontitis patients monitored following
initial periodontal treatment
Effectiveness of routine periodontal treatment
with and without adjunctive metronidazole
therapy in a sample of mentally retarded
adolescents
Clinical significance of non-surgical
periodontal therapy: an evidence-based
perspective of scaling and root planing
Lasers in periodontics: a review of the
literature
Comparative analysis between a modified
ultrasonic tip and hand instruments on clinical
parameters of periodontal disease
The short-term effectiveness of non-surgical
treatment in reducing levels of interleukin1beta and proteases in gingival crevicular fluid
from patients with type 2 diabetes mellitus and
Long-term effect of tetracycline fibers on
recurrent lesions in periodontal maintenance
patients
J Clin Periodontol
27
Ann R Australas Coll
Dent Surg
19
Undersea Hyperb Med
29
J Antimicrob Chemother
12
3
22 Suppl B
897-903
No CAL data
183
Conference proceedings
159-66
Experimental treatment
(hyperbaric oxygen)
171-7
No CAL data provided
J Clin Periodontol
34
2
137-47
No control group
J Clin Periodontol
25
1
15-23
No control group
J Periodontol
81
1
15-23
No CAL data
J Clin Periodontol
23
6
523-31
No control group
J Periodontol
54
11
658-65
Not SRP
16-Jun
Review
J Clin Periodontol
29 Suppl 2
J Periodontol
77
4
545-64
Review
J Periodontol
64
8
694-700
No passive control
J Periodontol
79
11
2143-50
Not 6 month trial
Periodontal Clin Investig
16
1
13-Aug
No control
Page 96
Cortelli, J. R., D. R. Aquino, S. C.
Cortelli, J. Carvalho-Filho, C. V.
Roman-Torres and F. O. Costa
Cortelli, S. C., F. O. Costa, T.
Kawai, D. R. Aquino, G. C.
Franco, K. Ohara, C. V. RomanTorres and J. R. Cortelli
Cortelli, S. C., J. R. Cortelli, M.
Holzhausen, G. C. Franco, R. Z.
Rebelo, A. S. Sonagere, S.
Queiroz Cda and F. O. Costa
2008
2009
2009
Cosyn, J. and I. Wyn
2006
Cosyn, J., I. Wyn, T. De Rouck
and M. M. Sabzevar
2006
and M. M. Sabzevar
2006
and M. M. Sabzevar
2007
Crespi, R., P. Cappare, I.
Toscanelli, E. Gherlone and G. E.
Romanos
Dannewitz, B., K. Lippert, N. P.
Lang, M. S. Tonetti and P.
Eickholz
Darby, I. B., P. J. Hodge, M. P.
Riggio and D. F. Kinane
Daudt, F. A., C. K. Rosing, G. A.
Chiapinotto and R. V. Oppermann
De Micheli, G., A. K. de Andrade,
V. T. Alves, M. Seto, C. M.
Pannuti and S. Cai
De Micheli, G., A. K. P. De
Andrade, V. T. E. Alves, M. Seto,
C. M. Pannuti and S. Cai
Dean, J. W., G. L. Branch-Mays,
T. C. Hart, R. A. Reinhardt, B.
Shapiro, E. A. Santucci and J.
Lessem
Del Peloso Ribeiro, E., S.
Bittencourt, F. H. Nociti, Jr., E. A.
Sallum, A. W. Sallum and M. Z.
Casati
July 2015
2007
2009
2005
2011
2011
2011
A double-blind randomized clinical trial of
subgingival minocycline for chronic
periodontitis
Diminished treatment response of
periodontally diseased patients infected with
the JP2 clone of Aggregatibacter
(Actinobacillus) actinomycetemcomitans
Essential oils in one-stage full-mouth
disinfection: double-blind, randomized clinical
trial of long-term clinical, microbial and
salivary effects
A systematic review on the effects of the
chlorhexidine chip when used as an adjunct to
scaling and root planing in the treatment of
Clinical benefits of subgingival chlorhexidine
varnish application as an adjunct to same-day
full-mouth root planing: a pilot study. Journal
of Periodontology 77, 1074-1079.
Long-term clinical effects of chlorhexidine
varnish implemented treatment strategy for
Subgingival chlorhexidine varnish
administration as an adjunct to same-day fullmouth root planing. I. Clinical observations
Effects of Er:YAG laser compared to
ultrasonic scaler in periodontal treatment: a 2year follow-up split-mouth clinical study
Supportive periodontal therapy of furcation
sites: non-surgical instrumentation with or
without topical doxycycline
Clinical and microbiological effect of scaling
and root planing in smoker and non-smoker
chronic and aggressive periodontitis patients
Effect of the topical application of triclosan in
periodontally treated patients
Efficacy of high intensity diode laser as an
adjunct to non-surgical periodontal treatment:
a randomized controlled trial
Efficacy of high intensity diode laser as an
adjunct to non-surgical periodontal treatment:
A randomized controlled trial
J Oral Sci
50
3
259-65
No CAL data
J Clin Microbiol
47
7
2018-25
No control group
J Clin Periodontol
36
4
333-42
No CAL data
J Periodontol
77
2
257-64
Review
J Periodontol
77
3
1074-1079.
J Periodontol
77
3
406-415
J Periodontol
78
3
430-7
J Periodontol
78
7
1195-200
J Clin Periodontol
36
6
514-22
Subset of Tonetti 2012
J Clin Periodontol
32
2
200-6
No control group
24
2
205-10
Not 6 month trial
Lasers Med Sci
26
1
43-8
Duplicate
Lasers Med Sci
26
1
43-48
short
2003
Topically applied minocycline microspheres:
why it works
Compend Contin Educ
Dent
24
4
247-50,
252-7; quiz
258
2007
Comparative study of ultrasonic
instrumentation for the non-surgical treatment
of interproximal and non-interproximal
furcation involvements
J Periodontol
78
2
224-30
short
Not commercially avail in
US
CHX Varnish not available
in US
Laser not adjunct
No control no CAL
No control group
Page 97
D'Ercole, S., R. Piccolomini, G.
Capaldo, G. Catamo, G. Perinetti
and L. Guida
2006
Derdilopoulou, F. V., J. Nonhoff,
K. Neumann and A. M. Kielbassa
2007
Doungudomdacha, S., A.
Rawlinson, T. F. Walsh and C. W.
Douglas
2001
Drisko, C. H.
1998
Drisko, C. L., C. M. Cobb, W. J.
Killoy, B. S. Michalowicz, B. L.
Pihlstrom, R. A. Lowenguth, J. G.
Caton, M. Encarnacion, M.
Knowles and J. M. Goodson
1995
Dubrez, B., J. M. Graf, P.
Vuagnat and G. Cimasoni
1990
Dukic, W., I. Bago, A. Aurer and
M. Roguljic
2012
Eberhard, J., P. M. Jervoe-Storm,
I. Needleman, H. Worthington
and S. Jepsen
Eberhard, J., S. Jepsen, P. M.
Jervoe-Storm, I. Needleman and
H. V. Worthington
Ehmke, B., H. Schmidt, T.
Beikler, C. Kopp, H. Karch, B.
Klaiber and T. F. Flemmig
Ehmke, B., A. Moter, T. Beikler,
E. Milian and T. F. Flemmig
Eick, S., A. Renatus, M. Heinicke,
W. Pfister, S. I. Stratul and H.
Jentsch
Eickholz, P., T. S. Kim, T. Burklin,
B. Schacher, H. H. Renggli, M. T.
Schaecken, R. Holle, A. Kubler
and P. Ratka-Kruger
Eickholz, P., T. S. Kim, B.
Schacher, P. Reitmeir, T. Burklin
and P. Ratka-Kruger
July 2015
Effectiveness of ultrasonic instruments in the
therapy of severe periodontitis: a comparative
clinical-microbiological assessment with
curettes
Microbiological findings after periodontal
therapy using curettes, Er:YAG laser, sonic,
and ultrasonic scalers
Effect of non-surgical periodontal treatment on
clinical parameters and the numbers of
Porphyromonas gingivalis, Prevotella
intermedia and Actinobacillus
actinomycetemcomitans at adult periodontitis
sites
New Microbiol
29
2
101-10
Not randomized without
proper control; compared
SRP to ultrasonic
J Clin Periodontol
34
7
588-98
No CAL data
J Clin Periodontol
28
5
437-45
Not RCT
The use of locally delivered doxycycline in the
treatment of periodontitis. Clinical results
J Clin Periodontol
25
11 Pt 2
947-52;
discussion
978-9
Evaluation of periodontal treatments using
controlled-release tetracycline fibers: clinical
response
J Periodontol
66
8
692-9
J Periodontol
61
12
725-31
Not RCT
Increase of interproximal bone density after
subgingival instrumentation: a quantitative
radiographical study
Clinical Effectiveness of Diode Laser Therapy
as an Adjunct to Non-Surgical Periodontal
Treatment: A Randomized Clinical Study
J Periodontol
2008
Full-mouth treatment concepts for chronic
periodontitis: a systematic review
J Clin Periodontol
2008
Full-mouth disinfection for the treatment of
adult chronic periodontitis
Rev
1999
2005
2012
Clonal infection with Actinobacillus
actinomycetemcomitans following periodontal
therapy
Adjunctive antimicrobial therapy of
periodontitis: long-term effects on disease
progression and oral colonization
Hyaluronic Acid as an Adjunct After Scaling
and Root Planing - A Prospective
Randomized Clinical Trial
Not 6 month trial
35
7
591-604
Review
1
CD004622
Review
No CAL data
J Dent Res
78
9
1518-1524
J Periodontol
76
5
749-59
J Periodontol
Continuation of Flemmig
1998 trial per Philippe
2002
Non-surgical periodontal therapy with
adjunctive topical doxycycline: a double-blind
randomized controlled multicenter study
J Clin Periodontol
29
2
108-17
Not available commercially
(concentration)
2005
Subgingival topical doxycycline versus
mechanical debridement for supportive
periodontal therapy: a single blind randomized
controlled two-center study
Am J Dent
18
6
341-6
Not adjunctive use of doxy
Page 98
El-Sharkawy, H., N. Aboelsaad,
M. Eliwa, M. Darweesh, M.
Alshahat, A. Kantarci, H. Hasturk
and T. E. Van Dyke
2010
El-Shinnawi et al.
2003
Elter, J. R., H. P. Lawrence, S.
Offenbacher and J. D. Beck
1997
Engebretson, S. P., J. T. Grbic,
R. Singer and I. B. Lamster
2002
Erdemir, E. O., I. Duran and S.
Haliloglu
2004
Faria-Almeida, R., A. Navarro and
A. Bascones
2006
Feng, H. S., C. C. Bernardo, L. L.
Sonoda, F. Hayashi, G. A.
Romito, L. A. De Lima, R. F.
Lotufo and C. M. Pannuti
2011
Feres, M., A. D. Haffajee, K.
Allard, S. Som and S. S.
Socransky
2001
Feres, M., L. C. Gursky, M.
Faveri, C. O. Tsuzuki and L. C.
Figueiredo
Flemmig, T. F., B. Epp, Z.
Funkenhauser, M. G. Newman,
K. S. Kornman, I. Haubitz and B.
Klaiber
Fourmousis, I., M. S. Tonetti, A.
Mombelli, B. Lehmann, N. P.
Lang and U. Bragger
Friesen, L. R., K. B. Williams, L.
S. Krause and W. J. Killoy
2009
The effect of alendronate sodium on alveolar
bone loss in periodontitis (clinical trial)
Meta-analysis of the effect of systemic
metronidazole as an adjunct to scaling and
root planing for adult periodontitis
GCF IL-1beta profiles in periodontal disease
Effects of smoking on clinical parameters and
the gingival crevicular fluid levels of IL-6 and
TNF-alpha in patients with chronic
periodontitis
Clinical and metabolic changes after
conventional treatment of type 2 diabetic
patients with chronic periodontitis
Subgingival ultrasonic instrumentation of
residual pockets irrigated with essential oils: a
randomized controlled trial
Change in subgingival microbial profiles in
adult periodontitis subjects receiving either
systemically-administered amoxicillin or
metronidazole
Clinical and microbiological benefits of strict
supragingival plaque control as part of the
active phase of periodontal therapy
J Periodontol
81
11
1635-43
J Int Acad Perio
5
1
5-10
J Periodontal Res
32
6
487-96
Review
J Clin Periodontol
29
1
48-53
Not RCT
J Clin Periodontol
31
2
99-104
Not RCT
J Periodontol
77
4
591-8
Not RCT
J Clin Periodontol
38
7
637-43
J Clin Periodontol
28
7
597-609
No passive control
J Clin Periodontol
36
10
857-67
CHX rinse - not medical
adjunct
Systemic non-SDD host
modulation
1995
Adjunctive supragingival irrigation with
acetylsalicylic acid in periodontal supportive
therapy
J Clin Periodontol
22
6
427-33
No CAL data
1998
Evaluation of tetracycline fiber therapy with
digital image analysis
J Clin Periodontol
25
9
737-45
No CAL data
J Periodontol
73
1
13-9
22
3
215-9
Not 6 month trial
25
1
103-8
short
J Clin Periodontol
26
2
63-6
maintenance phase study
using OTC product
2002
Funosas, E. R., L. Escovich and
L. Maestri
2009
Funosas, E., G. Feser, L.
Escovich and L. Maestri
2012
Furuichi, Y., B. Rosling, A. R.
Volpe and J. Lindhe
1999
July 2015
Adjunctive treatment of chronic periodontitis
with daily dietary supplementation with
omega-3 Fatty acids and low-dose aspirin
Controlled local delivery of tetracycline with
polymer strips in the treatment of periodontitis
The use of topical subgingival gels of nonsteroidal anti-inflammatory drugs (NSAIDs) as
an adjunct to non-surgical management of
Alteration of hemostasis in patients treated
with subgingival NSAIDs during periodontal
therapy
The effect of a triclosan/copolymer dentifrice
on healing after non-surgical treatment of
recurrent periodontitis
Page 99
Garrett, S., L. Johnson, C. H.
Drisko, D. F. Adams, C. Bandt, B.
Beiswanger, G. Bogle, K. Donly,
W. W. Hallmon, E. B. Hancock, P.
Hanes, C. E. Hawley, R. Kiger,
W. Killoy, J. T. Mellonig, A.
Polson, F. J. Raab, M. Ryder, N.
H. Stoller, H. L. Wang, L. E.
Wolinsky, G. H. Evans, C. Q.
Harrold, R. M. Arnold, G. L.
Southard and et al.
Garrett, S., D. F. Adams, G.
Bogle, K. Donly, C. H. Drisko, W.
W. Hallmon, E. B. Hancock, P.
Hanes, C. E. Hawley, L. Johnson,
R. Kiger, W. Killoy, J. T. Mellonig,
F. J. Raab, M. Ryder, N. Stoller,
A. Polson, H. L. Wang, L. E.
Wolinsky, R. A. Yukna, C. Q.
Harrold, M. Hill, V. B. Johnson
and G. L. Soouthard
Garrett, S., D. F. Adams, G.
Bogle, K. Donly, C. H. Drisko, W.
W. Hallmon, E. B. Hancock, P.
Hanes, C. E. Hawley, L. Johnson,
R. Kiger, W. Killoy, J. T. Mellonig,
F. J. Raab, M. Ryder, N. Stoller,
A. Polson, H. L. Wang, L. E.
Wolinsky, R. A. Yukna, C. Q.
Harrold, M. Hill, V. B. Johnson
and G. L. Southard
Gebaraa, E. C., A. N. Pustiglioni,
L. A. de Lima and M. P. Mayer
Giannopoulou, C., E. Andersen,
P. Brochut, D. Plagnat and A.
Mombelli
Giusti, J. S. M., C. R. Fontana, D.
Gonpalves, C. Kurachi and V.
Bagnato
Gmur, R., U. P. Saxer and B.
Guggenheim
Gomes, S. C., F. B. Piccinin, C.
Susin, R. V. Oppermann and R.
A. Marcantonio
Gomez, C., A. Dominguez, A. I.
Garcia-Kass and J. A. GarciaNunez
July 2015
1999
Two multi-center studies evaluating locally
delivered doxycycline hyclate, placebo control,
oral hygiene, and scaling and root planing in
the treatment of periodontitis
J Periodontol
70
5
490-503
2000
The effect of locally delivered controlledrelease doxycycline or scaling and root
planing on periodontal maintenance patients
over 9 months
J Periodontol
71
1
22-30
Duplicate
2000
The effect of locally delivered controlledrelease doxycycline or scaling and root
planing on periodontal maintenance patients
over 9 months
J Periodontol
71
1
22-30
Subset of Garrett 1999
Oral Health Prev Dent
1
1
29-35
No CAL data
J Periodontol
77
4
707-13
No CAL data
Photodiagnosis and
Photodynamic Therapy
8
2
180-181
Not 6 month trial
Schweiz Monatsschr
Zahnmed
104
4
430-9
J Periodontol
78
8
1515-21
Not SRP
Lasers Med Sci
26
4
453-63
No CAL data
2003
2006
2011
1994
2007
2011
Propolis extract as an adjuvant to periodontal
treatment
Enamel matrix derivative and systemic
antibiotics as adjuncts to non-surgical
periodontal treatment: biologic response
Clinical attachment level (CAL) gain in
periodontics using photodynamic therapy as
adjunct treatment
Effects of blunt scaling on periodontal status
and subgingival microorganisms. A pilot study
Effect of supragingival plaque control in
smokers and never-smokers: 6-month
evaluation of patients with periodontitis
Adjunctive Nd:YAG laser application in
chronic periodontitis: clinical, immunological,
and microbiological aspects
Re: Q2, doxy not used as
adjunct. Re: Q1: retx at 4
months all sites regardless
of status
Trial not long enough
between treatment and
measurement 1
Page 100
Goodson, J. M., J. C. Gunsolley,
S. G. Grossi, P. S. Bland, J.
Otomo-Corgel, F. Doherty and J.
Comiskey
Gordon, J., C. Walker, C.
Hovliaras and S. Socransky
2007
1990
Graziani, F., S. Cei, A. Guerrero,
F. La Ferla, M. Vano, M. Tonetti
and M. Gabriele
2009
Greenstein, G.
2006
Griffiths, G. S., G. J. Smart, J. S.
Bulman, G. Weiss, J. Shrowder
and H. N. Newman
2000
Griffiths, G. S., R. Ayob, A.
Guerrero, L. Nibali, J. Suvan, D.
R. Moles and M. S. Tonetti
2011
Grisi, D. C., S. L. Salvador, L. C.
Figueiredo, S. L. Souza, A. B.
Novaes and M. F. Grisi
Grossi, S. G., J. M. Goodson, J.
C. Gunsolley, J. Otomo-Corgel,
P. S. Bland, F. Doherty and J.
Comiskey
Grossi, S. G., F. B. Skrepcinski,
T. DeCaro, D. C. Robertson, A.
W. Ho, R. G. Dunford and R. J.
Genco
2002
Efficacy of clindamycin hydrochloride in
refractory periodontitis: 24-month results
Lack of short-term adjunctive effect of
systemic neridronate in non-surgical
periodontal therapy of advanced generalized
chronic periodontitis: an open labelrandomized clinical trial
Local drug delivery in the treatment of
periodontal diseases: assessing the clinical
significance of the results
Comparison of clinical outcomes following
treatment of chronic adult periodontitis with
subgingival scaling or subgingival scaling plus
metronidazole gel
Amoxicillin and metronidazole as an
adjunctive treatment in generalized
aggressive periodontitis at initial therapy or retreatment: a randomized controlled clinical
trial
Effect of a controlled-release chlorhexidine
chip on clinical and microbiological
parameters of periodontal syndrome
J Periodontol
78
8
1568-79
short
J Periodontol
61
11
686-91
Not an RCT
J Clin Periodontol
36
5
419-27
in US
J Periodontol
77
4
565-78
Review
J Clin Periodontol
27
12
910-7
in US
J Clin Periodontol
38
1
43-9
Aggressive perio
J Clin Periodontol
29
10
875-81
Reinserted CHX chips into
failing pockets at 3 and 6
months
2007
Mechanical therapy with adjunctive
minocycline microspheres reduces redcomplex bacteria in smokers
J Periodontol
78
9
1741-50
short
1997
Treatment of periodontal disease in diabetics
reduces glycated hemoglobin
J Periodontol
68
8
713-9
Data in unusable format
J Periodontol
72
3
349-53
short
J Clin Periodontol
32
3
244-53
In preference to 9 month
data in Gurkan 2008
J Clin Periodontol
15
6
353-9
No control group
J Clin Periodontol
35
8
696-704
Aggressive perio
Gunsolley, J. C., G. M. Yeung, J.
H. Butler and T. C. Waldrop
2001
Gurkan, A., S. Cinarcik and A.
Huseyinov
2005
Gusberti, F. A., S. A. Syed and N.
P. Lang
1988
Haas, A. N., G. D. de Castro, T.
Moreno, C. Susin, J. M. Albandar,
R. V. Oppermann and C. K.
Rosing
2008
July 2015
Minocycline HCl microspheres reduce redcomplex bacteria in periodontal disease
therapy
Is loss of attachment due to root planning and
scaling in sites with minimal probing depths a
statistical or real occurrence?
Adjunctive subantimicrobial dose doxycycline:
effect on clinical parameters and gingival
crevicular fluid transforming growth factor-beta
levels in severe, generalized chronic
periodontitis
Combined antibiotic (metronidazole) and
mechanical treatment effects on the
subgingival bacterial flora of sites with
recurrent periodontal disease
Azithromycin as an adjunctive treatment of
aggressive periodontitis: 12-months
randomized clinical trial
Page 101
Haffajee, A. D., M. A. Cugini, S.
Dibart, C. Smith, R. L. Kent, Jr.
and S. S. Socransky
1997
Haffajee, A. D., M. Patel and S.
S. Socransky
2008
Haffajee, A. D., N. G. Uzel, E. I.
Arguello, G. Torresyap, D. M.
Guerrero and S. S. Socransky
2004
Haffajee, A. D., S. Dibart, R. L.
Kent, Jr. and S. S. Socransky
1995
Haffajee, A. D., S. S. Socransky
and J. C. Gunsolley
2003
Hallmon, W. W. and T. D. Rees
2003
Hanes, P. J. and J. P. Purvis
2003
Hanioka, T., M. Tanaka, M.
Ojima, S. Shizukuishi and K.
Folkers
1994
Heasman, P. A., G. I. McCracken
and N. Steen
2002
Hellden, L. B., M. A. Listgarten
and J. Lindhe
1979
Heller, D., V. M. Varela, M. X.
Silva-Senem, M. C. Torres, E. J.
Feres-Filho and A. P. Colombo
2011
Herrera, D., M. Sanz, S. Jepsen,
I. Needleman and S. Roldan
2002
Hou, G. L. and C. C. Tsai
1989
July 2015
The effect of SRP on the clinical and
microbiological parameters of periodontal
diseases
Microbiological changes associated with four
different periodontal therapies for the
Clinical and microbiological changes
associated with the use of combined
antimicrobial therapies to treat "refractory"
periodontitis
Clinical and microbiological changes
associated with the use of 4 adjunctive
systemically administered agents in the
treatment of periodontal infections
Systemic anti-infective periodontal therapy. A
systematic review
Local anti-infective therapy: mechanical and
physical approaches. A systematic review
Local anti-infective therapy: pharmacological
agents. A systematic review
Effect of topical application of coenzyme Q10
on adult periodontitis
Supportive periodontal care: the effect of
periodic subgingival debridement compared
with supragingival prophylaxis with respect to
clinical outcomes
The effect of tetracycline and/or scaling on
human periodontal disease
Impact of systemic antimicrobials combined
with anti-infective mechanical debridement on
the microbiota of generalized aggressive
periodontitis: a 6-month RCT
A systematic review on the effect of systemic
antimicrobials as an adjunct to scaling and
root planing in periodontitis patients
Clinical observations of the effects of
nonsurgical periodontal therapy on human
J Clin Periodontol
24
5
324-34
Not RCT
Oral Microbiol Immunol
23
2
148-57
No CAL data
J Clin Periodontol
31
10
869-77
Not RCT
J Clin Periodontol
22
8
618-27
RCT comparing different
systemic antibiotics and
anti-inflamatory agents.
BUT, a little less than half of
the patients also received
modified widman flap
surgery. Since data is not
available for those who did
not have the flap surgery,
cannot distinguish the effect
of the surgery from the
effect of the systemic
agents.
Ann Periodontol
8
1
115-81
Review
Ann Periodontol
8
1
99-114
Review
Ann Periodontol
8
1
79-98
Review
Mol Aspects Med
15 Suppl
s241-8
short
J Clin Periodontol
29 Suppl 3
163-72;
discussion
195-6
J Clin Periodontol
6
4
222-30
Data in unusable format
J Clin Periodontol
38
4
355-64
Aggressive perio
J Clin Periodontol
29 Suppl 3
Gaoxiong Yi Xue Ke Xue
Za Zhi
5
136-59;
discussion
160-2
2
72-86
Review
Review
Not RCT
Page 102
Hou, G. L., C. C. Tsai and A. S.
Weisgold
1997
Hou, G. L., C. C. Tsai and A. S.
Weisgold
1996
Hung, H. C. and C. W. Douglass
2002
Hussein, I., M. Ranka, A. Gilbert
and K. Davey
2007
Ingela, L. G., A. Barbro and T.
Helene
2009
Ioannou, I., N. Dimitriadis, K.
Papadimitriou, D. Sakellari, I.
Vouros and A. Konstantinidis
2009
Jain, R., F. Mohamed and M.
Hemalatha
2012
Jansson, H., G. Bratthall and G.
Soderholm
2003
Jeffcoat, M. K., K. S. Bray, S. G.
Ciancio, A. R. Dentino, D. H.
Fine, J. M. Gordon, J. C.
Gunsolley, W. J. Killoy, R. A.
Lowenguth, N. I. Magnusson, S.
Offenbacher, K. G. Palcanis, H.
M. Proskin, R. D. Finkelman and
M. Flashner
Jeffcoat, M., S. Parry, M.
Sammel, B. Clothier, A. Catlin
and G. Macones
Jeffcoat, M. K., K. G. Palcanis, T.
W. Weatherford, M. Reese, N. C.
Geurs and M. Flashner
Jenkins, W. M., S. H. Said, M.
Radvar and D. F. Kinane
Jenkins, W. M., T. W.
MacFarlane, W. H. Gilmour, I.
Ramsay and D. MacKenzie
July 2015
1998
2011
2000
2000
1989
periodontal disease. II. Ultrasonic scaling and
root planing for 6 months
Ultrasonic scaling therapy in advanced
periodontitis. IV. A long-term study over six
years
The effect of ultrasonic scaling therapy in
periodontitis III. A longitudinal study over three
years
Meta-analysis of the effect of scaling and root
planing, surgical treatment and antibiotic
therapies on periodontal probing depth and
attachment loss
Locally delivered antimicrobials in the
management of periodontitis: a critical review
of the evidence for their use in practice
Full-mouth versus quadrant-wise scaling clinical outcome, efficiency and treatment
discomfort
Hand instrumentation versus ultrasonic
debridement in the treatment of chronic
periodontitis: a randomized clinical and
microbiological trial
Minocycline containing local drug delivery
system in the management of chronic
periodontitis: A randomized controlled trial
Clinical outcome observed in subjects with
recurrent periodontal disease following local
treatment with 25% metronidazole gel
Adjunctive use of a subgingival controlledrelease chlorhexidine chip reduces probing
depth and improves attachment level
compared with scaling and root planing alone
Periodontal infection and preterm birth:
successful periodontal therapy reduces the
risk of preterm birth
Use of a biodegradable chlorhexidine chip in
the treatment of adult periodontitis: clinical
and radiographic findings
Effect of subgingival scaling during supportive
therapy
Systemic metronidazole in the treatment of
periodontitis
Kaohsiung J Med Sci
13
2
103-16
Not RCT
Kaohsiung J Med Sci
12
1
25-35
Not RCT
J Clin Periodontol
29
11
975-86
Review
Review
Dent Update
34
8
494-496,
499496502,
505-506
Swedish dental journal
33
3
105-113
No CAL data
J Clin Periodontol
36
2
132-41
No control
J Indian Soc Periodontol
16
2
179-83
Not available in US - 2%
mino gel
J Periodontol
74
3
372-7
short
J Periodontol
69
9
989-97
CHX chip reapplied in select
sites at 3 months
BJOG
118
2
250-6
No CAL data
J Periodontol
71
2
256-62
CHX chip reapplied in select
sites at 3 months
J Clin Periodontol
27
8
590-6
Not RCT
J Clin Periodontol
16
7
443-50
Not an RCT
Page 103
Jervoe-Storm, P. M., E. Semaan,
H. AlAhdab, S. Engel, R.
Fimmers and S. Jepsen
2006
Johnson, L. R., N. H. Stoller, A.
Polson, C. Q. Harrold, M. Ryder
and S. Garrett
2002
Jones, C. L., K. M. Milsom, P.
Ratcliffe, A. Wyllie, T. V.
Macfarlane and M. Tickle
2011
Jonsson, B., K. Ohrn, P. Lindberg
and N. Oscarson
2010
Jordan, A. R., P. Gangler and H.
P. Johren
2006
Kaldahl, W. B., K. L. Kalkwarf, K.
D. Patil, M. P. Molvar and J. K.
Dyer
Kaldahl, W. B., K. L. Kalkwarf, K.
D. Patil, M. P. Molvar and J. K.
Dyer
33
3
209-15
No untreated control
J Clin Periodontol
29
2
87-91
No passive control
BMC Oral Health
11
J Clin Periodontol
37
10
912-9
Eur J Med Res
11
6
232-235
35
Not perio
No passive control
Not RCT
Long-term evaluation of periodontal therapy:
II. Incidence of sites breaking down
J Periodontol
67
2
103-8
So SRP-only data
1996
Long-term evaluation of periodontal therapy: I.
Response to 4 therapeutic modalities
J Periodontol
67
2
93-102
Incomplete data
Photomed Laser Surg
27
1
9-Nov
Aggressive perio
J Periodontol
78
7
1201-8
Aggressive perio
J Clin Periodontol
34
10
880-91
No passive control
Int Dent J
58
3
151-8
Not 6 month trial
J Periodontol
79
11
2021-8
Review
Int J Dent Hyg
5
4
225-31
No CAL data
J Clin Periodontol
30
12
1024-30
OTC triclosan
Clin Oral Investig
11
4
391-9
2009
Kaner, D., C. Christan, T.
Dietrich, J. P. Bernimoulin, B. M.
Kleber and A. Friedmann
2007
Kaner, D., J. P. Bernimoulin, W.
Hopfenmuller, B. M. Kleber and
A. Friedmann
2007
Kara, C., T. Demir, R. Orbak and
A. Tezel
2008
Karlsson, M. R., C. I. Diogo
Lofgren and H. M. Jansson
2008
Kasaj, A., A. Chiriachide and B.
Willershausen
2007
July 2015
The effects of subgingival calculus on the
clinical outcomes of locally-delivered
controlled-release doxycycline compared to
scaling and root planing
Clinical outcomes of single-visit oral
prophylaxis: a practice-based randomised
controlled trial
Evaluation of an individually tailored oral
health educational programme on periodontal
health
Clinical treatment outcomes of periodontal
therapy in HIV-seropositive patients
undergoing highly active antiretroviral therapy
J Clin Periodontol
1996
Kamma, J. J., V. G. Vasdekis and
G. E. Romanos
Kerdvongbundit, V. and U. M.
Wikesjo
Kim, T. S., A. Schenk, D.
Lungeanu, P. Reitmeir and P.
Eickholz
Clinical outcomes of quadrant root planing
versus full-mouth root planing
2003
2007
The effect of diode laser (980 nm) treatment
on aggressive periodontitis: evaluation of
microbial and clinical parameters
Timing affects the clinical outcome of
adjunctive systemic antibiotic therapy for
generalized aggressive periodontitis
Controlled-delivery chlorhexidine chip versus
amoxicillin/metronidazole as adjunctive
antimicrobial therapy for generalized
aggressive periodontitis: a randomized
Effect of Nd: YAG laser irradiation on the
treatment of oral malodour associated with
The effect of laser therapy as an adjunct to
non-surgical periodontal treatment in subjects
with chronic periodontitis: a systematic review
The adjunctive use of a controlled-release
chlorhexidine chip following treatment with a
new ultrasonic device in supportive
periodontal therapy: a prospective, controlled
clinical study
Effect of triclosan on healing following nonsurgical periodontal therapy in smokers
Nonsurgical and surgical periodontal therapy
in single-rooted teeth
Not an RCT. Some patients
had aggressive periodontitis
Page 104
Kinane, D. F. and M. Radvar
1997
Kinane, D. F. and M. Radvar
1999
Knofler, G. U., R. E. Purschwitz
and H. F. Jentsch
2007
Knofler, G. U., R. E. Purschwitz
and H. F. R. Jentsch
2007
Knofler, G., R. Purschwitz, H.
Jentsch, G. Birkenmeier and H.
Schmidt
2008
Knofler, G. U., R. E. Purschwitz,
S. Eick, W. Pfister, M. Roedel and
H. F. Jentsch
Kocher, T., J. Konig, P. Hansen
and A. Ruhling
2011
2001
Koromantzos, P. A., K.
Makrilakis, X. Dereka, S.
Offenbacher, N. Katsilambros, I.
A. Vrotsos and P. N. Madianos
2012
Koshy, G., Y. Kawashima, M. Kiji,
H. Nitta, M. Umeda, T. Nagasawa
and I. Ishikawa
2005
Kruck, C., S. Eick, G. U. Knofler,
R. E. Purschwitz and H. F.
Jentsch
2012
Kurtis, B., G. Tuter, M. Serdar, S.
Pinar, I. Demirel and U. Toyman
2007
Kurtis, B., G. Tuter, M. Serdar, S.
Pinar, I. Demirel and U. Toyman
2007
Kuru, L., B. Kuru, U. Noyan, A.
Kukrer, T. Acar and S. Yilmaz
2012
L, M. S., D. C. Andia, M. Z.
Casati, F. H. Nociti, Jr., E. A.
Sallum, J. Gollwitzer and C. B.
Walker
2007
July 2015
The effect of smoking on mechanical and
antimicrobial periodontal therapy
A six-month comparison of three periodontal
local antimicrobial therapies in persistent
periodontal pockets
Clinical evaluation of partial- and full-mouth
scaling in the treatment of chronic
periodontitis
Clinical evaluation of partial- and full-mouth
scaling in the treatment of chronic
periodontitis
Gingival crevicular fluid levels of aspartate
aminotransferase and alpha2-macroglobulin
before and after topical application of
metronidazole or scaling and root planing
Microbiologic findings 1 year after partial- and
full-mouth scaling in the treatment of
moderate chronic periodontitis
Subgingival polishing compared to scaling
with steel curettes: a clinical pilot study
Effect of non-surgical periodontal therapy on
C-reactive protein, oxidative stress, and matrix
metalloproteinase (MMP)-9 and MMP-2 levels
in patients with type 2 diabetes: a randomized
controlled study
Effects of single-visit full-mouth ultrasonic
debridement versus quadrant-wise ultrasonic
debridement
Clinical and microbiologic results 12 months
after scaling and root planing with different
irrigation solutions in patients with moderate
chronic periodontitis: a pilot randomized trial
GCF MMP-8 levels in smokers and nonsmokers with chronic periodontitis following
scaling and root planing accompanied by
systemic use of flurbiprofen
Gingival crevicular fluid prostaglandin E(2)
and thiobarbituric acid reactive substance
levels in smokers and non-smokers with
chronic periodontitis following phase I
periodontal therapy and adjunctive use of
flurbiprofen
Effects of adjunctive local or systemic
metronidazole with non-surgical periodontal
therapy on periodontal clinical parameters and
gingival crevicular fluid biomarkers
Microbiologic changes following administration
of locally delivered doxycycline in smokers: a
15-month follow-up
J Periodontol
68
5
467-72
short
J Periodontol
70
1
7-Jan
Tx not commercially
avaiable
J Periodontol
78
11
2135-42
J Periodontol
78
11
2135-2142
Comparing SRP methods
Quintessence Int
39
5
381-9
Elyzol not available in US
Quintessence Int
42
9
e107-17
J Clin Periodontol
28
2
194-9
Not an RCT
J Periodontol
83
1
10-Mar
Data in unusable format (%
reduction from baseline)
J Clin Periodontol
32
7
734-43
No passive control
J Periodontol
83
3
312-20
Duplicate
J Periodontol
78
10
1954-61
short
J Periodontol
78
1
104-11
short
Nobel Medicus
8
1
89-94
short
J Periodontol
78
11
2143-9
No new data (Machion
2004, 2006)
Duplicate
CHX gel not available in US
Page 105
Lane, N., G. C. Armitage, P.
Loomer, S. Hsieh, S. Majumdar,
H. Y. Wang, M. Jeffcoat and T.
Munoz
2005
Lang, N. P., W. C. Tan, M. A.
Krahenmann and M. Zwahlen
2008
Lee, J. Y., Y. M. Lee, S. Y. Shin,
Y. J. Seol, Y. Ku, I. C. Rhyu, C. P.
Chung and S. B. Han
2004
Leiknes, T., K. N. Leknes, O. E.
Boe, R. J. Skavland and T. Lie
2007
Lekovic, V., E. B. Kenney, F. A.
Carranza, Jr. and B. Endres
1983
Leonhardt, A., C. Bergstrom, L.
Krok and G. Cardaropoli
2006
Leonhardt, A., C. Bergstrom, L.
Krok and G. Cardaropoli
2007
Leyes Borrajo, J. L., L. Garcia
Varela, G. Lopez Castro, I.
Rodriguez-Nunez and M. G.
Torreira
2004
Lie, T., G. Bruun and O. E. Boe
1998
Lin, S. J., Y. K. Tu, S. C. Tsai, S.
M. Lai and H. K. Lu
2012
Loesche, W. J., S. A. Syed, E. C.
Morrison, G. A. Kerry, T. Higgins
and J. Stoll
Loesche, W. J., E. Schmidt, B. A.
Smith, E. C. Morrison, R.
Caffesse and P. P. Hujoel
Loggner Graff, I., B. Asklow and
H. Thorstensson
Loos, B., R. Kiger and J.
Egelberg
Lopez, N. J., A. Quintero, P. A.
Casanova, C. I. Ibieta, V. Baelum
and R. Lopez
July 2015
Bisphosphonate therapy improves the
outcome of conventional periodontal
treatment: results of a 12-month, randomized,
placebo-controlled study
A systematic review of the effects of fullmouth debridement with and without
antiseptics in patients with chronic
periodontitis
Effect of subantimicrobial dose doxycycline as
an effective adjunct to scaling and root planing
Topical use of a metronidazole gel in the
treatment of sites with symptoms of recurring
chronic inflammation
The effect of metronidazole on human
periodontal disease. A clinical and
bacteriological study
Healing following ultrasonic debridement and
PVP-iodine in individuals with severe chronic
periodontal disease: a randomized, controlled
clinical study
Microbiological effect of the use of an
ultrasonic device and iodine irrigation in
patients with severe chronic periodontal
disease: a randomized controlled clinical
study
Diode laser (980 nm) as adjunct to scaling
and root planing
Effects of topical metronidazole and
tetracycline in treatment of adult periodontitis
Non-surgical periodontal therapy with and
without subgingival minocycline administration
in patients with poorly controlled type II
diabetes: a randomized controlled clinical trial
J Periodontol
76
7
1113-22
J Clin Periodontol
35
8 Suppl
21-Aug
Review
J Periodontol
75
11
1500-8
Adjunct more than 1 week
after SRP
J Periodontol
78
8
1538-44
Not available US
J Periodontol
54
8
476-80
short
Acta Odontol Scand
64
5
262-6
Debridement not SRP
Acta Odontol Scand
65
1
52-9
No CAL data
Photomed Laser Surg
22
6
509-512
Not 6 month trial
J Periodontol
69
7
819-27
Clin Oral Investig
16
2
599-609
in US
1984
Metronidazole in periodontitis. I. Clinical and
bacteriological results after 15 to 30 weeks
J Periodontol
55
6
325-35
CCT
1991
Effects of metronidazole on periodontal
treatment needs
J Periodontol
62
4
247-57
CAL data not at 6 months
Swed Dent J
33
3
105-13
Full vs quadrant no control
J Clin Periodontol
14
1
29-33
No passive control
J Periodontol
83
3
267-78
Duplicate
2009
1987
2012
Full-mouth versus quadrant-wise scaling-clinical outcome, efficiency and treatment
discomfort
An evaluation of basic periodontal therapy
using sonic and ultrasonic scalers
Effects of periodontal therapy on systemic
markers of inflammation in patients with
metabolic syndrome: a controlled clinical trial
Page 106
Lopez, N. J., A. Quintero, P. A.
Casanova, C. I. Ibieta, V. Baelum
and R. Lopezi
2012
Lulic, M., I. Leiggener Gorog, G.
E. Salvi, C. A. Ramseier, N.
Mattheos and N. P. Lang
2009
Lundstrom, A., L. A. Johansson
and S. E. Hamp
1984
MacAlpine, R., I. Magnusson, R.
Kiger, M. Crigger, S. Garrett and
J. Egelberg
Machtei, E. E., E. Hausmann, M.
Schmidt, S. G. Grossi, R.
Dunford, R. Schifferle, K. Munoz,
G. Davies, J. Chandler and R. J.
Genco
1985
Effects of periodontal therapy on systemic
markers of inflammation in patients with
metabolic syndrome: A controlled clinical trial
One-year outcomes of repeated adjunctive
photodynamic therapy during periodontal
maintenance: a proof-of-principle randomizedcontrolled clinical trial
Effect of combined systemic antimicrobial
therapy and mechanical plaque control in
patients with recurrent periodontal disease
Antimicrobial irrigation of deep pockets to
supplement oral hygiene instruction and root
debridement. I. Bi-weekly irrigation
J Periodontol
83
3
267-278
No SRP control group
J Clin Periodontol
36
8
661-6
Maintenance study with
mixed tx
J Clin Periodontol
11
5
321-30
No CAL data
J Clin Periodontol
12
7
568-77
Debridement not SRP
Not RCT
1998
Radiographic and clinical responses to
periodontal therapy
J Periodontol
69
5
590-5
Machtei, E. E., I. Hirsh, M. Falah,
E. Shoshani, A. Avramoff and A.
Penhasi
2011
Multiple applications of flurbiprofen and
chlorhexidine chips in patients with chronic
periodontitis: a randomized, double blind,
parallel, 2-arms clinical trial
J Clin Periodontol
38
11
1037-43
Head to head- no control
Machtei, E. E., M. Schmidt, E.
Hausmann, S. Grossi, R.
Dunford, G. Davies, J. Chandler
and R. J. Genco
2000
Outcome variables in periodontal research:
means and threshold-based site changes
J Periodontol
71
4
555-61
Not RCT
Madden, T. E., B. Herriges, L. D.
Boyd, G. Laughlin, G. Chiodo and
D. Rosenstein
2008
J Contemp Dent Pract
9
5
16-Sep
Not properly controlled
Magnusson, I., W. B. Clark, S. B.
Low, J. Maruniak, R. G. Marks
and C. B. Walker
1989
J Clin Periodontol
16
10
647-53
Not RCT
J Clin Periodontol
21
9
628-37
Not randomized allocation to
antibiotics; Repeated SRP
in all pts
Photomed Laser Surg
30
3
160-6
No CAL data
J Periodontal Res
41
6
503-12
Not RCT
J Clin Periodontol
35
10
885-896
Not 6 month trial
Magnusson, I., S. B. Low, W. P.
McArthur, R. G. Marks, C. B.
Walker, J. Maruniak, M. Taylor, P.
Padgett, J. Jung and W. B. Clark
Makhlouf, M., M. M. Dahaba, J.
Tuner, S. A. Eissa and T. A.
Harhash
1994
2012
Mantyla, P., M. Stenman, D.
Kinane, T. Salo, K. Suomalainen,
S. Tikanoja and T. Sorsa
2006
Matarazzo, F., L. C. Figueiredo,
S. E. B. Cruz, M. Faveri and M.
Feres
2008
July 2015
Alterations in HbA1c following minimal or
enhanced non-surgical, non-antibiotic
treatment of gingivitis or mild periodontitis in
type 2 diabetic patients: a pilot trial
Effect of non-surgical periodontal therapy
combined with adjunctive antibiotics in
subjects with "refractory" periodontal disease.
(I). Clinical results
Treatment of subjects with refractory
periodontal disease
Effect of adjunctive low level laser therapy
(LLLT) on nonsurgical treatment of chronic
periodontitis
Monitoring periodontal disease status in
smokers and non-smokers using a gingival
crevicular fluid matrix metalloproteinase-8specific chair-side test
Clinical and microbiological benefits of
systemic metronidazole and amoxicillin in the
treatment of smokers with chronic
periodontitis: A randomized placebo-controlled
study
Page 107
Matarazzo, F., L. C. Figueiredo,
S. E. Cruz, M. Faveri and M.
Feres
2008
Matesanz, P., D. Herrera, A.
Echeverria, A. O'Connor, I.
Gonzalez and M. Sanz
2012
Matisko, M. W. and N. F. Bissada
1993
Matsumoto, S., H. Ogawa, S.
Soda, S. Hirayama, N.
Amarasena, Y. Aizawa and H.
Miyazaki
Maze, G. I., R. A. Reinhardt, R. K.
Agarwal, J. K. Dyer, D. H.
Robinson, L. M. DuBois, G. J.
Tussing and C. R. Maze
McColl, E., K. Patel, G. Dahlen,
M. Tonetti, F. Graziani, J. Suvan
and L. Laurell
Mdala, I., A. D. Haffajee, S. S.
Socransky, B. F. de Blasio, M.
Thoresen, I. Olsen and J. M.
Goodson
Mendonca, A. C., V. R. Santos, F.
V. Ribeiro, J. A. Lima, T. S.
Miranda, M. Feres and P. M.
Duarte
Mestnik, M. J., M. Feres, L. C.
Figueiredo, G. Soares, R. P.
Teles, D. Fermiano, P. M. Duarte
and M. Faveri
Michalowicz, B. S., B. L.
Pihlstrom, C. L. Drisko, C. M.
Cobb, W. J. Killoy, J. G. Caton, R.
A. Lowenguth, C. Quinones, M.
Encarnacion, M. Knowles and et
al.
Michalowicz, B. S., B. L.
Pihlstrom, C. L. Drisko, C. M.
Cobb, W. J. Killoy, J. G. Caton, R.
A. Lowenguth, C. Quinones, M.
Encarnacion, M. Knowles and J.
M. Goodson
July 2015
systemic metronidazole and amoxicillin in the
treatment of smokers with chronic
periodontitis: a randomized placebo-controlled
study
A randomized clinical trial on the clinical and
microbiological efficacy of a xanthan gel with
chlorhexidine for subgingival use
Short-term sequential administration of
amoxicillin/clavulanate potassium and
doxycycline in the treatment of
recurrent/progressive periodontitis
J Clin Periodontol
35
10
885-96
Clin Oral Investig
Duplicate
Not available in US
J Periodontol
64
6
553-8
Incorrect control group
2009
Effect of antimicrobial periodontal treatment
and maintenance on serum adiponectin in
type 2 diabetes mellitus
J Clin Periodontol
36
2
142-8
No CAL data
1995
Response to intracrevicular controlled delivery
of 25% tetracycline from poly(lactide/glycolide)
film strips in SPT patients
J Clin Periodontol
22
11
860-7
Tetracycline film strips not
commercially available
J Clin Periodontol
33
2
141-50
No passive control
J Oral Microbiol
4
J Clin Periodontol
39
4
368-76
No passive control
J Clin Periodontol
39
10
955-61
Aggressive perio
2006
2012
2012
2012
Supportive periodontal therapy using
mechanical instrumentation or 2% minocycline
gel: a 12 month randomized, controlled, single
masked pilot study
Multilevel analysis of clinical parameters in
chronic periodontitis after root planing/scaling,
surgery, and systemic and local antibiotics: 2year results
Surgical and non-surgical therapy with
systemic antimicrobials for residual pockets in
type 2 diabetics with chronic periodontitis: a
pilot study
The effects of adjunctive metronidazole plus
amoxicillin in the treatment of generalized
aggressive periodontitis: a 1-year doubleblinded, placebo-controlled, randomized
clinical trial
No new data (Goodson
2012)
1995
controlled-release tetracycline fibers:
maintenance response
J Periodontol
66
8
708-15
Duplicate
1995
controlled-release tetracycline fibers:
Maintenance response
J Periodontol
66
8
708-715
Page 108
Mizrak, T., G. N. Guncu, F.
Caglayan, T. A. Balci, G. S. Aktar
and F. Ipek
2006
Mombelli, A., B. Lehmann, M.
Tonetti and N. P. Lang
1997
Mombelli, A., F. A. Gusberti and
N. P. Lang
1989
Mongardini, C., D. van
Steenberghe, C. Dekeyser and
M. Quirynen
1999
Moreira, R. M. and E. J. FeresFilho
2007
Muller, H. P., J. Hartmann and L.
Flores-de-Jacoby
1986
Nassar, P. O., C. S. Walker, C. S.
Salvador, F. A. Felipetti, S. R.
Orrico and C. A. Nassar
2012
Nassrawin, N. A.
2010
Newman, M. G., K. S. Kornman
and F. M. Doherty
1994
Nogueira-Filho, G. R., B. T. Rosa
and J. R. David-Neto
Novak, M. J., D. R. Dawson, 3rd,
I. Magnusson, K. Karpinia, A.
Polson, A. Polson, M. E. Ryan, S.
Ciancio, C. H. Drisko, D. Kinane,
C. Powala and M. Bradshaw
Obeid, P. R., W. D'Hoore and P.
Bercy
Offenbacher, S., J. D. Beck, K.
Moss, L. Mendoza, D. W.
Paquette, D. A. Barrow, D. J.
Couper, D. D. Stewart, K. L.
Falkner, S. P. Graham, S. Grossi,
J. C. Gunsolley, T. Madden, G.
Maupome, M. Trevisan, T. E. Van
Dyke and R. J. Genco
July 2015
Effect of a controlled-release chlorhexidine
chip on clinical and microbiological
parameters and prostaglandin E2 levels in
gingival crevicular fluid
Clinical response to local delivery of
tetracycline in relation to overall and local
periodontal conditions
Treatment of recurrent periodontal disease by
root planing and Ornidazole (Tiberal). Clinical
and microbiological findings
One stage full- versus partial-mouth
disinfection in the treatment of chronic adult or
generalized early-onset periodontitis. I. Longterm clinical observations
Comparison between full-mouth scaling and
root planing and quadrant-wise basic therapy
of aggressive periodontitis: 6-month clinical
results
Clinical alterations in relation to the
morphological composition of the subgingival
microflora following scaling and root planing
J Periodontol
77
3
437-43
Retreat with chip at 3
months
J Clin Periodontol
24
7
470-7
J Clin Periodontol
16
1
38-45
No control group
J Periodontol
70
6
632-45
J Periodontol
78
9
1683-8
Aggressive perio
J Clin Periodontol
13
9
825-32
Not randomized
Diabetes Res Clin Pract
96
1
35-9
No passive control
Eastern Mediterranean
Health Journal
16
2
162-165
No passive control
J Periodontol
65
7
685-91
Undersea Hyperb Med
37
2
107-14
Experimental treatment
(hyperbaric oxygen)
2008
Combining host modulation and topical
antimicrobial therapy in the management of
moderate to severe periodontitis: a
randomized multicenter trial
J Periodontol
79
1
33-41
Experimental therapy (localsystemic combined)
2004
Comparative clinical responses related to the
use of various periodontal instrumentation
J Clin Periodontol
31
3
193-9
No passive control
2010
2009
Lipid profile of people with diabetes mellitus
type 2 and periodontal disease
Effect of smoking on the response to
nonsurgical periodontal therapy
A 6-month multi-center evaluation of
adjunctive tetracycline fiber therapy used in
conjunction with scaling and root planing in
maintenance patients: clinical results
Effects of hyperbaric oxygen therapy on the
treatment of severe cases of periodontitis
Results from the Periodontitis and Vascular
Events (PAVE) Study: a pilot multicentered,
randomized, controlled trial to study effects of
periodontal therapy in a secondary prevention
model of cardiovascular disease
J Periodontol
80
2
190-201
No appriate control group.
This study compared SRP
to a "community group" that
was provided no treatment.
But community group was
given a referral for perio
treatment to be provided
elsewhere, and some in that
group received prophy, SRP
and/or perio surgery.
Page 109
Oliveira (de Lima Oliviera), A. P.,
M. de Faveri, L. C. Gursky, M. J.
Mestnik, M. Feres, A. D. Haffajee,
S. S. Socransky and R. P. Teles
Oringer, R. J., K. F. Al-Shammari,
W. A. Aldredge, V. J. Iacono, R.
M. Eber, H. L. Wang, B. Berwald,
R. Nejat and W. V. Giannobile
Oringer, R. J., T. E. Van Dyke
and J. Lessem
Oz, S. G., O. Fentoglu, A.
Kilicarslan, G. S. Guven, M. D.
Tanrtover, Y. Aykac and T. Sozen
Paolantonio, M., S. D'Ercole, A.
Pilloni, D. D'Archivio, L. Lisanti, F.
Graziani, B. Femminella, G.
Sammartino, L. Perillo, S. Tete,
G. Perfetti, G. Spoto, R.
Piccolomini and G. Perinetti
Papapanou, P. N., A. M.
Neiderud, E. Disick, E. Lalla, G.
C. Miller and G. Dahlen
2012
Effects of periodontal therapy on GCF
cytokines in generalized aggressive
periodontitis subjects
J Clin Periodontol
39
3
295-302
Aggressive perio
2002
Effect of locally delivered minocycline
microspheres on markers of bone resorption
J Periodontol
73
8
835-42
No CAL data
2002
The challenge of treating periodontal patients
who smoke--the efficacy of Arestin
4
3
89-94
Subpopulation of 2 RCTs
mixed
2007
Beneficial effects of periodontal treatment on
metabolic control of hypercholesterolemia
South Med J
100
7
686-91
3-month study
2009
Clinical, microbiologic, and biochemical
effects of subgingival administration of a
Xanthan-based chlorhexidine gel in the
treatment of periodontitis: a randomized
multicenter trial
J Periodontol
80
9
1479-92
2004
Longitudinal stability of serum immunoglobulin
G responses to periodontal bacteria
J Clin Periodontol
31
11
985-90
No control group
Papli, R. and J. M. Lewis
1989
Refractory chronic periodontitis: effect of oral
tetracycline hydrochloride and root planning
Aust Dent J
34
1
60-8
Paquette, D., R. Oringer, J.
Lessem, S. Offenbacher, R.
Genco, G. R. Persson, E. A.
Santucci and R. C. Williams
2003
Locally delivered minocycline microspheres
for the treatment of periodontitis in smokers
J Clin Periodontol
30
9
787-94
No CAL data
Perinetti, G., M. Paolantonio, C.
Cordella, S. D'Ercole, E. Serra
and R. Piccolomini
2004
J Clin Periodontol
31
4
273-81
CHX gel not avail US
J Periodontol
74
6
916-932
Review
J Periodontol
75
6
830-838
Review
J Periodontol
74
6
916-32
Duplicate
J Periodontol
75
6
830-8
Duplicate
J Clin Periodontol
21
2
107-12
Debridement not SRP
J Clin Periodontol
19
9 Pt 2
715-22
Not available in US
J Clin Periodontol
25
4
322-9
Prevention study
Pavia, M., C. G. A. Nobile and I.
F. Angelillo
Pavia, M., C. G. A. Nobile, A.
Bianco and I. F. Angelillo
Pavia, M., C. G. Nobile and I. F.
Angelillo
Pavia, M., C. G. Nobile, A. Bianco
and I. F. Angelillo
2003
2004
2003
2004
Pavicic, M. J., A. J. van
Winkelhoff, N. H. Douque, R. W.
Steures and J. de Graaff
1994
Pedrazzoli, V., M. Kilian and T.
Karring
1992
Persson, R. E., G. R. Persson, L.
V. Powell and H. A. Kiyak
1998
July 2015
Clinical and microbiological effects of
subgingival administration of two active gels
on persistent pockets of chronic periodontitis
patients
Meta-analysis of local tetracycline in treating
Meta-analysis of local metronidazole in the
Meta-analysis of local tetracycline in treating
Meta-analysis of local metronidazole in the
Microbiological and clinical effects of
metronidazole and amoxicillin in Actinobacillus
actinomycetemcomitans-associated
periodontitis. A 2-year evaluation
Comparative clinical and microbiological
effects of topical subgingival application of
metronidazole 25% dental gel and scaling in
the treatment of adult periodontitis
Periodontal effects of a biobehavioral
prevention program
Not RCT
Page 110
1983
Comparison of surgical and nonsurgical
treatment of periodontal disease. A review of
current studies and additional results after
61/2 years
J Clin Periodontol
10
5
524-41
Review
Pihlstrom, B. L., L. F. Wolff, M. B.
Bakdash, E. M. Schaffer, J. R.
Jensen, Jr., D. M. Aeppli and C.
L. Bandt
1987
Salt and peroxide compared with conventional
oral hygiene. I. Clinical results
J Periodontol
58
5
291-300
SRP not performed
Pons-Vicente, O., E. ValmasedaCastellon, L. Berini-Aytes and C.
Gay-Escoda
2009
Oral Surg Oral Med Oral
Pathol Oral Radiol Endod
107
3
e11-9
Not chronic perio
Pradeep, A. R. and M. S. Thorat
2010
J Periodontol
81
2
214-22
Pihlstrom, B. L., R. B. McHugh, T.
H. Oliphant and C. Ortiz-Campos
Pradeep, A. R., M. Kumari, N. S.
Rao, S. S. Martande and S. B.
Naik
Pradeep, A. R., N. Kalra, N.
Priyanka and S. B. Naik
2012
2012
Pradeep, A. R., N. S. Rao, P.
Bajaj and M. Kumari
2012
Pradeep, A. R., N. S. Rao and S.
B. Naik
2012
Pradeep, A. R., A. Sharma, N. S.
Rao, P. Bajaj, S. B. Naik and M.
Kumari
2012
Pradeep, A. R., N. Kalra, N.
Priyanka, E. Khaneja, S. B. Naik
and S. P. Singh
2012
Preshaw, P. M., A. F. Hefti and
M. H. Bradshaw
2005
Preshaw, P. M., M. J. Novak, J.
Mellonig, I. Magnusson, A.
Polson, W. V. Giannobile, R. W.
Rowland, J. Thomas, C. Walker,
D. R. Dawson, D. Sharkey and M.
H. Bradshaw
2008
Purucker, P., H. Mertes, J. M.
Goodson and J. P. Bernimoulin
2001
July 2015
Effect on pocket depth and attachment level of
manual versus ultrasonic scaling of lower
second molars following lower third molar
extraction: a randomized controlled trial
Clinical effect of subgingivally delivered
simvastatin in the treatment of patients with
chronic periodontitis: a randomized clinical
trial
Clinical Efficacy of Subgingivally Delivered
1.2% Atorvastatin in Chronic Periodontitis: A
Microbiological outcomes of systemic
ornidazole use in chronic periodontitis. Part II
Efficacy of Subgingivally Delivered
Simvastatin in the Treatment of Type 2
Diabetes Subjects With Chronic Periodontitis:
A Randomized Double Blinded Controlled
Clinical Trial
Efficacy of Varying Concentrations of
Subgingivally Delivered Metformin in the
Treatment of Chronic Periodontitis: A
Local drug delivery of alendronate gel for the
treatment of patients with chronic periodontitis
with diabetes mellitus: a double-masked
Systemic ornidazole as an adjunct to nonsurgical periodontal therapy in the treatment
of chronic periodontitis: a randomized, doublemasked, placebo-controlled clinical trial
Adjunctive subantimicrobial dose doxycycline
in smokers and non-smokers with chronic
periodontitis
J Periodontol
14
2
50-4
No CAL data
J Periodontol
J Periodontol
J Periodontol
83
10
1322-8
J Periodontol
83
9
1149-54
Retx all pts at all intervals
and not just failing sites
J Clin Periodontol
32
6
610-6
Retrospective analysis
Modified-release subantimicrobial dose
doxycycline enhances scaling and root
planing in subjects with periodontal disease
J Periodontol
79
3
440-52
Systemic sustained release
SDD Doxy - experimental
Local versus systemic adjunctive antibiotic
therapy in 28 patients with generalized
aggressive periodontitis
J Periodontol
72
9
1241-5
Aggressive perio
Page 111
Qadri, T., F. Javed, P. Poddani, J.
Tuner and A. Gustafsson
Quee, T. C., E. C. Chan, C. Clark,
C. Lautar-Lemay, M. J. Bergeron,
J. Bourgouin and J. Stamm
Quirynen, M., C. Soers, M.
Desnyder, C. Dekeyser, M.
Pauwels and D. van Steenberghe
Quirynen, M., C. Mongardini, M.
de Soete, M. Pauwels, W.
Coucke, J. van Eldere and D. van
Steenberghe
Quirynen, M., M. De Soete, G.
Boschmans, M. Pauwels, W.
Coucke, W. Teughels and D. van
Steenberghe
Ramfjord, S. P., R. G. Caffesse,
E. C. Morrison, R. W. Hill, G. J.
Kerry, E. A. Appleberry, R. R.
Nissle and D. L. Stults
Rassameemasmaung, S., A.
Sirikulsathean, C. Amornchat, P.
Maungmingsook, P.
Rojanapanthu and W.
Gritsanaphan
Ratka-Kruger, P., D. Mahl, D.
Deimling, J. S. Monting, I.
Jachmann, E. Al-Machot, A.
Sculean, M. Berakdar, P. M.
Jervoe-Storm and A. Braun
Reddy, M. S., K. G. Palcanis, M.
L. Barnett, S. Haigh, C. H.
Charles and M. K. Jeffcoat
2011
1987
2005
2000
Lasers Med Sci
26
6
763-6
No CAL data
J Periodontol
58
9
594-601
Not available in USA
J Clin Periodontol
32
4
390-400
No CAL data
J Clin Periodontol
27
8
578-89
2006
Benefit of "one-stage full-mouth disinfection"
is explained by disinfection and root planing
within 24 hours: a randomized controlled trial
J Clin Periodontol
33
9
639-47
Not available in US
(Corsodyl)
1987
4 modalities of periodontal treatment
compared over 5 years
J Clin Periodontol
14
8
445-52
No passive control
2008
Topical application of Garcinia mangostana L.
pericarp gel as an adjunct to periodontal
treatment
Complement Ther Med
16
5
262-7
Not 6 month trial
2012
Er:YAG laser treatment in supportive
periodontal therapy
J Clin Periodontol
39
5
483-9
No passive control
J Clin Periodontol
20
9
635-40
Anti-inflammatory
Ann Periodontol
8
1
Dec-37
Review
J Periodontol
62
5
317-21
Not adjunctive
J Periodontol
67
6
562-71
No passive control
J Periodontol
68
4
346-52
Not randomized
1993
Reddy, M. S., N. C. Geurs and J.
C. Gunsolley
2003
Reinhardt, R. A., G. K. Johnson
and L. M. DuBois
1991
Renvert, S., G. Dahlen and M.
Wikstrom
1996
Renvert, S., G. Dahlen and B.
Snyder
1997
July 2015
Long-term effects of a single application of a
water-cooled pulsed Nd:YAG laser in
supplement to scaling and root planing in
patients with periodontal inflammation
The role of adjunctive Rodogyl therapy in the
treatment of advanced periodontal disease. A
longitudinal clinical and microbiologic study
A 0.05% cetyl pyridinium chloride/0.05%
chlorhexidine mouth rinse during maintenance
phase after initial periodontal therapy
The role of chlorhexidine in the one-stage fullmouth disinfection treatment of patients with
advanced adult periodontitis. Long-term
clinical and microbiological observations
Efficacy of meclofenamate sodium
(Meclomen) in the treatment of rapidly
progressive periodontitis
Periodontal host modulation with
antiproteinase, anti-inflammatory, and bonesparing agents. A systematic review
Clinical effects of closed root planing
compared to papilla reflection and fiber optic
augmentation
Treatment of periodontal disease based on
microbiological diagnosis. Relation between
microbiological and clinical parameters during
5 years
subgingival antimicrobial irrigation with citric
acid as evaluated by an enzyme
immunoassay and culture analysis
Page 112
Ribeiro (Del Peloso Ribeiro), E.,
S. Bittencourt, G. M. Ambrosano,
F. H. Nociti, Jr., E. A. Sallum, A.
W. Sallum and M. Z. Casati
Ribeiro Edel, P., S. Bittencourt, E.
A. Sallum, A. W. Sallum, F. H.
Nociti, Jr. and M. Z. Casati
Rodrigues, I. F., L. Machion, M.
Z. Casati, F. H. Nociti, Jr., S. de
Toledo, A. W. Sallum and E. A.
Sallum
2006
Povidone-iodine used as an adjunct to nonsurgical treatment of furcation involvements
J Periodontol
77
2
211-7
Retreated failing sites as per
initial therapy
2010
Non-surgical instrumentation associated with
povidone-iodine in the treatment of
interproximal furcation involvements
J Appl Oral Sci
18
6
599-606
Retreated failing sites as per
initial therapy
2007
Clinical evaluation of the use of locally
delivered chlorhexidine in periodontal
maintenance therapy
J Periodontol
78
4
624-8
Chip placed 3 mo. After
baseline so not adjunct;
second chip not adjunct but
tx alone
Minerva Stomatol
54
2-Jan
43-51
Lasers Med Sci
25
6
891-9
Not 6 month trial
J Clin Periodontol
29
4
342-50
Unusable data format
Romano, F., I. Torta, C.
Debernardi and M. Aimetti
2005
Romeo, U., G. Palaia, R. Botti, V.
Leone, J. P. Rocca and A.
Polimeni
2010
Rooney, J., W. G. Wade, S. V.
Sprague, R. G. Newcombe and
M. Addy
2002
Rosa, E. F., P. Corraini, V. F. De
Carvalho, G. Inoue, E. F. Gomes,
J. P. B. Lotufo, G. De Micheli and
C. M. Pannuti
Rosa, E. F., P. Corraini, V. F. de
Carvalho, G. Inoue, E. F. Gomes,
J. P. Lotufo, G. De Micheli and C.
M. Pannuti
Rosling, B. G., J. Slots and R. L.
Webber
Rosling, B. G., J. Slots, R. L.
Webber, L. A. Christersson and
R. J. Genco
Rosling, B., M. K. Hellstrom, P.
Ramberg, S. S. Socransky and J.
Lindhe
Rudhart, A., P. Purucker, A.
Kage, W. Hopfenmuller and J. P.
Bernimoulin
Rupf, S., I. Brader, D. Vonderlind,
S. Kannengiesser, K. Eschrich, I.
Roeder and K. Merte
Ryder, M. I., B. Pons, D. Adams,
B. Beiswanger, V. Blanco, G.
Bogle, K. Donly, W. Hallmon, E.
B. Hancock, P. Hanes, C.
Hawley, L. Johnson, H. L. Wang,
July 2015
Debridement and local application of
tetracycline in the management of persistent
periodontitis. Clinical and microbiological
results after 12 months
Non-surgical periodontal therapy assisted by
potassium-titanyl-phosphate laser: a pilot
study
Adjunctive effects to non-surgical periodontal
therapy of systemic metronidazole and
amoxycillin alone and combined. A placebo
controlled study
2011
A prospective 12-month study of the effect of
smoking cessation on periodontal clinical
parameters
J Clin Periodontol
38
6
562-571
Not RCT
2011
A prospective 12-month study of the effect of
smoking cessation on periodontal clinical
parameters
J Clin Periodontol
38
6
562-71
Duplicate
J Clin Periodontol
10
5
487-514
Duplicate
J Clin Periodontol
10
5
487-514
J Clin Periodontol
28
11
1023-31
Retreatment per initial
therapy
J Periodontol
69
10
1148-54
Elyzol
J Periodontol
76
11
1942-9
Not enough information on
laser use parameters
J Clin Periodontol
26
10
683-91
Doxy not adjunct
1983
1983
2001
1998
2005
1999
Microbiological and clinical effects of topical
subgingival antimicrobial treatment on human
periodontal disease
Microbiological and clinical effects of topical
subgingival antimicrobial treatment on human
periodontal disease
The use of PVP-iodine as an adjunct to nonsurgical treatment of chronic periodontitis
Local metronidazole application in
maintenance patients. Clinical and
microbiological evaluation
In vitro, clinical, and microbiological evaluation
of a linear oscillating device for scaling and
root planing
Effects of smoking on local delivery of
controlled-release doxycycline as compared to
scaling and root planing
Page 113
L. Wolinsky, R. Yukna, A. Polson,
G. Carron and S. Garrett
Sahrmann, P., M. A. Puhan, T.
Attin and P. R. Schmidlin
2010
Systematic review on the effect of rinsing with
povidone-iodine during nonsurgical
periodontal therapy
J Periodontal Res
45
2
153-164
Review
Sakellari, D., I. D. Vouros, E.
Aristodemou, A. B.
Konstantinidis, S. Socransky and
M. Goodson
2005
Tetracycline fibers as an adjunct in the
treatment of nifedipine-induced gingival
enlargement
J Periodontol
76
6
1034-9
Not perio
Sakellari, D., I. Vouros and A.
Konstantinidis
2003
The use of tetracycline fibres in the treatment
of generalised aggressive periodontitis:
clinical and microbiological findings
5
2
52-60
Aggressive perio
Sakellari, D., I. Ioannidis, M.
Antoniadou, T. Slini and A.
Konstantinidis
2010
adjunctive, locally delivered chlorhexidine on
patients with chronic periodontitis
12
1
20-6
Duplicate of citation under
Dimitra 2010 (included, CHX
chip)
2008
Tetracycline gel as an adjunct to surgical root
debridement
Am J Dent
21
3
168-70
Surgical therapy
2002
Local antimicrobial therapy after initial
periodontal treatment
J Clin Periodontol
29
6
540-50
Head to head- no control
J Periodontal Res
47
1
45-54
SRP delivery method
J Periodontol
80
8
1237-1245
J Periodontol
80
8
1237-45
7
3
70-9
5
4
106-15
Sallum, A. W., R. Vasconcelos
Alves, L. F. Teixeira Damis, P. F.
Roesler Bertolini, F. H. Nociti
Junior and E. A. Sallum
Salvi, G. E., A. Mombelli, L.
Mayfield, A. Rutar, J. Suvan, S.
Garrett and N. P. Lang
Santos, V. R., F. V. Ribeiro, J. A.
Lima, T. S. Miranda, M. Feres, M.
F. Bastos and P. M. Duarte
Santos, V. R., J. A. Lima, A. C.
De Mendonca, M. B. B. Maximo,
M. Faveri and P. M. Duarte
Santos, V. R., J. A. Lima, A. C.
De Mendonca, M. B. Braz
Maximo, M. Faveri and P. M.
Duarte
Sastravaha, G., G. Gassmann, P.
Sangtherapitikul and W. D.
Grimm
Sastravaha, G., P. Yotnuengnit,
P. Booncong and P.
Sangtherapitikul
Schlagenhauf, U., P. Stellwag
and A. Fiedler
Schwarz, F., A. Sculean, M.
Berakdar, T. Georg, E. Reich and
J. Becker
July 2015
2012
2009
2009
2005
2003
Partial- and full-mouth scaling and root
planing in type 2 diabetic subjects: a 12-mo
follow-up of clinical parameters and levels of
cytokines and osteoclastogenesis-related
factors
Effectiveness of full-mouth and partial-mouth
scaling and root planing in treating chronic
periodontitis in subjects with type 2 diabetes
Effectiveness of full-mouth and partial-mouth
scaling and root planing in treating chronic
periodontitis in subjects with type 2 diabetes
Adjunctive periodontal treatment with Centella
asiatica and Punica granatum extracts in
supportive periodontal therapy
Adjunctive periodontal treatment with Centella
asiatica and Punica granatum extracts. A
preliminary study
Duplicate
Compared SRP done over 2
days to SRP by quadrant
over 21 days. No control
group with no SRP
1990
Subgingival irrigation in the maintenance
phase of periodontal therapy
J Clin Periodontol
17
9
650-3
Data in unusable format (%
reduction from baseline)
2003
Clinical evaluation of an Er:YAG laser
combined with scaling and root planing for
non-surgical periodontal treatment. A
controlled, prospective clinical study
J Clin Periodontol
30
1
26-34
No adequate SRP only
control
Page 114
J. Becker
2003
Schwarz, F., A. Sculean, T.
Georg and E. Reich
2001
J. Becker
2003
Schwarz, F., K. Bieling, S.
Venghaus, A. Sculean, S. Jepsen
and J. Becker
2006
Sculean, A., F. Schwarz, M.
Berakdar, G. E. Romanos, M.
Brecx, B. Willershausen and J.
Becker
Sculean, A., F. Schwarz, M.
Berakdar, G. E. Romanos, N. B.
Arweiler and J. Becker
Serino, G., B. Rosling, P.
Ramberg, M. K. Hellstrom, S. S.
Socransky and J. Lindhe
2004
2004
2001
Sgolastra, F., A. Petrucci, R.
Gatto, G. Marzo and A. Monaco
2011
Gatto, M. Giannoni and A.
Monaco
2011
Sgolastra, F., R. Gatto, A.
Petrucci and A. Monaco
2012
Gatto and A. Monaco
2012
Gatto and A. Monaco
2012
Shar, A. and A. R. Pradeep
2012
Sharma, A. and A. R. Pradeep
2012
July 2015
Clinical evaluation of an Er:YAG laser
combined with scaling and root planing for
non-surgical periodontal treatment. A
controlled, prospective clinical study
Periodontal treatment with an Er: YAG laser
compared to scaling and root planing. A
controlled clinical study
Periodontal treatment with an Er:YAG laser or
scaling and root planing. A 2-year follow-up
split-mouth study
Influence of fluorescence-controlled Er:YAG
laser radiation, the Vector system and hand
instruments on periodontally diseased root
surfaces in vivo
Non-surgical periodontal treatment with a new
ultrasonic device (Vector-ultrasonic system) or
hand instruments
Periodontal treatment with an Er:YAG laser
compared to ultrasonic instrumentation: a pilot
study
The effect of systemic antibiotics in the
treatment of patients with recurrent
periodontitis
Photodynamic therapy in the treatment of
chronic periodontitis: a systematic review and
meta-analysis
Long-term efficacy of subantimicrobial-dose
doxycycline as an adjunctive treatment to
scaling and root planing: a systematic review
and meta-analysis
Effectiveness of systemic
amoxicillin/metronidazole as adjunctive
therapy to scaling and root planing in the
treatment of chronic periodontitis: a
systematic review and meta-analysis
Effectiveness of systemic
amoxicillin/metronidazole as an adjunctive
therapy to full-mouth scaling and root planing
in the treatment of aggressive periodontitis: a
systematic review and meta-analysis
Efficacy of Er:YAG laser in the treatment of
chronic periodontitis: systematic review and
meta-analysis
Clinical efficacy of 1% Alendronate gel in
adjunct to mechanotherapy in the treatment of
aggressive periodontitis: A randomized
Clinical efficacy of 1% alendronate gel in
adjunct to mechanotherapy in the treatment of
J Clin Periodontol
30
1
26-34
Duplicate
J Periodontol
72
3
361-7
Laser not as adjunct
J Periodontol
74
5
590-6
Laser not as adjunct
J Clin Periodontol
33
3
200-8
No control group
J Clin Periodontol
31
6
428-33
SRP delivery method
J Periodontol
75
7
966-73
Laser not used as adjunct
J Clin Periodontol
28
5
411-8
Not RCT
Lasers Med Sci
Review
J Periodontol
82
11
1570-81
Review
J Periodontol
83
10
1257-69
Review
J Periodontol
83
6
731-43
Review
Lasers Med Sci
27
3
661-73
Review
J Periodontol
83
1
19-26
Duplicate and incorrect
reference
J Periodontol
83
1
19-26
Aggressive perio
Page 115
Sharma, A. and A. R. Pradeep
2012
Shiloah, J. and M. R. Patters
1996
Shiloah, J. and M. R. Patters
1996
Sigusch, B. W., A. Guntsch, A.
Pfitzner and E. Glockmann
2005
Sigusch, B. W., A. Pfitzner, T.
Nietzsch and E. Glockmann
2005
Sigusch, B. W., A. Pfitzner, T.
Nietzsch and E. Glockmann
2005
Sigusch, B., M. Beier, G. Klinger,
W. Pfister and E. Glockmann
2001
Silva, M. P., M. Feres, T. A.
Oliveira Sirotto, G. M. Silva
Soares, J. A. Velloso Mendes, M.
Faveri and L. C. Figueiredo
2011
Silva, M. P., M. Feres, T. A.
Sirotto, G. M. Soares, J. A.
Mendes, M. Faveri and L. C.
Figueiredo
2011
Slot, D. E., T. J. Koster, S.
Paraskevas and G. A. Van der
Weijden
Slot, D. E., A. A. Kranendonk, S.
Paraskevas and F. Van der
Weijden
aggressive periodontitis: a randomized
Clinical efficacy of 1% alendronate gel as a
local drug delivery system in the treatment of
chronic periodontitis: a randomized, controlled
clinical trial
Repopulation of periodontal pockets by
microbial pathogens in the absence of
supportive therapy
Repopulation of periodontal pockets by
microbial pathogens in the absence of
supportive therapy
Enhanced root planing and systemic
metronidazole administration improve clinical
and microbiological outcomes in a two-step
treatment procedure
Periodontal dressing (Vocopac) influences
outcomes in a two-step treatment procedure
Periodontal dressing (Vocopac(registered
trademark)) influences outcomes in a two-step
treatment procedure
A 2-step non-surgical procedure and systemic
antibiotics in the treatment of rapidly
progressive periodontitis
metronidazole alone or with amoxicillin as
adjuncts in the treatment of chronic
periodontitis: A randomized placebo-controlled
clinical trial
metronidazole alone or with amoxicillin as
adjuncts in the treatment of chronic
periodontitis: a randomized placebo-controlled
clinical trial
J Periodontol
83
1
8-Nov
J Periodontol
67
2
130-9
CAL data not separated by
treatment
J Periodontol
67
2
130-9
Duplicate
J Periodontol
76
6
991-7
Aggressive perio
J Clin Periodontol
32
4
401-5
Duplicate
J Clin Periodontol
32
4
401-405
Aggressive perio
J Periodontol
72
3
275-83
Not only SRP includes
enhanced root planing
J Clin Periodontol
38
9
828-837
Not 6 month trial
J Clin Periodontol
38
9
828-37
Duplicate
2008
The effect of the Vector scaler system on
human teeth: a systematic review
Int J Dent Hyg
6
3
154-65
Review
2009
The effect of a pulsed Nd:YAG laser in nonsurgical periodontal therapy
J Periodontol
80
7
1041-56
Review
Smith, S. R., D. M. Foyle, J.
Daniels, S. Joyston-Bechal, F. C.
Smales, A. Sefton and J. Williams
2002
A double-blind placebo-controlled trial of
azithromycin as an adjunct to non-surgical
treatment of periodontitis in adults: clinical
results
J Clin Periodontol
29
1
54-61
No CAL data
Soder, P. O., L. Frithiof, S.
Wikner, F. Wouters, P. E.
Engstrom, B. Rubin, U. Nedlich
and B. Soder
1990
The effect of systemic metronidazole after
non-surgical treatment in moderate and
advanced periodontitis in young adults
J Periodontol
61
5
281-8
No CAL data
Soder, B., U. Nedlich and L. J. Jin
1999
Longitudinal effect of non-surgical treatment
and systemic metronidazole for 1 week in
J Periodontol
70
7
761-71
No 1 year data
July 2015
Page 116
smokers and non-smokers with refractory
periodontitis: a 5-year study
Soskolne, W. A., P. A. Heasman,
A. Stabholz, G. J. Smart, M.
Palmer, M. Flashner and H. N.
Newman
1997
Soskolne, W. A., H. M. Proskin
and A. Stabholz
2003
Stabholz, A., W. A. Soskolne, M.
Friedman and M. N. Sela
1991
Stabholz, A., L. Shapira, D.
Mahler, Y. Gellman, T. Ramon, E.
Dolev, M. Schwartz, L. Berger, H.
M. Proskin, R. D. Finkelman, M.
Flashner, B. Kolatch and A.
Soskolne
Stelzel, M. and L. Flores-deJacoby
Swierkot, K., C. I.
Nonnenmacher, R. Mutters, L.
Flores-de-Jacoby and R. Mengel
Sustained local delivery of chlorhexidine in the
treatment of periodontitis: a multi-center study
Probing depth changes following 2 years of
periodontal maintenance therapy including
adjunctive controlled release of chlorhexidine
The use of sustained release delivery of
chlorhexidine for the maintenance of
periodontal pockets: 2-year clinical trial
J Periodontol
68
1
32-8
Retreatment with chip at 3
months in select pockets
J Periodontol
74
4
420-7
Not RCT
J Periodontol
62
7
429-33
2000
Using the PerioChip in treating adult
periodontitis: an interim report
Compend Contin Educ
Dent
21
4
325-8, 330,
332 passim;
quiz 338
2000
Topical metronidazole application as an
adjunct to scaling and root planing
J Clin Periodontol
27
6
447-52
Not available in US
2009
One-stage full-mouth disinfection versus
quadrant and full-mouth root planing
J Clin Periodontol
36
3
240-9
Taggart, J. A., R. M. Palmer and
R. F. Wilson
1990
A clinical and microbiological comparison of
the effects of water and 0.02% chlorhexidine
as coolants during ultrasonic scaling and root
planing
J Clin Periodontol
17
1
32-7
CHX as coolant
Timmerman, M. F., G. A. van der
Weijden, T. J. van Steenbergen,
M. S. Mantel, J. de Graaff and U.
van der Velden
1996
Evaluation of the long-term efficacy and safety
of locally-applied minocycline in adult
periodontitis patients
J Clin Periodontol
23
8
707-16
Tomasi, C., T. Koutouzis and J. L.
Wennstrom
2008
J Periodontol
79
3
431-9
Not SRP (debridement)
Tomasi, C. and J. L. Wennstrom
2011
J Periodontol
82
2
210-8
Not SRP (debridement)
Tonetti, M. S., P. Cortellini, G.
Carnevale, M. Cattabriga, M. de
Sanctis and G. P. Pini Prato
1998
J Clin Periodontol
25
9
728-36
Not available US
Tonetti, M. S., N. P. Lang, P.
Cortellini, J. E. Suvan, P.
Eickholz, I. Fourmousis, H.
Topoll, T. Vangsted and B.
Wallkamm
2012
J Clin Periodontol
39
5
475-82
14% not commercially
available
July 2015
Locally delivered doxycycline as an adjunct to
mechanical debridement at retreatment of
periodontal pockets
Locally delivered doxycycline as an adjunct to
mechanical debridement at retreatment of
periodontal pockets: outcome at furcation
sites
A controlled multicenter study of adjunctive
use of tetracycline periodontal fibers in
mandibular class II furcations with persistent
bleeding
Effects of a single topical doxycycline
administration adjunctive to mechanical
debridement in patients with
persistent/recurrent periodontitis but
acceptable oral hygiene during supportive
periodontal therapy
Not RCT
Page 117
Tunkel, J., A. Heinecke and T. F.
Flemmig
2002
Unsal, E., M. Akkaya and T. F.
Walsh
1994
Valerio Lopes, B. M., L. H.
Theodoro, R. F. Melo, G. M. De
Azevedo Thompson and R. A.
Chierici Marcantonio
Vandekerckhove, B. N., M.
Quirynen and D. van
Steenberghe
Vandekerckhove, B. N., C. M.
Bollen, C. Dekeyser, P. Darius
and M. Quirynen
Van der Weijden, G. A. and M. F.
Timmerman
Van Steenberghe, D., B. Rosling,
P. O. Soder, R. G. Landry, U. Van
Der Velden, M. F. T. Timmerman,
E. F. McCarthy, G. Vandenhoven,
C. Wouters, M. Wilson, J.
Matthews and H. N. Newman
Varela, V. M., D. Heller, M. X.
Silva-Senem, M. C. M. B. Torres,
A. P. V. Colombo and E. J. FeresFilho
Varela, V. M., D. Heller, M. X.
Silva-Senem, M. C. Torres, A. P.
Colombo and E. J. Feres-Filho
Walker, C. B., J. M. Gordon, I.
Magnusson and W. B. Clark
Wennstrom, J. L., H. N. Newman,
S. R. MacNeill, W. J. Killoy, G. S.
Griffiths, D. G. Gillam, L. Krok, I.
G. Needleman, G. Weiss and S.
Garrett
2010
1997
1996
2002
1999
2011
2011
1993
A systematic review of efficacy of machinedriven and manual subgingival debridement in
the treatment of chronic periodontitis
Influence of a single application of subgingival
chlorhexidine gel or tetracycline paste on the
clinical parameters of adult periodontitis
patients
Clinical and microbiologic follow-up
evaluations after non-surgical periodontal
treatment with erbium:YAG laser and scaling
and root planing
The use of tetracycline-containing controlledrelease fibers in the treatment of refractory
periodontitis
Full- versus partial-mouth disinfection in the
treatment of periodontal infections. Long-term
clinical observations of a pilot study
A systematic review on the clinical efficacy of
subgingival debridement in the treatment of
A 15-month evaluation of the effects of
repeated subgingival minocycline in chronic
adult periodontitis
Systemic antimicrobials adjunctive to a
repeated mechanical and antiseptic therapy
for aggressive periodontitis: A 6-month
Systemic antimicrobials adjunctive to a
repeated mechanical and antiseptic therapy
for aggressive periodontitis: a 6-month
A role for antibiotics in the treatment of
refractory periodontitis
72-81;
discussion
90-1
J Clin Periodontol
29 Suppl 3
J Clin Periodontol
21
5
351-5
J Periodontol
81
5
682-691
Duplicate citation of
included article Lopes
J Periodontol
68
4
353-61
Not RCT
J Periodontol
67
12
1251-9
J Clin Periodontol
55-71;
discussion
90-1
29 Suppl 3
Review
Not 6 month trial
Review
J Periodontol
70
6
657-667
J Periodontol
82
8
1121-1130
J Periodontol
82
8
1121-30
Duplicate
J Periodontol
64
8 Suppl
772-81
Review
Aggressive perio
2001
Utilisation of locally delivered doxycycline in
non-surgical treatment of chronic periodontitis.
A comparative multi-centre trial of 2 treatment
approaches
J Clin Periodontol
28
8
753-61
Control group different from
experimental group
Wennstrom, J. L., L. Heijl, G.
Dahlen and K. Grondahl
1987
Periodic subgingival antimicrobial irrigation of
periodontal pockets (I). Clinical observations
J Clin Periodontol
14
9
541-50
For SRP part of trial, not
long enough (20 weeks)
Westfelt, E., H. Rylander, G.
Dahlen and J. Lindhe
1998
J Clin Periodontol
25
7
536-41
Not randomized
Williams, R. C., D. W. Paquette,
S. Offenbacher, D. F. Adams, G.
C. Armitage, K. Bray, J. Caton, D.
2001
J Periodontol
72
11
1535-44
No CAL data (ARESTIN)
July 2015
The effect of supragingival plaque control on
the progression of advanced periodontal
disease
Treatment of periodontitis by local
administration of minocycline microspheres: a
controlled trial
Page 118
L. Cochran, C. H. Drisko, J. P.
Fiorellini, W. V. Giannobile, S.
Grossi, D. M. Guerrero, G. K.
Johnson, I. B. Lamster, I.
Magnusson, R. J. Oringer, G. R.
Persson, T. E. Van Dyke, L. F.
Wolff, E. A. Santucci, B. E. Rodda
and J. Lessem
Wilson T.G, Jr., M. K. McGuire,
G. Greenstein and M. Nunn
1997
Wilson, T. G., Jr., M. K. McGuire,
G. Greenstein and M. Nunn
1997
Winkel, E. G., A. J. Van
Winkelhoff, M. F. Timmerman, T.
Vangsted and U. Van der Velden
1997
Wong, M. Y., C. L. Lu, C. M. Liu,
L. T. Hou and W. K. Chang
1998
Worthington, H. and I.
Needleman
Xajigeorgiou, C., D. Sakellari, T.
Slini, A. Baka and A.
Konstantinidis
Yamaoka, M., T. Uematsu, T.
Shiba, T. Matsuura, Y. Ono, M.
Ishizuka, H. Naramoto, M.
Takahashi, M. Sugiura-Tomita, K.
Iguchi, S. Yamashita and K.
Furusawa
Yek, E. C., S. Cintan, N.
Topcuoglu, G. Kulekci, H. Issever
and A. Kantarci
Yen, C. A., P. D. Damoulis, P. C.
Stark, P. L. Hibberd, M. Singh
and A. S. Papas
2005
2006
J Periodontol
68
11
1029-1032
J Periodontol
68
11
1029-32
Duplicate
J Clin Periodontol
24
8
573-9
Not RCT
J Formos Med Assoc
97
7
490-7
Periodontol 2000
37
J Clin Periodontol
33
11-Sep
Not a trial
4
254-64
Aggressive perio
2008
Effect of inorganic polyphosphate in
periodontitis in the elderly
Gerodontology
25
1
7-Oct
2010
Efficacy of amoxicillin and metronidazole
combination for the management of
generalized aggressive periodontitis
J Periodontol
81
7
964-74
Aggressive perio
2008
The effect of a selective cyclooxygenase-2
inhibitor (celecoxib) on chronic periodontitis
J Periodontol
79
1
104-13
Photomed Laser Surg
30
6
325-30
Not 6 month trial
Yilmaz, S., B. Kut, H. Gursoy, B.
Eren-Kuru, U. Noyan and T. Kadir
2012
Zandbergen, D., D. E. Slot, C. M.
Cobb and F. A. Van der Weijden
2012
Zee, K. Y., D. H. Lee and E. F.
Corbet
2006
July 2015
Tetracycline fibers plus scaling and root
planing versus scaling and root planning
alone: Similar results after 5 years
Tetracycline fibers plus scaling and root
planing versus scaling and root planing alone:
similar results after 5 years
Effects of metronidazole in patients with
"refractory" periodontitis associated with
Bacteroides forsythus
Clinical response of localized recurrent
periodontitis treated with scaling, root planing,
and tetracycline fiber
Evidence-based periodontal disease
prevention and treatment: introduction
Clinical and microbiological effects of different
antimicrobials on generalized aggressive
periodontitis
Er:YAG laser versus systemic metronidazole
as an adjunct to nonsurgical periodontal
therapy: a clinical and microbiological study
The Clinical Effect of Scaling and Root
Planing and The Concomitant Administration
of Systemic Amoxicillin and Metronidazole: A
Systematic Review
Repeated oral hygiene instructions alone, or
in combination with metronidazole dental gel
with or without subgingival scaling in adult
periodontitis patients: a one-year clinical study
J Periodontol
Review
8
4
125-35
Subgingival scaling - no root
planing - possible cross over
effect from gel arm
Page 119
Zingale, J., L. Harpenau, G.
Bruce, D. Chambers and W.
Lundergan
2012
The effectiveness of scaling and root planing
with adjunctive time-release minocycline using
an open and closed approach for the
treatment of periodontitis
Gen Dent
60
4
300-5
No CAL data
Excluded studies and reasons for exclusion – updated literature search
Author
Year
Ahamed, S., Jalaluddin, M.,
Khalid, I., Moon, N., Shaf, T. K.
and Ali, F. M.
2013
Balata, M. L., Andrade, L. P.,
Santos, D. B., Cavalcanti, A. N.,
Tunes Uda, R., Ribeiro Edel, P.
and Bittencourt, S.
2013
Dilsiz, A., Canakci, V. and Aydin,
T.
2013
Dilsiz, A. and Sevinc, S.
2014
Engebretson, S. P., Hyman, L.
G., Michalowicz, B. S.,
Schoenfeld, E. R., Gelato, M. C.,
Hou, W., Seaquist, E. R., Reddy,
M. S., Lewis, C. E., Oates, T. W.,
Tripathy, D., Katancik, J. A.,
Orlander, P. R., Paquette, D. W.,
Hanson, N. Q. and Tsai, M. Y.
Euzebio Alves, V. T., de Andrade,
A. K., Toaliar, J. M., Conde, M.
July 2015
Title
The use of controlled release locally delivered
10% doxycycline hyclate gel as an adjunct to
scaling and root planing in the treatment of
chronic periodontitis: clinical and
microbiological results
Photodynamic therapy associated with fullmouth ultrasonic debridement in the treatment
of severe chronic periodontitis: a randomizedcontrolled clinical trial
Clinical effects of potassium-titanyl-phosphate
laser and photodynamic therapy on outcomes
of treatment of chronic periodontitis: a
randomized controlled clinical trial
KTP laser therapy as an adjunctive to scaling
and root planing in treatment of chronic
periodontitis
Journal
Volume
Page
Reason if Exclude
J Contemp Dent Pract
14
1080-6
Not an RCT
J Appl Oral Sci
21
208-14
Debridement (no root
planing)
J Periodontol
84
278-86
Duplicate with Dilsiz 2012
(already included)
KTP laser not available in
US
Acta Odontol Scand
2013
The effect of nonsurgical periodontal therapy
on hemoglobin A1c levels in persons with type
2 diabetes and chronic periodontitis: a
310
2523-32
include
SRP retreated at all sites at
3 months (Question 1)
2013
Clinical and microbiological evaluation of high
intensity diode laser adjutant to non-surgical
periodontal treatment: a 6-month clinical trial
Clin Oral Investig
17
87-95
Duplicate with Alves 2012
(already included)
Page 120
C., Zezell, D. M., Cai, S., Pannuti,
C. M. and De Micheli, G.
Feres, M., Soares, G. M.,
Mendes, J. A., Silva, M. P.,
Faveri, M., Teles, R., Socransky,
S. S. and Figueiredo, L. C.
Fiorini, T., Susin, C., da Rocha, J.
M., Weidlich, P., Vianna, P.,
Moreira, C. H., Bogo Chies, J. A.,
Rosing, C. K. and Oppermann, R.
V.
Franco, E. J., Pogue, R. E.,
Sakamoto, L. H., Cavalcante, L.
L., Carvalho, D. R. and de
Andrade, R. V.
Giannopoulou, C., Cappuyns, I.,
Cancela, J., Cionca, N. and
Mombelli, A.
Gomes, S. C., Romagna, R.,
Rossi, V., Corvello, P. C. and
Angst, P. D.
Jain, M., Dave, D., Jain, P.,
Manohar, B., Yadav, B. and
Shetty, N.
Kapellas, K., Maple-Brown, L. J.,
Bartold, P. M., Brown, A., O'Dea,
K., Slade, G. D., Celermajer, D.
S., Jamieson, L. M. and Skilton,
M. R.
Kondreddy, K., Ambalavanan, N.,
Ramakrishna, T. and Kumar, R.
S.
Kucukcoskun, M., Baser, U.,
Oztekin, G., Kiyan, E. and Yalcin,
F.
Kumar, A. K., Reddy, N. R.,
Babu, M., Kumar, P. M., Reddy,
V. S. and Chavan, C. V.
July 2015
1149-58
1/2 of intervention group
also had CHX rinse. Data
not stratefied between
groups that had CHX and
groups that did not.
2012
Metronidazole alone or with amoxicillin as
adjuncts to non-surgical treatment of chronic
periodontitis: a 1-year double-blinded,
placebo-controlled, randomized clinical trial
2013
Effect of nonsurgical periodontal therapy on
serum and gingival crevicular fluid cytokine
levels during pregnancy and postpartum
2014
Increased expression of genes after
periodontal treatment with photodynamic
therapy
2012
Effect of photodynamic therapy, diode laser,
and deep scaling on cytokine and acutephase protein levels in gingival crevicular fluid
of residual periodontal pockets
J Periodontol
83
2014
Supragingival treatment as an aid to reduce
subgingival needs: a 450-day investigation
Braz Oral Res
28
2013
Efficacy of xanthan based chlorhexidine gel as
an adjunct to scaling and root planing in
treatment of the chronic periodontitis
J Indian Soc Periodontol
17
2014
Effect of a periodontal intervention on pulse
wave velocity in Indigenous Australians with
periodontal disease: The PerioCardio
9
e44
Publication type (abstract)
16
553-7
Not an RCT
J Periodontol
84
863-70
Not randomized
Contemp Clin Dent
4
303-6
Less than 6 months (8
weeks)
2012
2013
2013
Effectiveness of a controlled release
chlorhexidine chip (PerioCol-CG) as an
adjunctive to scaling and root planing when
compared to scaling and root planing alone in
the treatment of chronic periodontitis: A
comparative study
Initial periodontal treatment for prevention of
chronic obstructive pulmonary disease
exacerbations
Estimation of prostaglandin E2 levels in
gingival crevicular fluid in periodontal health,
disease and after treatment
J Clin Periodontol
39
48
126-33
unsure
Less than 6 months
(calculated to be 23 weeks);
also, mean CAL not
reported
Photodiagnosis Photodyn
Ther
11
41-7
Less than 6 months; not an
RCT
1018-27
No CAL data; Other
treatment (DSL and PDT)
are not in conjunction with
SRP
no SRP-nly control
439-43
Chlosite gel not available in
US
Page 121
Martinez, G. L., Koury, J. C.,
Brito, F., Fischer, R. G.,
Gustafsson, A. and Figueredo, C.
M.
Matesanz, P., Herrera, D.,
Echeverria, A., O'Connor, A.,
Gonzalez, I. and Sanz, M.
Meulman, T., Giorgetti, A. P.,
Gimenes, J., Casarin, R. C.,
Peruzzo, D. C. and Nociti, F. H.,
Jr.
2014
2013
2013
Miremadi, S. R., De Bruyn, H.,
Steyaert, H., Princen, K.,
Sabzevar, M. M. and Cosyn, J.
2014
Muller Campanile, V. S.,
Giannopoulou, C., Campanile, G.,
Cancela, J. A. and Mombelli, A.
2013
Pera, C., Ueda, P., Casarin, R.
C., Ribeiro, F. V., Pimentel, S. P.,
Casati, M. Z. and Cirano, F. R.
2012
Petelin, M., Perkic, K., Seme, K.
and Gaspirc, B.
2014
Pradeep, A. R., Bajaj, P.,
Agarwal, E., Rao, N. S., Naik, S.
B., Kalra, N. and Priyanka, N.
2013
Pradeep, A. R., Singh, S. P.,
Martande, S. S., Naik, S. B., N,
P., Kalra, N. and Suke, D. K.
2014
Putt, M. S. and Proskin, H. M.
2013
Santos, V. R., Lima, J. A.,
Miranda, T. S., Goncalves, T. E.,
Figueiredo, L. C., Faveri, M. and
Duarte, P. M.
2013
July 2015
The impact of non-surgical periodontal
treatment on serum levels of long chainpolyunsaturated fatty acids: a pilot
A randomized clinical trial on the clinical and
microbiological efficacy of a xanthan gel with
chlorhexidine for subgingival use
One stage, full-mouth, ultrasonic debridement
in the treatment of severe chronic periodontitis
in smokers: a preliminary, blind and
A randomized controlled trial on immediate
surgery versus root planing in patients with
advanced periodontal disease: a costeffectiveness analysis
Single or repeated antimicrobial photodynamic
therapy as adjunct to ultrasonic debridement
in residual periodontal pockets: clinical,
microbiological, and local biological effects
Double-masked randomized clinical trial
evaluating the effect of a triclosan/copolymer
dentifrice on periodontal healing after onestage full-mouth debridement
Effect of repeated adjunctive antimicrobial
photodynamic therapy on subgingival
periodontal pathogens in the treatment of
Local drug delivery of 0.5% azithromycin in
the treatment of chronic periodontitis among
smokers
levofloxacin in the treatment of chronic
periodontitis: a randomized, placebocontrolled clinical trial
Custom tray application of peroxide gel as an
adjunct to scaling and root planing in the
treatment of periodontitis: results of a
randomized controlled trial after six months
Full-mouth disinfection as a therapeutic
protocol for type-2 diabetic subjects with
chronic periodontitis: twelve-month clinical
outcomes: a randomized controlled clinical
trial
J Periodontal Res
49
268-74
months)
Clin Oral Investig
17
55-66
Chlosite gel not available in
US
15
83-90
Data only in graph and
cannot be abstracted
J Clin Periodontol
41
164-71
Compared SRP to surgery
8-Jan
planing)
909-16
planing) AND not medical
adjunct (OTC)
Lasers in Medical
Science
J Periodontol
83
experitmental tx with
multiple PDT episodes;
improper control (scaler)
Lasers Med Sci
Aust Dent J
58
34-40
J Investig Clin Dent
Experimental gel
(researcher-prepared)
J Clin Dent
24
100-7
No CAL data
J Clin Periodontol
40
155-62
Page 122
Shiloah, J., Bland, P. S.,
Scarbecz, M., Patters, M. R.,
Stein, S. H. and Tipton, D. A.
2014
Slot, D. E., Timmerman, M. F.,
Versteeg, P. A., van der Velden,
U. and van der Weijden, F. A.
2012
Tuter, G., Ozdemir, B., Kurtis, B.,
Serdar, M., Yucel, A. A. and
Ayhan, E.
2013
Wehmeyer, M. M., Kshirsagar, A.
V., Barros, S. P., Beck, J. D.,
Moss, K. L., Preisser, J. S. and
Offenbacher, S.
2013
July 2015
The effect of long-term aspirin intake on the
outcome of non-surgical periodontal therapy in
smokers: a double-blind, randomized pilot
study
Adjunctive clinical effect of a water-cooled
Nd:YAG laser in a periodontal maintenance
care programme: a randomized controlled trial
Short term effects of non-surgical periodontal
treatment on gingival crevicular fluid levels of
tissue plasminogen activator (t-PA) and
plasminogen activator inhibitor 2 (PAI-2) in
patients with chronic and aggressive
periodontitis
A randomized controlled trial of intensive
periodontal therapy on metabolic and
inflammatory markers in patients With ESRD:
results of an exploratory study
J Periodontal Res
49
102-9
OTC
J Clin Periodontol
39
1159-65
No CAL data
Arch Oral Biol
58
391-6
weeks) and not an RCT
Am J Kidney Dis
61
450-8
Treatment is SRP+adjunct
vs no tx (not vs SRP alone)
Page 123
Appendix 3 – Study characteristics, outcomes data, and critical appraisals of individual
trials
Scaling and root planing – Study characteristics
Citation: Author,
Year
Country
Special population?
(e.g. smokers) and other data
regarding inclusion - exclusion
criteria for patients and teeth
Severity of disease
(e.g. refractory, mild,
moderate)
Control
Test subject
subject age
age (mean,
(mean,
median, range
median, range
as described)
as described)
Control
Control
Dose/ duration/
frequency/ timing if
applicable
Test (typically
adjunct)
Test (typically adjunct)
Dose/ duration/ frequency/
timing including
simultaneous/ before/ after
Was standard counseling
mentioned as part of
control treatment?
Trial design
(split mouth /
parallel group /
cross over)
Duration of
study
Adverse events reported
Berglundh, 1998
Sweden
no mention of cigarettes or any health
condition
advanced periodontal
disease
35-58 years
no subgingival treatment
and placebo
Placebo not described
SRP+placebo
local anesthesia 3-5 sessions
unspecified operator / placebo
not described
oral hygiene instruction
and one session of supragingival
scaling. The oral hygiene
instruction was, if indicated,
reinforced during the course of
the trial.
Split mouth for
these data
(Factorial)
12 months
NR
Chen 2012
China
Adults with type 2 diabetes aged 38 to 81;
with a ≥ 1 mm mean clinical attachment
loss ([AL]; including slight, moderate, and
severe periodontitis
Chronic periodontitis
Group 3. No TX or OHI
n/a
Group 1: SRP at baseline and
subgingival debridement at 3
months. Group 2: SRP at
baseline and supragingival
prophy at 3 months
no. Control group specifically
received no OHI
Parallel group
6 months
no patients reported adverse events
Parallel group
6 months
Group 1: 59.86 ±
9.48 Group 2:
57.91 ± 11.35
Group 1: SRP at baseline
and subgingival
debridement at 3 months.
63.2 ± 8.51
Group 2: SRP at baseline
and supragingival prophy
at 3 months
No
Jones 1994
Q1 only
Note: data read
from figure; only
max whisker value
plotted in figure
U.S.
presence of at least two sites on different
teeth in one quadrant, excluding third
molars, that had probing depths of 7 mm
or greater. In addition, the subgingival
presence by anaerobic culture of one or
more of the following pathogens had to be
demonstrated at these sites before the Moderate to advanced adult
subject was included: Porphyromonas
periodontitis
gingivalis, Prevotella intermedia, and/or
Actinobacillus actinomycetemcomitans /
not pregnant or lactating / no chronic
systemic diseases / no antibiotic prophy
for dental tx / systemic antibiotics or
continuous non-steroidal antiinflammatory drugs within the previous 3
months or chronic low-dose tetracycline
51 patients (age
range 28 to 68) were randomized
into one of four treatment
groups, no info on specific groups
No treatment
No treatment (NoTx) in which
no scaling and root planing or
subgingival minocycline was
utilized at any site in any
quadrant. A supragingival
irrigation with a sterile
saline placebo was applied by
means of an irrigating syringe
in the study quadrant for
approximately 30 seconds in
an attempt to create patient
blinding. / The nonstudy
quadrants
received
no
supragingival or subgingival
treatment during the course of
the experiment and thus each
patient received only one
treatment type.
47 ±9 (range 35-65)
Group 4: supragingival
coronal polish
single episode by hygienist
No treatment
N/A
SRP only
Scaling and root planing only
(SRP) in which scaling and, root
planing was accomplished on all
teeth in the study quadrant. / A
supragingival irrigation with a
sterile saline placebo was
applied by means of an
A standardized oral hygiene
irrigating syringe in the study
regimen was presented to
quadrant for approximately 30 each patient at the beginning of
seconds in an attempt to create the study, but no professional
patient blinding. No treatment
supragingival cleaning was
was performed in the other performed except for scaling and
quadrants / The nonstudy root planing as indicated above.
quadrants
received
no
supragingival or subgingival
treatment during the course of
the experiment and thus each
patient received only one
treatment type.
AE information was not reported
Unclear as to exact reason. 51 started the study and
39 completed with evaluable data sets. Any site which
had undergone a 2 mm or greater loss of relative
clinical attachment as compared to baseline was
considered to be a progressing
Group 2: SRP by a
hygienist;
Kahl, 2007
Lindhe 1983
Germany
Sweden
Neill 1997 (SRP vs
no tx)
DATA IN FIGURE
AND TEXT
INCONSISTENT
no exclusion criteria, included smokers 8
of 20 subjects
no
moderate to advanced
chronic perio (5-8mm)
disease. At least 20
remaining teeth and 4 pairs
of diseased sites around
37-52 years of
contralateral premolars and 37-52 years of age
age
incisors where pockets
could be probed to ≥6mm
and where ≥40% of the
alveolar bone had been lost
[Group 3: SRP by a
dentist; data not being
used]
SRP
No
U.S.
probing
depths > 4 mm with radiographic bone
loss
moderate to severe adult
periodontitis (PD 4mm or
greater)
average age of 44 years (range 3353)
No treatment
No treatment
SRP
Generalized Periodontitis
(50% bone loss)
range:32-72
No treatment + placebo
Ultrasonic and hand
instruments
SRP+placebo
single episode
yes
split mouth
6 months
Did not seek or report adverse events
Once by quadrant
yes
Split mouth
50 weeks
6 months
None reported; minimal post-op pain reported
Split mouth
24 weeks
Parallel group
6 months
Patient perceptions on pain, analgesics, body temp,
oral ulcerations & other adverse events were collected
via VAS questionnaire at the end of treatment (after 4th
quad; after debridement). RESULTS: no differences
between groups; none reported acute problems.
Mechanical SRP was used to
remove calculus and other
Split mouth
deposits from the root surfaces
Yes; but only mentioned for no
to achieve the endoint of a
quadrants
treatment group (not SRP
smoot, glass-like root surface.
randomly
group); patient plaque control
Ultrasonic instrumentation was
assigned to one of
instructions
included where appropriate, and
three experimental
the site was irrigated with a
groups:
sterile saline solution.
15 current smokers, 17 non-smokers, not
asked about past smoking
Ng, 1998
Ribeiro (DEL
PELOSO), 2008
USA
Brazil
Thirty-two subjects (18 males and 14
females, ranging in age from 32 to 72
years) with generalized Periodontitis
were selected according to the following
criteria: 1) radiographic bone loss
greater than 50% in at least 2 matching
tooth types per subject and 2) periodontal
probing depth ≥5 mm in 1 or more sites
in at least 2 matching tooth types.
Inclusion: Non-smokers only; CAL
≥5mm; 8 teeth with pocket depth ≥5 mm,
2 of which ≥7mm and 2 ≥6mm;
Exclusion: no perio tx or antibiotics for
previous 6 months; no systemic
pathogies; no pregnant women; no
medical disorders req prophy antibiotics
or drugs known to affect perio status; no
ortho;
Severe chronic
periodontitis
Mean = 45.5
(range 30-66
years)
Mean = 38.9
(range 33-55
years)
SRP (quadrant)
12 of 27 smokers
Rotundo 2010
(SRP vs no tx)
Italy
2 teeth per quad with PD 4-9 mm with
BOP; presence of at least one incisor,
premolar and molar per quad
Moderate to severe chronic
50.5 ± 11.7 years
periodontitis
50.5 ± 11.7
years
Supragingival prophy at
the end of the study
No
Van Dyke 2002
U.S.
at least two teeth
having one site each with pocket depth
(PD) >=6mm and with prostaglandin E2
(PG E2) levels > 66.2ng/ml in gingival
crevicular fluid.
Moderate to severe
periodontitis
Not stated
Not stated
No tx
Prior to start of study, supra
calculus removed for all
subjects, Test and Control;
Quadrant scaling with 1 week
interval between Quad scaling
with ultrasonic and gracey
currets; no time limit for
appointment; local anesthesia
used as necessary; Monthly:
maintenance program of
professional supraging
plaque contol and
reinforcement of OHI; Retreatment at 3 months for
PPD ≥5mm and BOP
One appointment / using
mechanical
instruments (ultrasonics, hand
instruments, polishing) was
performed. For ethical
reasons, this control quadrant
was treated at the end of the
study as needed
For those patients receiving
no Tx or SRP only irrigation
of ,the surrounding test area
was performed
using sterile wvater or saline
to ensure patient blinding.
Perio debridement (one
session)
SRP
SRP
received placebo capsules via
oral administration (1 capsule
per day).
One session of full-mouth
periodontal debridement using
an ultrasonic scaler (Profi III).
Specific tips were used (33
Probe, Amdent, Stockholm,
Sweden). 45 minute time limit;
local anesthesia used as
necessary. Monthly:
maintenance program of
professional supraging plaque
contol and reinforcement of
OHI; Re-treatment at 3
months for PPD ≥5mm and
BOP
no
All patients initially received
detailed information on the
etiology of period disease and
instructions for proper, selfperformed plaque control
measures, including inter-dental
cleaning with dental floss and
inter-dental toothbrushes. In the
initial sessions, patients also had
plaque retentive factors (caries,
excess of restorations and
supragingival calculus) removed.
The baseline measurements
were done 30 days after this
initial phase.
One appointment / Gracey’s
curettes and an ultrasonic
device (Mini- Piezons, EMS
Electro Medical Systems S.A.,
Nyon, Switzerland) were used.
For all treatments, the
instrumentation was carried out
until the operator felt a planed
Split mouth; Each
and well-debrided dental
strategy was
OHI for all patients as well as full
surface. Subgingival root
randomly
mouth supragingival prophy
planing and/or laser application
assigned and
using ultrasonic / hand
were performed in the sites with
performed in
instruments
a periodontal PDX4 mm. The
one of the four
sites with a PDo4mm were
quadrants
treated using ultrasonic device
and hand instrument/ polishing.
A 60-s rinse with 0.12%
chlorhexidine digluconate was
prescribed twice a day for 1
week. Patients were recalled for
control and supportive
For those patients receiving no
Tx or SRP only irrigation
of ,the surrounding test area
was performed
using sterile wvater or saline to
ensure patient blinding.
No
Parallel
Complications: 5 perio abscesses reported, none in
the SRP alone group; 1 pt reported fever during the 1st
week post-tx
immediately at the end of treatment, the only
statistically significant difference resulted between SRP
and S ( p50.0132) (Table 3).
6 months
6 months
After 1 week, no difference was observed for pain (
p=0.5968) and chewing discomfort ( p=0.3151)
between the four types of treatments. However, the
SRP procedure caused a higher dental
hypersensitivity than the S treatment
(p50.0294) (Table 3).
6-months: Regarding the patient-centred analysis
based on the questionnaire, the variables pain
(p=0.4732), dental hypersensitivity (p=0.3135) and
chewing discomfort (p=0.9574), did not show
any statistically significant difference among the
procedures (Table 3).
An SRP + MPTS patient experienced two adverse
events (AEs) - a black hairy tongue ruled to be
possibly dtug related by the investigator and abscess
formation at study sites with oedema, which was not
considered to be related to study medication. There
were three AEs reported in the no Tx group: toothache
in a tooth adjacent to a study tooth, ulcerative
stomatitis, and melena. They were not related to study
medication. An SRP patient reported an event of
myalgia, and SRP patient reported an event of a
gramulomatous lesion, and an MPTS patient reported
an event of toothache in a non-study tooth, and SRP +
MPTS patient reported an event of rhinitis, and an
MPTS patient reported an event of headache.
Regarding the gingival margin, the SRP + MPTS
group tended to display the! least redness and swelling
at 14 days and one month. The same trend was
obsetved at six months, but to a lesser degree
There was no significant difference in intensity and
extent of tooth staining at any assessment point among
the treatment groups. There -were no abnormal clinical
chemistry or haemnatological results observed in the
study for any of
the groups.
July 2015
Page 124
Scaling and root planing - Updated literature
Citation:
Author, Year
Country
Special population?
(e.g. smokers) and other
data regarding inclusion exclusion criteria for
patients and teeth
Severity of disease (e.g.
refractory, mild, moderate)
Test subject
age (mean,
median, range
as described)
Zhou, 2014
china
patients with COPD. Exclude:
asthma, pero tx in last 6
months
chronic PD
63.9 +/- 9.44
July 2015
Control subject
age (mean,
median, range
as described)
Control
Scaling group:
65.3 +/- 7.54. No 1. Supragingival Scaling;
tx group: 68.0 +/2. No tx control
7.64
Control
timing if applicable
Test (typically
adjunct)
n/a
SRP
Was standard
Trial design
Dose/ duration/ frequency/ timing
counseling
(split mouth / Duration of
including simultaneous/ before/ mentioned as part of parallel group
study
after
control treatment?
/ cross over)
timing not stated
yes
parallel
2 years
not reported
Page 125
Scaling and root planing – Outcomes data
Citation: Author, Year
Outcome
measure
Time period for
data presented
in this
abstraction
Other time
No. Sites treated per
periods for
mouth / No. sites averaged
which data are
per tooth
available
Test sample size
Baseline
Test mean
Baseline
Test SD or
SE (list
value)
Baseline
Test sample
size at end of
test period
Test mean at end of
test period
Test SD or SE
(list value) at
end of test
period
SD or SE?
Mean gain
TEST
(Baselinefinal)
Mean SD
(or SE)
gain, TEST
Control sample
size
Baseline
Control
mean
Baseline
Control SD
Control sample
or SE (list
size at end on
value)
test period
Baseline
Control
mean at
end of test
period
Control SD or SE
(list value) at end
of test period
SD or SE?
Mean gain
CONTROL
(baseline-final)
Mean SD (or
SE) gain,
CONTROL
Caries
data
8
NR
NR
8
NR
NR
SD
0.7
0.3
8
NR
NR
8
NR
NR
SD
-0.3
0.3
NR
Group 1: 45 Group 2:
45
Group 1: 3.57
Group 2: 2.95
Group 1: 1.31
Group 2: 1.21
Group 1: 42
Group 2: 43
Group 1: 3.20 Group 2:
2.55
Group 1: 1.23
Group 2: 1.16
SD
Not reported
Not reported
Group 3; 44
3.37
1.24
Group 3; 41
3.41
1.23
SD
Not reported
Not reported
Not
reported
Not reported
Not stated
0.58
0.14
12 or 13 (not stated)
11.04
1
10
Not reported
Not reported
Not stated
0.08
0.16
Berglundh, 1998
PAL, overall
(Groups 3 and 4)
12 months
2 months
Chen 2012
CAL
6 months
1.5, 3 months
6 sites per tooth, full mouth
assessment
1, 3, 6 months
The "experimental
sites" were two sites in each patient that
met the entrance criteria of probing
depths >7 mm and detectable levels of
the target microbial species. The "study
quadrant" was the quadrant in each
patient that contained the experimental
sites / CAL at 6 sites per tooth / study
sites in the study quadrant were
averaged per subject and subjects were
averaged to create group means
12 or 13 (not stated)
10.77
1.22
6
Presented in graphic
form with exact change
difficult to tell. Text
reports that at 6 months,
there was a significant
difference
between the SRP group
and the NoTx group
(P <0.05, Duncan's
multiple range test).
Unclear. It appears that all teeth
in each quadrant were
analyzed. One quad
20
11.2
1.7
not reported
10.8
1.6
Assume SD from
value and text
CHANGE IN
RAL LEVELS:
Group 2 DHY
moderate
pockets:0.5m
m.
not reported
20
11.5
2.9
not reported
11.4
2.6
Assume SD from value and text
CHANGE IN
RAL LEVELS
Group 4
moderate
pockets: 0.2mm
not reported
not
reported
Unclear. It appears that all teeth
in each quadrant were
analyzed. One quad
20
13.6
2.2
not reported
12.5
2.4
Assume SD from
value and text
CHANGE IN
RAL LEVELS:
Group 2 DHY
deep pockets:
1.2mm.
not reported
20
12.9
1.4
not reported
12.4
2.5
Assume SD from value and text
CHANGE IN
RAL LEVELS
Group 4 deep
pockets:0.2mm
not reported
not
reported
se
SRP mean
difference =
1.4
SRP SE =
0.3
se
SRP control
difference = 0.4
SRP control
SE = 0.4
Jones 1994
Q1 only
Note: data read from figure; only max
whisker value plotted in figure
Mean change
from baseline,
CAL, mm
6 months
RAL (Moderate
pockets 3-6mm);
estimated from
figures 5 and 6
6 months
Kahl, 2007
Also reporting Proportion of sites demonstrating
>=2 mm PAL gain or loss at the12-month reexamination.
No notes
NA,
severe
Unit of analysis was the subject. Duncan's multiple
caries
range test was used to make comparisons
were not
between group means as well as group mean
included
changes from baseline. A value of <0.05 was
in the
considered statistically significant. The chisquare
study.
test was used to analyze data reflecting the
No data
percentage of sites showing change
presented
.
Has data on use of Vector ultrasonic irrigated with
hydroxylapatite particles (group 1).
The power calculation revealed that when the
sample size is 9, there is 80% power to detect a
difference in means of 0.40
3 mo
RAL (6-8mm);
estimated from
figures 5 and 6
Lindhe 1983
The examination included all teeth and 4
sites of each tooth; mesial, buccal, distal
and lingual. For each variable, individual
mean values were calculated.
Statstical analysis notes
No mention of tooth loss
102/4
CAL 1/2 mouth
6 months
50 weeks
10, 20 30 50
weeks
6 months
1 week, 1 month,
3 months
1/2 mouth
7
7.4
0.5
7
nr
nr
Not reported
Not reported
Not reported
7
7.9
0.6
7
nr
nr
Has data on use of Vector ultrasonic irrigated with
hydroxylapatite particles (group 1).
The power calculation revealed that when the
sample size is 9, there is 80% power to detect a
difference in means of 0.40
no
t-test on difference, anova
Not
reported
Comparisons by individual tooth utilized ANOVA,
Kruskal-Wallis nonparametric ANOVA, and chisquare tests; SD or SE not defined; figure data
different from text data
Not reported
Not
reported
Experimental unit was the subject in all statistical
analyses. These data were adjusted by Duncan's
multiple range test for multiple comparisons.
Within each treatment group, data from baseline
and 24 weeks were compared and analyzed by
Student t-test. The data of the with-scaling and
without-scaling were also compared and analyzed
by Student t-test. Statistical significance was
accepted at probability level of ≤0.05 for all tests.
Mod: ± 1.46
Deep: ±1.04
NA
1.0
Neill 1997 (SRP vs no tx)
DATA IN FIGURE AND TEXT
INCONSISTENT
Ng, 1998
CAL gain, mm
CAL
24 weeks
3 weeks, 6
weeks, 12 weeks,
24 weeks
6 months
Baseline, 3 and 6
months
10 pts, 186 total teeth: 91 laser,
49 SRP and 46 NT
10 people; 49 teeth
Not reported
Not reported
10 people; 49
teeth
8 (32 people divided
among 4 test groups;
each split between SRP
and no treatment)
CAL:9.0
CAL:1.9
8
CAL:9.9
CAL:0.8
SD
Moderate: 7.61
Deep: 9.42
Mod: ± 0.94
Deep: ±1.92
13
Not reported
Not reported
SD
744 total sites: 364 laser, 196
SRP and 184 NT
1 site per treatment combination
(many arms in trial)
"All teeth were matched
accoring to tooth type in both
groups
Note: different
from figure,
which plots
approximately
1.3 mm
1.7
10 people; 46 teeth
Not reported
Not reported 10 people; 46 teeth
Not reported
Not reported
8
CAL:9.5
CAL:2.3
Moderate:
1.21mm
Deep: 2.41
12
Mod: ± 0.98
Deep: ±0.92
Moderate: 7.72
mm
Mod: ± 1.23
Not reported
Not reported
Not reported
8
CAL:10.4
CAL:0.5
SD
12
Not reported
Not reported
SD
Estimated 1.3
Not given;
from other
Figure indicates
data reported
0.5
in paper
Not reported
RAL (Relative
Attachment Level)
at baseline; RAL
gain at endpoint
"moderate" and
"deep" pockets
undefined
Ribeiro (DEL PELOSO), 2008
An individual
occlusal stent was
fabricated of selfcuring clear resin
to create fixed
landmarks and to
standardize the
location and
angulation of
periodontal
probes. RAL was
measured from
the stent to the
bottom of
periodontal
pocket.
At least 8 teeth with a PPD of ≥5
mm and BOP. At least 2 of the 8
qualifying teeth must have PPD≥7
mm, and the pockets of a further
two teeth must have PPD≥6 mm;
minimum of 20 teeth in both jaws
(wisdom teeth excluded)
13
108 sites in the test group
104 sites in the control
group
Deep: 9.16
Deep: ±1.91
Moderate:
1.52mm
Deep: 2.40 mm
Power calculation to determine 1.0 difference in
CAL; Friedman test used to detect intragroup
differences in RAL, and the Mann–Whitney test
was used to detect intergroup differences at each
time interval. The Wilcoxon test was used to
compare moderate and deep pockets in each
group.
There was no difference between groups
regarding the proportions of sites presenting a
RAL gain of >2mm at any experimental time.
Operator training; examiner calibration for intra
examiner reliability Site = unit of analysis, ReML
method for fitting mixed model, full factorial for
Er:YAG laser and SRP, post-hoc Tukey-Kramer
honestly significant difference test
Rotundo 2010 (SRP vs no tx)
CAL
6 months
1 week, 3 and 6
months
27 pts, all teeth with at least 1
site with PD ≥ 4 mm; 6
sites/tooth
Not reported
27 people; 422 sites
6.1
1.6
26 people; 399
sites
5.6
2
(based on value,
assumed SD)
Not reported
Not reported
27 people; 387 sites
6.1
1.5
26 people; 365
sites
Not reported
5.9
2.2
Not reported
Not reported
(based on value, assumed SD)
Not
reported
The statistical analysis was intention to treat. In
particular, if a patient showed up at the 3-month
recall visit and not at the 6-month re-evaluation,
the clinical data were imputed to the 6-month
analysis
The sample size was calculated using a=0.05 and
the power (1- b)=80%. For the variability (s=SD),
the value of 0.6mm (Sculean et al. 2004) was used
considering clinical attachment level (CAL) gain as
a variable outcome. The minimum clinically
significant value (d) considered was 0.5mm
Change in CAL
(baseline given),
mm
12 (10 included in this
mean)
11.11
not given
12
0.54
0.18
SE
0.54
0.18
13
11.28
not given
13
0.24
0.25
SE
0.24
0.25
N/A
No notes
6 months
mean)
11.11
not given
9
0.6
0.28
SE
0.6
0.28
13
11.28
not given
11
0.28
0.19
SE
0.28
0.19
N/A
No notes
6 months
mean)
11.11
not given
10
0.45
0.2
SE
0.45
0.2
13
11.28
not given
12
0.23
0.3
SE
0.23
0.3
N/A
No notes
6 months
ALL TREATED
SITES
Van Dyke 2002
Months 1 and 3
Change in CAL
(baseline given),
mm
six sites on two teeth selected
for the
study. The two teeth were
selected based upon the
presence in at least one of the
sites (in each tooth) of A PD
6mm and GCF levels of PGE 2 >
66.2ng/ml. Although treatment
was administ’d only at sites
≥5mm on the study teeth,
clinical indices were monitored
at all six sites.
>=5 but <6 mm
SITES
Change in CAL
(baseline given),
mm
>=6 mm SITES
July 2015
Page 126
Citation:
Author, Year
Outcome measure
Zhou, 2014
CAL
July 2015
Time period for
No. Sites treated
data presented in
per mouth / No.
this abstraction (as
sites averaged per
close to 9 months
tooth
as possible)
1 year
not stated
Test sample
size
Baseline
Test mean
Baseline
20
4.58
Test
Test SD or
Mean
Mean SD
Test SD or SE
sample
Test mean at
SE (list
difference
(or SE)
(list value)
size at end end of test
value) at SD or SE?
TEST (final- difference,
Baseline
of test
period
end of test
baseline)
TEST
period
period
1.72
20
4.02
1.27
SD
NOT
REPORTED
NOT
REPORTED
Control
sample
size
Baseline
Control
mean
Baseline
Control SD or SE
(list value)
Baseline
20
Scale: 4.33
NoTx: 5.27
Scale: 1.45 NoTx
1.69
Control
Control SD
Control
sample
or SE (list
mean at end
size at end
value) at SD or SE?
of test
on test
end of test
period
period
period
Mean
difference
CONTROL
(finalbaseline)
Mean SD (or
SE)
Caries data
difference,
CONTROL
Scaling group:
Scaling: 1.05
3.93
No treatment:
No
1.59
treatment:5.49
NOT
REPORTED
NOT
REPORTED
20 for scaling
group, 19 for
no treatment
SD
not reported
2-sided hypothesis, signifcance set at
<0.05
Page 127
Scaling and root planing – Review authors’ judgment of each risk of bias item as low, unclear, or high for each included
study
Selection bias
Domain:
Random sequence
generation
Allocation concealment Masking of participants
Review
author's
judgment
Support for
judgment
randomly
created two
different samples
assigned sample
to tx
High
computer
generated
low
Citation:
Author, Year
Support for
judgment
Berglundh,
1998
Chen 2012
Jones 1994 Details not given
Performance bias
Review
author's
judgment
Support for
judgment
Not
described
unclear
Allocation
was
concealed
from
investigator
low
Masking of personnel
Review
author's
judgment
Support for
judgment
blind, placebo
used
Low
not
described,
but not likely
Unclear
Were the groups treated
the same except for the
intervention?
Review
author's
judgment
Support for
judgment
no mention
of masking
or blinding of
examiner or
therapist
high
not
described,
but not likely
Unclear
Detection bias
Attrition bias
Reporting bias
Masking of outcomes
assessment
Incomplete outcome
data (Include percent
lost to follow-up)
≤10% low; 11-20%
unclear; >20% high
Selective reporting
Review
author's
judgment
Support for
judgment
Review
author's
judgment
"if indicated
OHI"
High
no mention of
examiner
blinding
High
Groups 1 and
2 received
OHI, group 3
(control) did
not
high
not described
Unclear
less than 10%
attrition
low
all data was
reported
low
Low
39/51
completed
(24% lost)
from all arms;
test group
about 50%
lost
High
No bias detected
Low
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
no evidence of
clinical trial
registration
none lost
Low
Unclear
PAL reported but
not PD or other
perio measures
Unclear
No details
given
Unclear
Attemp made
to mask
Low
Not
described
Unclear
Yes
Low
Blinded at all
points in time
but sometimes
SRP tx was
obvious
high
not possible
high
not possible
high
Yes
Low
examiner was
blinded
Low
No dropouts
occurred
low
all data was
reported
low
Kahl, 2007
Drawing of a lot
low
senior
author, who
was not
involved in
the
treatment,
knew the
allocation
Lindhe 1983
randomized but
no method
reported
unclear
not reported
Unclear
double
blinded but
no details
Unclear
double
blinded but
no details
Unclear
Yes
Low
double blinded
but no details
Unclear
no info.
Assumed no
loss
Unclear
No bias detected
Low
Neill 1997
States random
assignment but
does not specify
how
Unclear
States
double blind
but does not
explain
Unclear
No details
given but
"double blind"
Unclear
No details
given but
"double
blind"
Unclear
OHI stated as
given to
control but not
mentioned if
given to other
groups
Unclear
No details
given but
"double blind"
Unclear
No loss to
follow up; data
details sparse
Unclear
All data reported
Low
Ng,1998
randomized but
no details
Unclear
not
discussed
high
Not possible
to mask
participants
to SRP/no tx
high
Not possible
to mask
personnel to
SRP/no tx
high
Yes
Low
Low
none lost
Low
reported on
primary&second
ary outcomes
Low
Ribeiro (DEL
PELOSO),
2008
Computer
generated
Low
another
person not
involved in
the study
Low
Not possible
High
Not possible
High
Yes
Low
Low
0 lost
Low
No bias detected
Low
Low
Envelope not
opened utnil
phase II tx
Low
No
Unclear
Examiner
was always
blinded as to
treatment
Low
Yes
Low
Examiner was
always blinded
as to treatment
Low
24/26
completed to
6 months; 1
lost; 1 ITT
only 3 month
data
Low
All data reported
Low
Unclear
Details not
provided
Unclear
control
subjects
received
irrigation
low
"evaluator
blinded"
low
Yes
Low
Evaluator
masked
Low
Up to 20%
lost
Unclear
No bias detected
Low
Random
assignement by
quad, opaque
sealed envelope
sequentially
Rotundo 2011
number,
computer
generated
random
permuted block
Van Dyke
2002
No details given
examiners all
masked to
treatment
group
assignment
Outcome
measurements
by blinded
examiner
Selection bias
Domain:
Random sequence
generation
Citation:
Author, Year
Zhou, 2014
Support for
judgment
computer
generated list
July 2015
Performance bias
Allocation concealment
Review
author's
judgment
Support for
judgment
low
identification was
concealed fromall
individuals directly
involved in the
study until final
examinations and
data collection
had been
concluded
Review
author's
judgment
low
Masking of participants
Support for
judgment
not possible
Review
author's
judgment
high
Support for
judgment
not possible
Review
author's
judgment
high
Were the groups
treated the same
except for the
intervention?
Support for
judgment
yes
Detection bias
Attrition bias
Reporting bias
Masking of outcomes
assessment
Incomplete outcome
lost to follow-up)
≤10% low; 11-20%
unclear; >20% high
Selective reporting
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
low
examinations
were conducted
by two trained
dentists who
were blinded to
the study
design
low
0 lost at 6
months, 1/60
lost at 1 year,
2/59 lost at 2
years
low
reported all
data
low
Page 128
Systemic low-dose doxycycline + SRP - Study characteristics
Citation:
Author,
Year
Special population?
patients and teeth
Country
Severity of disease
moderate)
Control
Test subject
subject age
age (mean,
(mean,
median,
median,
range as
range as
described)
described)
Control
Control
Dose/ duration/
applicable
Test (typically
adjunct)
Test (typically
adjunct)
Was standard
Trial design
Dose/ duration/
counseling
(split mouth
frequency/ timing mentioned as part / parallel
including
of control
group /
simultaneous/
treatment?
cross over)
before/ after
Duration
of study
Other time
periods for
which data
are available
OHI, written
one or two sessions of
instructions, and
SRP with a maximum
demonstration of Bass
of seven days
method, use of
between at the
interdental brushes and
Parallel
baseline visit, and
floss were provided
(multicenter)
doxycycline hyclate
each subject, both
(20 mg, twice/day)
control and test
started at the baseline
groups, at each
visit for 3 months,
treatment session.
12 months
Not reported
Baseline, 3, 6, 9
and 12 months
Type 1 and Type 2 Diabetics
Paper did not give % of smokers
in study population.
Al Mubarak
2010
Saudi
Arabia
Caton 2000
USA
Deo 2010
India
Emingil 2004
"Effectiveness
..."
CITE
TOGETHER Turkey
WITH Emingil
2004 "The
Effect of..."
SAME CAL
DATA
A specific diagnosis was not
one or two sessions of SRP with a
stated.
Inclusion criteria: diagnosis of
maximum of seven days between at
type I or II diabetes ≥ 1 yr;
the baseline visit and placebo tablets
diabetes under control by insulin Based on age of population
twice/day, started at the baseline
48 +/- 5 years 51 +/- 6 years
Twice/day, started at the
or oral hypoglycemic agent or and the inclusion criteria
visit, for 3 months
(Group 2)
(Group 1)
baseline visit for 3 months
both; constant type and dose of stipulating 5 mm to 8 mm
diabetic medication administered PPD, a diagnosis of moderate
full mouth supra and subgingival
to severe chronic
for previous 6 mo; good physical
debridement using ultrasonic and
periodontitis seems
condition ; no serious medical
hand instrumentation
appropriate.
issues or transmittable diseases;
no cardiac condition requiring
antibiotic prophylaxis; ≥ 18
remaining natural teeth with a
minimum of 6 sites in at least 2
BID (once in am, once in
periodontitis (at least 2 tooth
pm); 1 hour before meals
sites within each of 2
74% were past smokers, 40%
qualifying quadrants with 45: range 30- 47 range: 31SRP performed until the
SRP with Placebo
were current smokers
PD and CAL between 5 and
72
74
tooth and root surfaces
9mm, inclusive, which bled
were free from deposits
on probing
as determined by visual
or tactile examination
SRP+placebo / scaling and root
planing (SRP), using manual
(standard Gracey currettes) and
powered instruments (EMS±mini
placebo capsule b.i.d. for
37.1 ± 3.96 years
Pts with diabetes
Piezon) within 24 hours by the same the treatment period of six
examiner. Root surfaces were
months
instrumented until they became free
of deposits as determined by visual
or tactile examination.
four to six sessions by
the same
examiner. Tooth and root
surfaces were
instrumented under local
anesthesia up to 1 hour
allowed per quadrant until
No
Study patients had at least
they were free of all
14 natural teeth, at least
deposits as determined
None of the subjects were heavy
SRP+ placebo capsules
eight pockets with ≥5 mm
by
users of alcohol or tobacco.
44.90 ± 5.06 47.80 ± 8.40
probing depth (PD) and ≥4
visual or tactile
They were smoking less than five
37-53
39-61
placebo capsules
mm clinical attachment level
examination.
cigarettes per day. NOTE - 3 in
b.i.d. for 3 months
(CAL), and radiographic
LDD and 5 in placebo group
evidence of moderate to
Patients were also
noted as "current smokers"
advanced chronic
encouraged to continue
periodontitis
good oral hygiene and
given regular
maintenance therapy
(i.e., removal of any
supragingival plaque and
calculus) at every recall
No
Emingil 2008
Turkey
Smoking
status was classified as nonsmoker or current smoker.
Smokers in both treatment
groups were smoking less
than five cigarettes per day for
>5 years. Subjects who had
never smoked or who had
stopped smoking ≥5 years ago
were considered non-smokers. 4
in SDD and 6 in placebo
No
Emingil 2011
STUDY
RELATED TO
EMINGIL
2006
Turkey
July 2015
All subjects were either
non-smokers or smoked <5
cigarettes per day (11 in
the SDD and 10 in the placebo
group) and stayed as
such during the course of the
study.
SRP and LDD
(doxycycline
hyclate)
SRP with
doxycycline
20mg BID 1 hour
before meals; for 9
months
Not reported
parallel group
9 months
table of adverse events provided; 3 dropouts due to adverse events: 1 test and 2 3, 6, 12 months
from placebo
Systemic SDD
doxy+SRP
doxycycline hyclate
20 mg twice a day
(b.i.d) for 6 months
No
Parallel group
6 months
During the course of the study, wound
healing was uneventful. No patient showed
adverse reaction to SDD therapy. None of
the selected
patients dropped out before the
termination of the study.
Patients received oral
hygiene instruction at
each session,
including
toothbrushing
Parallel group
and the use of
interdental flossing or
interdental
brushing as
appropriate.
12 months
Collected throughout the study; Treatment
with LDD was well tolerated and none of
the patients reported any adverse effects 3, 6, 12 months
from the use of either LDD or placebo
capsules.
The treatment included
SRP that was carried out
in four to six sessions by
the same examiner (GE).
Oral hygiene
Tooth and root surfaces
instruction was given
The subject
All subjects had ≥14 natural
47.83 +/– 7.9
were instrumented under
SRP+subto the subjects at
44.50 +/– 5.2
was given motivation to reinforce the
teeth, at least eight pockets
local anesthesia (up to 1 antimicrobial dose 20 mg, twice a day for
each session on
oral hygiene as well as the regular
Parallel group
with probing depth (PD) ≥5
range: 39 to
hour per quadrant) until
doxycycline
3 months
toothbrushing and the
range:37 to 53
maintenance therapy, i.e., removal of
mm and clinical attachment
61
they were free of all
(SDD)
use of flossing or
any supragingival plaque and
level (CAL) ≥4 mm, and
deposits as determined
interdental brushing
calculus took place at every visit
radiographic evidence of
by visual or tactile
as appropriate
during the 6-month period.
examination / placebo
capsules twice a day for
3 months
6 months
Treatment with SDD was tolerated
well, and none of the subjects complained
of any adverse effects from the use of
SDD or placebo capsules.
3 months
12 months
Adverse event information was collected
at each visit. Treatment with SDD was welltolerated and none of the patients
reported any adverse effects from the use
of either SDD or placebo capsules.
3, 6, 9, 12
months
SRP+Low-Dose
Doxycycline
(LDD) Therapy:
20 mg capsule;
taken b.i.d. for 3
months; 1 hr
before eating
morning and
evening.
Adjunctive to SRP
(20 mg,
b.i.d.) for 3 months
None
SRP+placebo
Chronic periodontitis. All
patients were diagnosed
with moderateto-severe chronic
periodontitis according to
clinical and radiographic
findings and periodontal
history
Study patients had at least
14 natural teeth, at least
eight pockets with ≥5 mm
probing depth (PD) and ≥4
mm clinical attachment level
(CAL), and radiographic
evidence of moderate to
advanced chronic
periodontitis
scaling and root
planing (SRP), which was
carried out in four to six
Patients received oral
sessions by another
hygiene instruction at
oral hygiene was reinforced and
clinician. Dental surfaces
SRP+
SDD (20 mg
each session,
regular maintenance therapy (i.e.,
were instrumented under subantimicrobialper capsule; 2 x 1)
including
removal of any supragingival plaque
Parallel group
local anesthesia with <1 dose doxycycline was given at baseline toothbrushing and the
and calculus) was performed at
hour allowed per
(SDD)
for 3 months.
use of interdental
every recall visit
quadrant until they were
cleaning as
free of all deposits as
appropriate.
determined by visual or
tactile examination.
SRP+placebo
46.1 +/– 6.4
years
34 to 59
years
47.7 +/– 7.6
years
35 to 61
years
Page 129
Systemic low-dose doxycycline - Study characteristics (continued)
Citation:
Author,
Year
Gürken et al.
Int J Dent
Hyg
2008;6:84-92.
Haffajee 2007
Special population?
patients and teeth
Country
Control
Test subject
subject age
age (mean,
(mean,
median,
median,
range as
range as
described)
described)
35 males and female pts.
Inclusion criteria included
systemically healthy, at least 3
natural teeth in each quadrant
Diagnosed as having
and a total of 14 teeth. No pt.
severe generalized chronic
had a drug allergy, used
periodontitis defined as: >
NSAIDS, had taken an antibiotic
46.38+-7.63
46.77+-6.95
30% of sites with ≥ 5 mm
or received perio therapy in
(range: 34-59) (range: 35-59)
CAL and having at least 2
previous 3 months. Women
sites with PD ≥ 6 mm in
could not be pregnant, actively
each quad with BOP.
breast feeding or use oral
contraceptives. 4 and 5 smokers
in SDD and placebo groups,
respectively.
Turkey
U.S.
Severity of disease
moderate)
No
at least eight sites with PD>4 mm
/ no perio tx within previous 3
months / not pregnant or nursing
/ no systemic conditions
requiring antibiotics
Moderate chronic
periodontitis
47 +/- 11
43 +/- 15
Control
SRP+ Placebo
SRP at baseine and then at 3
maintenance SRP visits post baseline
Control
Dose/ duration/
applicable
Test (typically
adjunct)
SDD group
received a 20 mg
Placebo capsules taken
capsule; taken
b.i.d. 1 hr before morning b.i.d. 1 hr before
and evening meals for 3
morning and
months
evening meals for
3 months plus
SRP
SRP was performed a
quadrant
at a time under local
anaesthesia at
approximately weekly
intervals
SRP+Systemic
Periostat (SDD
doxycycline)
Test (typically
adjunct)
Was standard
Trial design
Dose/ duration/
counseling
(split mouth
frequency/ timing mentioned as part / parallel
including
of control
group /
simultaneous/
treatment?
cross over)
before/ after
SDD 20 mg.; b.i.d.
(12 hr intervals) for
three months
adjunctive to SRP
20 mg doxycycline
(SDD, Periostat) b.i.d.
for 12
weeks / started at first
SRP visit
Authors did not report
giving OHI or other Parallel group
instructions
No
Parallel group
Duration
of study
Other time
periods for
which data
are available
12 months
The authors reported no adverse events.
Baseline, 3, 6,
9 and 12
months
12 months
Two subjects in the
SDD group reported adverse events
including dizziness /tachycardia with the
administration of local anaesthetic for
SRP and a possible interaction between
the study medication and OTC vitamins
3 and 6 months
and calcium supplements. The subject
stopped taking the latter for the duration
of the SDD administration.
No adverse events were
reported in the SRP-only group
Institutionalized geriatric patients
aged 65 or older / equal exsmokers in each group (not
excluded)
baseline clinical attachment
levels (CAL) 5–9 mm, probing
depths (PD) 4–9 mm and
bleeding on probing
Mohammad
2005
USA
Needleman
2007
UK
Smokers; at least 16 teeth
U.S.
210 males & females comprised
the study population. Inclusion
criteria were: Evidence of
periodontitis (i.e., CAL and PD
between 5-9 mm with BOP in two
sites in each of two quads).
Exclusion criteria were:
pregnancy, lactation, serious
chronic medical condition (e.g.,
diabetes, kidney or liver
disease), acute syst infection,
previous prophy or perio Tx
within 90 days of baseline,
requirement for antibiotic
prophylaxis prior to dental Tx,
use of non-TCH antibiotic with 3
months of baseline,
hypersensitivity to TCH, or the
need for long-term (> 2 wks)
daily antacids containing
aluminum, calcium or
magnesium and participation in a
perio clinical trial within 12
months of baseline.
26 (25.5%) subjects in control
group were smokers. 41 (38.3%)
subjects in SDD group were
smokers.
Preshaw et al.
JP 2004
moderate-severe chronic
periodontitis
Excluded if:chronic use of
NSAIDs, steroids or
antibiotics, although use of subanalgesic doses of
aspirin for anti-platelet
aggregation was permitted / no
serious medical condition / no
diabetes / no perio therapy within
the last 6 months
Based on inclusion criteria
of CAL and PD between 5
and 9 mm with BOP,
patients presented with
moderate and severe
periodontitis.
Radiographic exam was
used to establish Dx of
chronic periodontitis and
severity of disease.
81 (range 72- 83 (range 7793)
90)
Mean=41.7
mean birth
year 1960.3
SD 7.6
Mean=44.2
mean birth
year 1957.8
SD 6.1
SRP + placebo
SRP at baseline and 20 mg
doxycycline 2x daily for 3 months
post baseline
SRP using local anesthesia and
manual and ultrasonic
Mean age of Mean age of
instrumentation. Following SRP,
48 yrs with a 48 yrs with a
subjects weere randomized into
range of
range of 34control and test groups. Authors did
35-75 yrs.
75 yrs.
not state who did SRP, i.e., RDH or
DDS. At month 9, all subjects
received a dental prophy and were
exited from study.
performed until the crown
and root surfaces were
visually and/or tactilely
free of all deposits /
placebo twice daily for
SRP + Systemic
the treatment
SDD doxycycline
period of the study (9
months), commencing at
baseline; one pill in
morning and one in
evening
20 mg doxycycline 2x
daily for 3 months post
baseline
Control group took a
placebo pill, b.i.d., 1 hr
prior to meals with a 12
hr interval. Placebo and
test SDD were identical in
appearance and
dispensed in 3-month
quantities for 9 months
SDD; 20 mg
doxycycline twice
daily commencing at
baseline; one pill in
morning and one in
evening
20 mg
SRP with 20mg
doxycycline 2x
doxycycline
daily for 3 months (Periostat) BID for3
post baseline
months post baseline
SRP + SDD
(doxycycline
hyclate)
SDD, 20 mg, b.i.d., 1
hr prior to morning
and evening meal with
a 12 hr interval. SDD
was dispensed in 3
month quantitie for a
total of 9 months.
At every appointment
oral hygiene
procedures were
reinforced. Following
parallel group
the month 9 visit, a
further dental
prophylaxis was
provided.
9 months
Not reported
3 and 6 months
all subjects received
smoking cessation
counseling prior to
study; all subjects
received OHI after
randomization
6 months
5 subjects, all in placebo group; minor
issues such as pulpal or periodontal
problems
1 and 3
months, but not
reported in
paper
Not Reported
parallel group
Double-blind,
radomized,
placebocontrolled,
multicenter,
parallel group.
Examiners
were
calibrated.
9 months
contacted monthly by telephone for the
recording of adverse events (AEs)
No (smokers included)
Preshaw 2008
US and
UK
untreated periodontitis
manifested by four periodontal
sites in each of two quadrants,
i.e., eight qualifying periodontal
sites, with aminimum of two
affected teeth per quadrant, with
all eight qualifying sites
demonstrating probing depth
(PD) ≥5 mm, attachment loss≥ 5
mm, and bleeding on probing
(BOP) score ≥1, with at least two
sites having bleeding scores≥2 /
not pregnant or nursing / no
serious medical conditions or
systemic infections / no dental
prophy within the last 30 days /
no non-tetracycline antibiotics
within 6 weeks of baseline;
no use of tetracycline antibiotics
within 3 months
of baseline;
July 2015
The % of subjects who experienced Txemergent adverse events (i.e., all causes)
was similar for control (61%) and SDD
(59%) subjects. Most frequent adverse
events were: infection, headache, pain
and influenza. There were no statistical
differences between placebo and SDD
groups regarding GI tract genito-urinary
Baseline, 3, 6
tract, photosensitivity, hypersensitivity,
and 9 months
enterocolitis, fever and
lymphadenopathies. One control subject
had an MI and one had severe asthma.
One SDD subject had chest tightening,
was hospitalized, but successfully
completed study. None of the serios
adverse events were considered related to
study product.
Periodontal disease
(unspecified)
48.5 ± 11.4
24 to 81
49.9 ± 11.0
23 to 82
SRP+placebo
SRP completed
within a maximum of 24
hours. SRP was
performed by supra- and
subgingival use of
ultrasonic
instruments followed by
hand instruments for
removal of plaque and
calculus deposits until
tooth surfaces
were smooth and calculus
could not be detected,
with a time limit of 1 hour
per quadrant. Ultrasonic
and universal or areaspecific curets were
used, as was local
anesthesia, based on
operator preference
In the SDD-40 group, 88 subjects
(66.2%) reported a total of 217 AEs; 94
subjects (70.7%) reported a total of 229
AEs in the placebo group
Systemic SDD
doxy+SRP
Oracea; 40 mg
modified release dose,
1x/day for 9 months
Not mentioned
Parallel group
9 months
In the SDD-40
3 and 6 months
group, the most frequently reported AEs
were headache (13 subjects; 9.8%) and
influenza and nasopharyngitis (each
Note that %
seven subjects; 5.3%).In the placebo
sites with CAL
group, the most frequently reported AEs
gains greater
were sensitivity of teeth (13 subjects;
than 2 or 3 mm
9.8%) and headache and nasopharyngitis
is provided
(each 10 subjects; 7.5%). AEs were
ranked as mild, moderate, or severe in
intensity, with the most common being
mild or moderate. Severe AEs were
recorded for nine (6.8%) subjects in the
SDD-40 group and 18 (13.5%) subjects
in the placebo group. No AE was
considered to be probably related to the
study medication in either group
Page 130
Systemic low-dose doxycycline - Outcomes data
July 2015
Page 131
Systemic low-dose doxycycline - Outcomes data (continued)
July 2015
Page 132
Systemic low-dose doxycycline - Review authors’ judgment of each risk of bias item as low, unclear, or high for each included study
Selection bias
Domain:
Random sequence generation
Review author's
judgment
Citation: Author, Year
Support for judgment
Mubarak, 2010
Subjects at each center
were allocated numbers
which were then used to
randomize the four
different groups (2
control and 2 test
groups). This was
achieved by distributing
the subject number
among the four study
groups by sequentially
allocating them to one of
four alphabetical codes
relating to a test group,
i.e., A for Group 1, B
for Group 2, etc.
low
Caton 2000
computer generated list
low
Deo 2010
Emingil 2008
Emingil 2011
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Reporting bias
Masking of outcomes
assessment
Selective reporting
Support for
judgment
Review
author's
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Did not include
those who took
other medications,
that did not show
for appointments
etc.
Low
No bias detected in
design or reporting of
data.
Low
Unclear
10%
low
No bias detected
Low
Unclear
No losses
Low
No bias detected
Low
Support for
judgment
Not Reported
Unclear
Subjects were
also blinded to the
prescribed
medication
(doxycycline
hyclate,
20 mg or placebo).
Low
SRP provided by
hygienists who were
blinded to assigned
treatment
Low
Yes
low
Examiners were
blinded
low
No details given
Unclear
double-masked
low
double-masked
low
yes
low
Masking not
mentioned
Low
Masking not
mentioned,
unmarked placebo
capsules
Unclear
Yes
Low
Masking not
mentioned
Support for
judgment
23 of 369 subjects
did not complete
the 12 month study
(6.2%)
No details given
Unclear
No details given
Unclear
Coin flip
Low
Study medications
were identical in
appearance.
Low
Double blind with
placebo control
group
Low
Double blind;
Examiner recording
data was unaware of
treatment.
Low
No differences
noted
Low
Examiner
masked
Low
20/30 completed 12
months
High
No bias detected
Low
Coin flip
Low
Study medications
were identical in
appearance
Low
Yes, and identical
capsules
Low
double blinded, but
no details
Unclear
No differences
noted
Low
Examiner
blinded
Low
Although 24/30
completed, power
calc indicates this
is adequate size
Unclear
No bias detected
Low
Low
placebo capsules
identical
in appearance but
containing inactive filler;
All
patients were
represented with a code;
coded bottles
Low
Double-masked
Low
Not specified
Unclear
No differences
noted
Low
Clinical
examiner
masked
Low
23/32 and 23/33
(70-72%)
completed
High
No bias detected
Low
Low
Not stated who was
responsible for coin
toss.
unclear
Double blind with
placebo control
group
Low
Double blind
Low
Yes
Low
Examiner
recording data
was unaware of
treatment
Low
11 lost (25%)
High
No bias detected;
reported primary and
secondary outcomes
Low
Unclear
No - single blinded
High
No-single blinded
High
Yes
Low
Masked
Low
67/98 subjects had
complete data for
all monitoring visits;
ITT used with
LOCF; if only
baseline data,
subject excluded
High
AL at 12 months for
pockets with baseline
PD>6 mm primary
outcome measure
Low
Unclear
Identical pills
Low
Nurses masked to
allocation
Low
Randomization after
SRP
Low
Unclear if
masked
Unclear
No losses
Low
No bias detected
Low
Low
blinded,
randomization not
broken until after
data analysis;
concealed
containers
Low
all patients given
SRP and either
doxycycline or
placebo
Low
blinded until
after data
analysis
Low
2/18 in placebo,
2/16 in control did
not complete study
(none due to
adverse events).
Intention to treat
analysis used.
Low
reported on
primary&secondary
outcomes
Low
Low
"Double-blind";
assume this was the
SRP procedure
prior to adjunct
Low
Low
Masking not
mentioned
Unclear
34/102 in control
group, 18/107 in
intervention group
lost
High
No bias detected;
reported primary and
secondary outcomes
Low
Coin flip
Gürkan et al. Int J Dent
Pt assigned by coin toss
Hyg 2008;6:84-92.
Haffajee 2007
Random number table
Low
Assignment by clinic cocoordinator
Mohammad 2005
computer assigned
randomisation
numbers
Low
No details given
Needleman, 2007
randomized by
comptuer
Low
allocation concealed until
after data analysis;
central randomization
Low
blinded,
randomization not
broken until after
data analysis;
concealed
containers
Preshaw et al. JP 2004
randomized but no
details
Uncelar
Did not Report
Unclear
Placebo and SDD
were identical in
appearance and all
received SRP
July 2015
Support for
judgment
Were the groups treated the
same except for the
intervention?
Attrition bias
Incomplete outcome data
(Include percent lost to
follow-up)
≤10% low; 11-20% unclear;
>20% high
Review author's
judgment
Review author's
judgment
Detection bias
Indistinguishable
placebo capsules
Emingil 2004
"Effectiveness..."
CITE TOGETHER WITH
Emingil 2004 "The Effect
of..." SAME CAL DATA
Performance bias
all patients given
SRP and either
doxycycline or
placebo
Page 133
Systemic antimicrobials: amoxicillin-metronidazole + SRP - Study characteristics
Citation:
Author, Year
Country
Berglundh, 1998
Sweden
Cionca 2009
Flemmig 1998
Goodson, 2012
Special population?
Test subject age
refractory, mild,
(mean, median,
moderate)
range as described)
no mention of cigarettes or any
health condition
Advanced periodontal
disease
35-58 years
adult chronic periodontitis
with the presence of at
least four teeth with a
No. Smoking history was recorded,
probing depth (PD) >4
Switzerland but smoking was not an exclusion
mm, clinical attachment
criterion.
loss (AL) ≥2 mm, and
radiographic evidence of
bone loss.
Germany
USA and
Sweden
untreated periodontitis-4
pockets > 6 mm :
moderate
no mention of smoking
Any systemic condition such as
AIDS or diabetes excluded;
Smokers included; no information
on past smokers
Control subject age
(mean, median,
range as described)
Moderate to severe
periodontitis; 4 teeth with
pockets > 5 mm and 8
teeth with CAL > 3 mm
50.6 +/– 8.6
50.5 +/– 13.6
48.9
54.4
46 ± 2.0
47 ± 2.6
Control
Control
Dose/ duration/ frequency/ timing if
applicable
Test (typically
adjunct)
SRP+placebo
local anesthesia 3-5 sessions unspecified
operator
scaling + AMX
MET
Mombelli 2005
Switzerland
Ribeiro, 2009
Brazil
Untreated perio; presence of
inter-proximal periodontal lesions in each
of tw o contra-lateral quadrants in the
region including the canine, premolars,
and the mesial aspect of the first molar,
and presence of Porphyromonas
gingivalis in a pooled subgingival plaque
sample from this region / no systemic
illness / not pregnant or lactating /
systemic antibiotics taken w ithin the
previous 2 months / no subgingival scaling
in the last year
Exclusion criteria were as follows:
periapical alterations on qualifying
teeth, medical disorders that
require prophylactic antibiotic
coverage or that could
influence the response to
treatment, scaling and root planing
in the preceding 6 months,
consumption of drugs known to
affect periodontal status (antibiotic,
anti-inflammatory, anticonvulsant,
immunosuppressant, or calcium
channel blocker) within the past 6
months, orthodontic therapy,
allergy to penicillin and/or
metronidazole, pregnancy and
smoking
Moderate to advanced
Severe Chronic
Periodontitis
Inclusion age range criteria: Age 25–65 years
46 (range:34-55)
46.2 (range 30-66)
AMX 375 mg tid metronidazole
250 mg tid for 14 days
The operator treated at least half of the periodontally
diseased teeth w ith thorough scaling and root planing to
the depth of the pocket under local anesthesia. Ultrasonic
instruments† w ere used first, follow ed by Gracey curets.
SRP+Systemic
The pockets w ere irrigated w ith a 0.1% aqueous
SRP +
metronidazole and
solution of chlorhexidine, and the subjects w ere
chlorhexidine +
amoxicillin
instructed to rinse the m outh w ith 0.2%
placebo
combined +
chlorhexidine tw ice daily for the next 10 days. The
chlorhexidine
operator treated the remainder of the dentition in the same
w ayw ithin 48 hours.At the end of the final treatment visit,
the subjects received the medications and w ere instructed
on how to take them.
scaling
SRP and CHX
rinsing
local anestehsia 2 hours per quadrant by
students - non-periodontist instructor if student
failed
under local anaesthesia in 4 weekly visits given
by therapist with unspecified qualifications /
0.12% CHX rinse 2xday
scaling + AMX
MET
SRP + AMX
MET(+ CHX rinse)
No (did not exclude smokers) /
Four subjects treated w ithout antibiotics,
and tw o treated w ith antibiotics w ere
smokers. With regards to pocket depth
reduction and CAL gain there seemed to
be a tendency of better clinical responses
in non-smokers, but small numbers
precluded a statistical evaluation.
Trial design (split
mouth / parallel
timing including simultaneous/
group / cross
control treatment?
before/ after
over)
No mention of anesthesia at most 45 minuntes of
scaling and no specification of operator
scaling + AMX
MET
Parallel group for
these data
(Factorial)
12 months
NR
metronidazole, 500 mg, and
amoxicillin,
375 mg, to be taken three times
per day for 7 days. Addition of
subgingival irrigation with 0.1%
and rinsing bid with 0.2% for 10
days
Instruction on proper oral
hygiene given to all pts
Parallel group
6 months
Recorded at 1 w eek, 3 and 6 months but only reported
at 1 w eek during the active period of medication.
The number of subjects presenting w ith stomach upset
w as similar in both groups (n = 4 in the placebo group
and n = 5 in the test group). How ever, the number of
subjects complaining about gastrointestinal problems,
notably diarrhea, w as higher in the test group (n = 6
versus n = 3). Cramps w ere noted
in five subjects in the test group. Tw o teeth, in tw o
subjects, w ere lost during the study, and tw o subjects
show ed evidence of suppuration despite therapy;
these events occurred in the placebo group.
AMX 375 mg tid metronidazole
250 mg tid + 0.06% CHX for 8
days
OHI at 3 month intervals
parallel
12 months
4/18 on AB had GI problems
Parallel group
24 months
1 dropped out due to nause vomiting and
development of oral candidiasis (miconazole)
1 developed diabetes
the patients were
instructed in proper oral
hygiene
Parallel group
12 months
Not reported
yes
parallel
6 months
reported -4 patients had GI from test group
and three from control group
Each patient in the study
was provided a powered
toothbrush (3D;
Oral B; Boston, MA) and a
triclosan- containing
toothpaste (Total®;
Colgate; Piscataway, NJ,
USA), and appropriate
500 mg AMX bid + 250 mg MET
devices for approximal
tid for 14 days
tooth cleaning. Patients
were instructed to perform
the oral hygiene procedures
twice daily.At each followup visit (3, 6, 12, 18 and 24
months) the patients’ oral
hygiene standard was
checked and reinforced
when indicated.
The two study teeth were treated as follows in a
single, separate session: Thorough scaling and
root planing to the depth of the periodontal defect,
followed by pocket irrigation with saline solution,
manual compression of gingival tissues for 5 min,
and the placement of a retraction chord
containing 10% potassium sulphate (Gingibraid
3a, Van R Dental Products, Oxnard, CA, USA).
250 mg metronidazole
SRP + Placebo
Next, an envelope containing the code for the
Systemic AMXand 375 mg amoxicillin were
medication +
randomized supplementary treatment was
MET + SRP + no
administered together three times
Placebo gel
opened, assigning Emdogains to one, and
Emdogain
a day for 7 days.
placebo to the other side. The retraction chords
were removed after 2 min in place, and then the
sites were rinsed with saline. PrefGel
was applied in the pockets during
2 min (Blomlo¨f & Lindskog 1995,
Blomlo¨f et al. 1996), followed by another saline
irrigation / Two placebos were administered three
times a day for 7 days.
SRP
oral hygiene instruction
and one session of
supragingival scaling.
The oral hygiene instruction
was, if indicated, reinforced
during the course
of the trial.
Duration of
study
AMX 375 mg and 250 mg MET tid
for 7 days
Systemic antimicrobials: amoxicillin-metronidazole + SRP - Updated literature
Citation:
Author, Year
Country
Special population?
patients and teeth
Test subject
age (mean,
median, range
as described)
Control subject
age (mean,
median, range
as described)
Control
Control
Test (typically
adjunct)
Miranda, 2014
Brazil
pts with diabetes
chronic perio; more
than 30% of the sites with PD and
clinical attachment level (CAL)
≥4 mm and a minimum of six teeth
with at least one site with PD and
CAL ≥5 mm and bleeding on
probing (BoP) at baseline.
54.0 +/- 8.2
53.7 +/-8.0
Placebo and SRP
3 times day for 14 days
SRP and MTZ and
AMX
July 2015
Was standard
Trial design
counseling
study
after
control treatment?
/ cross over)
400 mg MTZ and 500 mg AMX three
times a day for 14 days
Yes
parallel group
1 year
Diarrhea, headache, metallic taste, nausea/vomiting;
However, no significant differences
were observed between groups for
the number of subjects reporting
specific adverse effects
Page 134
Systemic antimicrobials: amoxicillin-metronidazole + SRP - Outcomes data
Citation:
Author, Year
Outcome measure
Time period for
data presented in
this abstraction
Other time periods
for which data are
available
mouth / No. sites
averaged per tooth
Test sample size
Baseline
Test mean
Baseline
Test SD or SE
(list value)
Baseline
Test sample size
at end of test
period
Test mean at
end of test
period
Test SD or SE
(list value) at
end of test
period
SD or
SE?
8
NR
NR
8
NR
NR
SD
Mean gain TEST
(Baseline-final)
Mean SD (or SE)
gain, TEST
0.8
0.4
Control sample
Control mean
size
Baseline
Baseline
Control SD or
SE (list value)
Baseline
Control sample Control mean at Control SD or SE
size at end on
end of test
(list value) at end
test period
period
of test period
SD or
SE?
Mean gain
CONTROL
(baseline-final)
Mean SD (or SE)
gain, CONTROL
0.7
0.3
Caries
data
102/4
PAL, overall (Groups 2
and 4)
Berglundh, 1998
12 months
2, 24 months
PAL 4-5 mm pockets
Cionca 2009
PAL >=6mm pockets
CAL = PD +REC,
where REC=positive if
gingival margin
located apical,
negative if located
coronal to the
cemento-enamel
junction
Baseline, 3 months
6 months
CAL gain, in mm
[change in CAL from
baseline}
The examination included
all teeth and 4
sites of each tooth;
mesial, buccal, distal
and lingual. For each
variable, individual
mean values were
calculated.
25 Subjects in the
Note: Number of
test group had 26.9
pockets with PD>4 mm
+/- 15.6
A total of 3,126 sites (six
decreased from 30 to 3
sites with PD >4
per tooth) were clinically
for placebo and 27 to
mm and BOP.
monitored at baseline and
0.5 for test
at 3 and 6 months
9 months
137/6
PAL 4-6 mm
9 months
137/6
PAL >= 7mm
9 months
137/6
3,6,9 months
NR, but 48 total
were enrolled in
beginning, and 38
completed the
study
NR, but 48 total
were enrolled in
beginning, and 38
completed the
study
NR, but 48 total
were enrolled in
beginning, and 38
completed the
study
NR
NR
8
NR
NR
SD
NR
0.6
0.3
0.7
0.3
1.8
0.5
1.3
0.4
6 sites of each tooth with
a pocket
>4 mm at baseline
PAL <=3 mm
Flemmig 1998
No mention of tooth loss
8
Not reported
Not reported
23
Not reported
Not reported
SD
0.9
0.4
26 Subjects in
the
placebo group
had 29.9 – 17.1
sites with PD >4
mm
and BOP.
NR
NR
18
NR
NR
NA
0.7 (estimated from
graph; not precise)
NR
NR, but 48 total
were enrolled in
beginning, and 38
completed the
study
NR
NR
18
NR
NR
NA
0.85 (estimated from
graph; not precise)
NR
NR
NR
18
NR
NR
NA
1.3 (estimated from
graph; not precise)
NR
6.35
0.27
26
NR
NR
SE
1.53
0.16
8
2.1
One systemic
AMX/Met and one
placebo
unavailable for 12month evaluation
not reported
not reported
Not
stated
1.7(estimated from
graph)
Not reported
Not reported
SD
1.62
8.15 (all
pockets)
0.55
13
NR, but 48 total
were enrolled in
beginning, and 38
completed the
study
NR, but 48 total
were enrolled in
beginning, and 38
completed the
study
Also reporting Proportion of sites demonstrating >=2 mm PAL
gain or loss at the12-month re-examination.
Not reported
Not reported
24
Not reported
Not reported
SD
0.9
0.4
Not
reported
The differences between patients in the treatment groups were
determined at each time point using the Mann-Whitney U test;
Backward stepwise
logistic regression was used to study various relationships
between results; comparisons statistics between groups not
described
NR
NR
20
NR
NR
NA
0.8 (estimated
from graph; not
precise)
NR
NR
No mention of tooth loss; sample size in subgroups not known;
attachment level changes in shallow pocket look suspicious error?
NR
NR
20
NR
NR
NA
0.85 (estimated
from graph; not
precise)
NR
NR
No mention of tooth lossample size in subgroups not known;
NR
NR
20
NR
NR
NA
0.7 (estimated
from graph; not
precise)
NR
NR
No mention of tooth lossample size in subgroups not known;
5.84
0.32
23
NR
NR
SE
0.92
0.21
nr
Smoking data presented for all tx groups combined (not usable)
7.3
1.9
One systemic
AMX/Met and one
placebo
unavailable for 12month evaluation
not reported
not reported
Not
stated
0.4 (estimated
from graph)
not reported in
graph
N/A
Confusing as to which data are site level and which are person
level as well as which groups combined; The best data are in
Figure 2; however, the data need to be read off the graph; data
from Table 2 at the subject-level may be useful for the systemic
(combining Emdo and no Emdo together)
Not reported
Not reported
1.21
0.43
nr
not reported
8.22 (all
pockets)
1.02
12
2.4
0.57
CAL(full mouth)
Goodson, 2012
Mombelli 2005
site specific available
in fig 3. (interproximal
sites with baseline
PPD >= 5 mm at 24
months:
SRP+SMA=1.44 +/0.09; SRP=0.94+/0.09; SEM, n=95 and
92 respectively, must
be no. sites)
29 (baseline mean
only reported for
those completing
the trial)
12 month
3,6,12,18,24
4 sites per tooth on all
teeth
12 months
10
days, as well as 2, 6,
and 12 months
after treatment.
One site per quadrant with
test or placebo gel in 2
groups using test or
placebo systemic
AMX/MET / ? One site
measured per tooth
(buccal)
(Baseline data of
those who
completed also
given)
6 months
3 months
146.4
13 subjects
Mean change from
baseline, CAL, mm
Appears data given
BY SITE
16 sites in 8
subjects
RAL (for "qualifying"
(PD ≥ 5mm and BOP
sites)
Ribeiro, 2009
5-6 mm pockets
RAL (for "qualifying"
(PD ≥ 5mm and BOP
sites)
July 2015
28
16 sites in 8
subjects
not reported in graph (Baseline data of
those who
completed also
given)
0.74
12 subjects
Not reported
Not reported
SD
2.22
1.18
SD
Not reported
Not reported
not reported
Page 135
Systemic antimicrobials: amoxicillin-metronidazole + SRP - Updated literature
Citation:
Author, Year
Outcome measure
Miranda, 2014
CAL
July 2015
Time period for
No. Sites treated
data presented in
per mouth / No.
sites averaged per
close to 9 months
tooth
as possible)
12 months
not stated
Test sample
size
Baseline
Test mean
Baseline
29
Full mouth: 4.6
Test
Test SD or
Mean
Mean SD
Test SD or SE
sample
Test mean at
SE (list
difference
(or SE)
(list value)
value) at SD or SE?
Baseline
of test
period
end of test
baseline)
TEST
period
period
Full mouth: 1.2
27
Full mouth: 3.7
Full mouth:
0.9
disease sites: disease sites:
SD for full
PD 4-6mm: PD 4-6mm:
mouth; SE for
1.36
0.10 (SE)
diseased
PD 7+mm:
PD 7+ mm:
sites
2.89
0.27
Control
sample
size
Baseline
Control
mean
Baseline
Control SD or SE
(list value)
Baseline
29
Full mouth:
4.6
Full mouth: 0.8
Control
Control SD
Control
sample
or SE (list
mean at end
size at end
value) at SD or SE?
of test
on test
end of test
period
period
period
23
Full mouth: 4.1
Full mouth:
0.9
Mean
difference
CONTROL
(finalbaseline)
Mean SD (or
SE)
Caries data
difference,
CONTROL
disease sites: disease sites:
SD for full
PD 4-6mm: PD 4-6mm:
mouth; SE for
0.77
0.10
Not reported
diseased
PD 7+mm:
PD 7+mm:
sites
1.78
0.26
None
Page 136
Systemic antimicrobials: metronidazole + SRP - Study characteristics
Citation:
Author, Year
Country
Palmer et al. Brit
Dent J 1 998;184:
548-552.
England
Local metro
(Elyzol) arm
excluded
Palmer et al. JCP
1999;26:158-163
England
Smoker
subset of
1998 paper.
Haffajee 2007
U.S.
(was in "other"
group)
Special population?
47 female and 43 males to yield 90
subject of which 28 were smokers.
Inclusion criteria were: good general
health, no antibiotics or periodontal
therapy in previous 6 months, affected
sites should have PD of ≥ 5 mm with
bone loss and CAL (from CEJ) of 2 mm
and 4 mm, respectively.
47 female and 43 males to yield 90
subject of which 28 were smokers.
Inclusion criteria were: good general
health, no antibiotics or periodontal
therapy in previous 6 months, affected
sites should have PD of ≥ 5 mm with
bone loss and CAL (from CEJ) of 2 mm
and 4 mm, respectively. α
No
at least eight sites with PD>4 mm / no
perio tx within previous 3 months / not
pregnant or nursing / no systemic
conditions requiring antibiotics
Severity of
disease (e.g.
refractory, mild,
moderate)
Test
Control
subject age subject age
(mean,
(mean,
median,
median,
range as
range as
described) described)
Control
Dose/ duration/
applicable
Control
Test (typically
adjunct)
Dose/ duration/
frequency/ timing
including
simultaneous/ before/
after
SRP + Syst
Metro
200 mg, t.i.d., for 7 days
Was standard
counseling
mentioned as
part of control
treatment?
Trial design (split mouth /
parallel group / cross over)
Duration of
study
Adverse events
reported
OHI (disclosing tabs,
brush, floss &
interproximal brush)
at baseline and 4
weeks later.
Parallel group
6 months
Not reported.
OHI (disclosing tabs,
brush, floss &
interproximal brush)
at baseline and 1
week following
completion of SRP
when all subjects
received a polishing
of teeth
Parallel group
6 months
Not Reported
SRP
stratified by severity
and whether subject
was a smoker or nonsmoker.
44.7±6.2
50.5 ± 6.1
Treated by RDH and consisted
of OHI, ultrasonic subgingival
scaling using anesthetic. Two
appts of 90 minutes each1
week apart during which two
contralateral quadrants were
treated.
Study did not use a
placebo drug. The control
group received SRP under
local anesthetic only.
SRP
44.7±6.2
Treated by RDH and consisted
(Among
50.5±6.1
of OHI, ultrasonic subgingival
stratified by severity
smokers:
(Smokers=50,
scaling using anesthetic. Two
and whether subject
mean=42.1,
nonappts of 90 minutes each1
was a smoker or non- among non- smokers=50.7)
week apart during which two
smoker.
smokers=46)
contralateral quadrants were
treated.
44 +/- 11
43 +/- 15
SRP at baseine and then at 3
maintenance SRP visits post
baseline
Smokers not excluded
Study did not use a
placebo drug. The
control group received SRP
under local anesthetic only.
Article used both of the
following terms: SRP and
subgingival scaling.
SRP was performed a
quadrant
at a time under local
anaesthesia at
approximately weekly
intervals
SRP + Syst
Metronidazole
SRP+Systemic
Metronidazole
200 mg, t.i.d., for 7 days
250 mg t.i.d. for 14 days
/started at first SRP visit
No
Parallel group
12 months
One subject in the MET
group reported dizziness
and a second subject
described diarrhoea
associated with the use
of the study medication.
reported in the SRP-only
group
Systemic antimicrobials: metronidazole + SRP - Updated literature:
Citation:
Author, Year
Preus, 2013
Country
norway
July 2015
Special population?
patients and teeth
Excluded patients with prior
Chronic perio (Also note that all
systematic periodontal
subjects went through prestudy
treatment, systemic diseases
hygiene phases-3 months- that
known to be association with included OHI, supragingival scaling,
perio, continuous medication
fl varnish, desentsititizing TP and
known to affect severity of
only included if >=5
perio, allergies to
sites with a PD >=5 mm should
metronidazole
remain.
Test subject
age (mean,
median, range
as described)
Control subject
age (mean,
median, range
as described)
Control
Control
3times day for 10 days starting the
day before the second SRP session
56.8 +/-8.3
54.9 +/- 8.5
SRP, CHX rinse after
SRP, Placebo
All groups rinsed with CHX for 1
minute with 10 mL 0.2% CHX postSRP sessions (treatment and control)
Test (typically
adjunct)
SRP, CHX rinse
after SRP, and
MET
Was standard
Trial design
counseling
study
after
control treatment?
/ cross over)
400 mg MET 3 times day for 10 days
Yes, including CHX gel
for 1 minute every night;
rinse with a 0.2% CHX
solution every morning for
9 days;
parallel
12 months
Diarrhea, nausea,headache, feeling unwell, metallic
taste, diziness /
Although patients allocated to the two groups
treated with metronidazole did report adverse effects
more often than did patients treated with placebo, no
statistically significant differences were observed
between groups regarding the occurrence of
adverse effects observed in conjunction with the
intervention (Table 4), when comparing side effects
in antibiotic groups (groups 1 and 3) against those in
the placebo groups (groups 2 and 4).
Page 137
Systemic antimicrobials: metronidazole + SRP - Outcomes data
Citation:
Author, Year
Palmer et al.
Brit Dent J
1 998;184: 548552.
Outcome measure
Other time
No. Sites treated
Time period for
periods for
per mouth / No. Test sample size
data presented in
which data sites averaged per
Baseline
this abstraction
are available
tooth
Test mean
Baseline
Mean attachment level gain
6 months (24
weeks)
Reported as mean
number of teeth/pt
and percentage of
sites ≥ 4.6 mm at
baseline. Control
Group: 27.4 ± 2.4
Baseline, 8
and 24 weeks teeth and 19.33 ±
10.79 percent sites
Syst Metro Group:
26.6 ± 3.6 teeth and
20.94 ± 10.08
percent sites
Only reported
attachment
level gains - no
baseline data
6 months
Reported as mean
number of teeth/pt.
Used Florida probe
at 6 sites/tooth.
Smoker/Control
27.4 teeth/pt
NonBaseline, 2
and 6 months smoker/Control
27.4 teeth/pt
Smoker/Syst Metro
27.3 teeth/pt.
Non-smoker/Syst
Metro
26.3 teeth/pt
Local metro
(Elyzol) arm
excluded
Palmer et al.
JCP
1999;26:158-163
mean change in CAL
Smoker subset
of 1998 paper.
Not reported
Test SD or SE
(list value)
Baseline
Only reported
attachment level
gains - no
baseline data
Test sample size at
end of test period
Syst Metro Group:
31 pts (10 smokers)
Smoker
pts
Not reported
Not reported
Test mean at
end of test
period
Test SD or SE
(list value) at end
of test period
Not reported
Not reported
Control
SD or Mean gain TEST Mean SD (or SE)
sample size
SE?
(Baseline-final)
gain, TEST
Baseline
SD
10
Not reported
Not reported
Not reported
SD
Non-smoker
21 pts
Probing AL, six sites per tooth at all teeth
excluding third molars; measured to
nearest mm using North Carolina probe At
Baselenie
12 month data are the changes in AL
from baseline
Haffajee 2007
(was in "other"
group)
Syst Metro
Group:
0.67
Reported as
mean change in
CAL. Smoker
0.43
Non-smoker
0.79
Control
mean
Baseline
Only reported
attachment
Syst Metro Group:
Not reported level gains ± 0.67
no baseline
data
Control SD or
Control sample
Control mean Control SD or SE
SE (list value) size at end on test at end of test (list value) at end of
Baseline
period
period
test period
Only reported
attachment level
gains - no
baseline data
Smoker ± 0.57
Non-smoker
± 0.70
Not
reported
Not reported
Not reported
27 pts (9 smokers)
Not reported
. Smoker Control
9 pts
Non-smoker
Not reported
Control
18
pts
Not reported
Not reported
SD or SE?
SD
Mean gain
CONTROL
(baseline-final)
Mean SD (or SE) Caries
gain, CONTROL data
0.51
± 0.43
12 months
Mean changes in AL in sites with
baseline PD>6mm
3 and 6
months
(read off figure,
final - baseline)
-0.39
3.21
0.78
24
Not reported
Not reported
SE
Sites>6mm:
-2.4
[Mean percent of sites exhibiting gain/loss
of AL>2mm also available at all time
points]
(Not stated,
all data: estimated
dropouts, but
off figure 1 as 0.1
the means
are given
(sites>6mm)
only for those
estimated off
who
Figure 2 as 0.4
completed
the study) =
Use these for SD
23
calculations for all
txs
SD
all data:
estimated off
figure 1 as 0.1
(read off figure, finalbaseline)
3.03
0.56
23
Not reported
Not reported
Only sites with baseling PD of ≥ 4.6 mm (as measured by
Florida probe) were evaluated. For frequency distribution,
sites were categorized as ≥ 4.6 mm and ≥ 7 mm. Data were
analyzed using analysis of variance. Power of test was
performed using the formula of Armitage and Berry.
Probing depths and attachment levels were recorded to the
nearest 0.2 mim at six points around all teeth with a Florida
(Florida Probe Corporation, Gainesville, Florida, USA)
computerised constant force probe using the pocket and
disk probes
Only sites with baseline PD ≥ 4.6 mm were evaluated
(equivalent to 5 mm using a manual probe). Mean PD and
Reported as mean
Smoker Control
change in CAL were calculated. Variables with skewed
change in CAL.
± 0.46
distributions were log transformed prior to analysis. Post-Tx
Smoker Control
Not
data were analyzed for differences using factorial analysis of
0.47
Reporte
Non-smoker
variance with equivalent baseline values as covariates.
Non-smoker
d
Control
Multiple linear regression analysis was applied to data with
Control
PD at 6 months as the dependent variable and smoking
± 0.43
0.53
status, antimicrobial therapy and severity of disease as
independent variables.
Bars are unclear;
(Not stated,
dropouts, but the
full mouth not noted means are given
how many
only for those who
completed the
study) = 24
Not
reported
SE
(sites>6mm)
estimated off
Figure 2 as 0.4
-0.15
Sites>6mm:
-1.2
Use these for SD
calculations for all
txs
N/A
Examiners formally calibrated / difference among groups at
each time point was sought using ANCOVA adjusting for
baseline values. / If significant differences
were found among the four groups, significance of
differences between pairs of treatment groups was
determined and the Bonferroni adjustment was used to
adjust for multiple comparisons. / power calculation with
reasonable values for SD and clinically signficant results
Systemic antimicrobials: metronidazole + SRP - Updated literature
Citation:
Author, Year
Outcome measure
Preus, 2013
CAL
July 2015
Time period for
No. Sites treated
data presented in
per mouth / No.
sites averaged per
close to 9 months
tooth
as possible)
12 months
4 sites per tooth:
mesial, buccal, distal,
and
lingual surfaces
Test sample
size
Baseline
Test mean
Baseline
46
2.06
Test
Test SD or
Mean
Mean SD
Test SD or SE
sample
Test mean at
SE (list
difference
(or SE)
(list value)
value) at SD or SE?
Baseline
of test
period
end of test
baseline)
TEST
period
period
1.11
45
1.21
0.73
sd
0.81 (0.67 to 0.96)
Control
sample
size
Baseline
Control
mean
Baseline
Control SD or SE
(list value)
Baseline
47
1.91
1.07
Control
Control SD
Control
sample
or SE (list
mean at end
size at end
value) at SD or SE?
of test
on test
end of test
period
period
period
46
1.29
0.8
sd
Mean
difference
CONTROL
(finalbaseline)
Mean SD (or
SE)
Caries data
difference,
CONTROL
0.64 (0.52 to 0.76)
not reported
None
Page 138
Systemic antimicrobials: azithromycin + SRP - Study characteristics
Citation:
Author, Year
Country
Special population?
(e.g. smokers) and other data regarding
inclusion - exclusion criteria for patients
and teeth
Severity of
disease (e.g.
refractory, mild,
moderate)
Test subject
age (mean,
median,
range as
described)
Control
subject age
(mean,
median,
range as
described)
Control
Control
51.0+/–8.8
years
SRP (quadrant)
Conventional SRP, 4-6 sessions with
an approximately 1 week interval; All
subjects received a professional
mechanical tooth cleaning once a
week by dental hygienists after
treatment.
SRP (full mouth)
plus systemic
azithromycin
43 +/- 15
SRP at baseine
and then at 3
maintenance
SRP visits post
baseline
SRP was performed a quadrant
at a time under local anaesthesia at
approximately weekly intervals
SRP+Systmic
Azithromycin
SRP (no
placebo)
2 sessions of SRP using ultrasonic
scalers and hand instruments
SRP+ CHX
rinse + placebo
using an ultrasonic
device and hand curettes / two 1.5-h
appointments, within 7 days / and the
adjunctive use of a 0.12%
chlorhexidine and 0.05% cetylpyridiniumchloride rinse (Perio
AidTratamientos, Dentaid) was
prescribedtwice a day for 15 days,
with 15 ml for30 s, immediately after
rinsing withwater after brushing /one
placebo per day
Test (typically
adjunct)
No (smokers excluded)
Gomi 2007
Haffajee 2007
Japan
U.S.
an average PD of >4 mm with BOP; and
radiographic
evidence of alveolar bone loss in each quadrant /
no systemic
or topical antibiotic treatment in the preceding 3
months
No
at least eight sites with PD>4 mm / no perio tx
within previous 3 months / not pregnant or nursing
/ no systemic conditions requiring antibiotics
Severe chronic
periodontitis
45.4 +/ – 14.3
years
47 +/- 14
Smokers not excluded
ONLY SMOKERS, ≥1 pack per day of cigarettes
for more than 5 years
Mascarenhas
2005
U.S.
at least five sites with probing depths (PD) of ≥5
mm with bleeding on probing (BOP) (Methods say
at least 6 sites)
moderate
to severe chronic
periodontitis
47 ± 10.06 (33- 45.34 ± 10.75
64* Range
(31-66* Range
No (list stratified for smokers
(>10 cigarettes per day) and non-smokers
(non-smokers, former smokers or smokers of <10
per day) / Smokers included and analyzed as
covariate but "could not be properly assessed"
Oteo 2010
Spain
untreated moderate chronic
periodontitis (Armitage 1999) with radiographic
moderate chronic
evidence of generalized alveolar bone loss >30%,
periodontitits (severe
(iii) presence of at least one pocket with PPD
perio EXCLUDED)
>5mm
per quadrant with bleeding on probing (BoP) / no
perio tx in last 3 years / NO severe periodontitis
with more than one tooth with a site with
PPD>7mm per quadrant except if it was scheduled
for extraction / no antibiotics in previous month /
not lactating or pregnant / no chronic diseases / no
use of NSAIDs / must have P. gingivalis
46.6, range
38–62
47.1, range
36–65
No (5 smokers in each group initially)
Sampaio 2011
Brazil
at least 15 teeth (excluding third molars) and at
least 30% of the sites with PD and CAL≥5mm and
bleeding on probing (BOP), a minimum of three
non-contiguous inter-proximal sites with PD and
CAL≥7mm and two other non-contiguous
inter-proximal sites with PD and CAL≥6 mm /
previous subgingival periodontal therapy,
pregnancy, nursing, systemic diseases that could
affect the progression of periodontal disease,
longterm administration of anti-inflammatories,
need for antibiotic coverage for routine dental
therapy, antibiotic therapy in the previous 6
months and allergy to AZM.
Generalized chronic
periodontitis
44.40 ± 7.42
43.52 ± 5.90
timing including simultaneous/
before/ after
Was standard
counseling
control treatment?
Trial design
(split
Duration
mouth /
of study
parallel
group)
After screening, all
subjects received
3 days prior to full mouth SRP,
10/17 people in test group took analgesic after
two or three visits of
azithromycin taken once per day for 3
treatment (control group not reported); 1/17 in test
toothbrushing instructions
days / full mouth SRP performed
group complained of mild diarrhea / In addition,
(TBIs) including the use
using curets for about 90 minutes / All
three subjects (17.6%) complained of
of interproximal cleaning Parallel group 25 weeks
subjects received a professional
hypersensitivity caused by gingival recession
aids such as floss and
mechanical tooth cleaning once a
within 1 month after treatment; however, it was a
interdental brushes,
week by dental hygienists after
mild degree, and there was symptomatic relief
depending on
treatment.
within 1 month.
individual needs, and
supragingival scaling
500 mg
once daily for 3 days / started at first
SRP visit
No
Parallel group 12 months
Two subjects in the AZ group reported adverse
events: one had an allergic reaction to the study
medication and the second had difficulty
swallowing the tablets, although this latter subject
completed the course of medication
reported in the SRP-only group
Placebo once a day for 5 days / fullmouth SRP performed under local
anaesthesia in four to six appointments
of approximately 2 h each. The
treatment of the entire oral cavity was
completed in a maximum period of 2
weeks using mainly manual
SRP + placebo
instruments / The end point for each
SRP appointment was ‘‘smoothness of
the scaled roots’’, which was checked
by the study coordinator / The placebo
therapy started immediately after the
last session of mechanical
instrumentation
SRP + systemic
azithromycin
SRP+CHX rinse+
systemic
azithromycin
Systemic
azithromycin
(+SRP)
the AZT + SRP (test) group received
the study drug for 5 days (two 250 mg
tablets the first day and one 250 mg
tablet for each of the next 4 days).
Tablets were taken 1 hour before or
two hours after a meal.
SRP+CHX rinse as per control / one
500 mg per day for 3 days
Pts advised not to use
mouthwash or rinse
during study period /
OHI at both SRP appts
followed by
demonstrations
parallel group
6 months
Not reported
At baseline visit,
standardized oral
hygiene instructions were
explained, including the
use of a manual
toothbrush and interParallel group
dental brushes (Vitis
Access softs and
Interproxs, Dentaid). /
Oral hygiene instructions
were reinforced at each
visit of SRP
6 months
One patient in the test group reported
diarrhoea probably associated with the
study medication. No adverse events
were reported in the control group.
1 year
On the last day of medication subjects answered a
questionnaire about any self-perceived sideeffects of the medication/ placebo. / Adverse
events were reported by four subjects from the
test group and three from the control group,
including diarrhoea (test group, n=2), headache
or dizziness (test group, n=1; control group, n=2),
excessive sleepiness (n=3 per group); metallic
taste (test group, n=2; control group, n=3) and
general unwellness (n=1 per group). All subjects
reported that the medications did not cause any
major disturbance in their daily routine and that
they would start the treatment again if necessary.
During the initial phase,
500 mg/day for 5 days / The antibiotic
instruction on proper
therapy started immediately
homecare techniques
after the last session of mechanical
and were given the same
instrumentation
dentifrice (Colgate Total)
to use during the study
period
Parallel
AZM 3 days, then FM SRP in one visit
or PM SRP in 3 visits.
No smokers
Yashima 2009
Japan
July 2015
≥20 remaining teeth; average probing depth (PD)
≥4 mm, with bleeding on probing (BOP) and
deepest PD ≥6 mm; unremarkable general health
based on medical history and clinical judgment;
and radiographic evidence of alveolar bone loss in
each quadrant / no use of systemic and topical
antibiotic treatment within 3 months prior to the
start of the study; no subgingival instrumentation
within 12 months prior to the start of the study; no
systemic illness or medicationvwith periodontal
manifestations; no pregnancy; and no smoking.
FMSRP+AZM:
51.1 ± 11.6
years
PMSRP+AZM:
50.8 ± 14.2
years
51.0 ± 10.6
years
CSRP conventional
SRP
FMSRP+AZM: azithromycin, 500 mg
once a day for 3 days, before
After screening,
full-mouth SRP was performed / Full- all subjects received two
mouth SRP was performed using a
or three sessions of
surgical loupe, Gracey curets,
toothbrushing
and ultrasonic instruments under local
instructions (TBI),
anesthesia in a single visit. The
including the use of
Conventional SRP was performed in
average treatment time was ~120
interproximal
six sessions, with an interval of 1 week
Systemic
minutes.
cleaning aids, depending
between sessions,
azithromycin
on the individual
using a surgical loupe, Gracey curets, (+SRP, either full
needs, and supragingival
and ultrasonic
or partial mouth)
PMSRP+AZM: After taking the
scaling. / After treatment,
instruments under local anesthesia.
medication, SRP of the whole mouth
was completed in three sessions within
professional
7 days, during the effective half-life of
mechanical tooth
systemically administered
cleaning once a month,
azithromycin. SRP was performed
which was performed by
using a surgical loupe, Gracey curets,
dental hygienists
and ultrasonic instruments under local
anesthesia. It took ~30 to 40 minutes
for each session (one-third of the full
mouth/session).
1 FM-SRP (+azithromycin) complained of
diarrhea
Page 139
Systemic antimicrobials: azithromycin + SRP - Updated literature
Citation:
Author, Year
Country
Special population?
patients and teeth
Test subject
age (mean,
median, range
as described)
Control subject
age (mean,
median, range
as described)
Control
Control
Test (typically
adjunct)
Han, 2012
Turkey
Excluded: severe medical
disorders including diabetes,
immunologic disordyers, any
history of systemic disease,
pregnancy, smoking >10
cigarettes per day
severe generalized chronic
periodontal disease
46.8 +/- 5.1
44.8 +/- 5.0
Placebo capule
1x day for 3 days
azithromycin
500mg
1x day for 3 days
Yes
parallel
6 months
none reported
Martande, 2014
India
Exclusion: systemic diseases
such as diabetes, smokers,
systmic antibiotics w/I prior 3
months, pregancy, SRP or
perio tx in prior 6 months,
immunocompromised
Moderate to severe periodontitis
harboring S.
Actinomycetemcomitans
32.6 (+/- 5.4)
33.3 (+/- 7.3)
Placebo capule
Placebo pill 1xday for 3 days
500mg AZ
1x day for 3 days
Yes, OHI
parallel
12 months
not assessed
July 2015
Was standard
Trial design
counseling
study
after
control treatment?
/ cross over)
Page 140
Systemic antimicrobials: azithromycin + SRP - Outcomes data
Citation:
Author, Year
Outcome measure
Gomi 2007
CAL
Haffajee 2007
Probing AL, six sites per
tooth at all teeth excluding
third molars; measured to
nearest mm using North
Carolina probe At
Baselenie
Time period for data
Other time
Test sample
presented in this
periods for
No. Sites treated per mouth /
size
abstraction (as close to which data are No. sites averaged per tooth
Baseline
9 months as possible)
available
25 weeks
Test SD or SE
(list value)
Baseline
Test sample
size at end of
test period
Test mean at
end of test
period
Test SD or SE
(list value) at
end of test
period
SD or
SE?
Mean gain
TEST
(Baselinefinal)
7.47
1.96
17
4.85
1.05
SD
Not reported
Mean SD (or Control sample
Control mean
SE) gain,
size
Baseline
TEST
Baseline
Not reported
Not reported
N/A
Subject unit of analysis; PD and CAL primary
outcomes measures; unpaired t-tests for
improvement within groups baseline to posttreatment; evel of significance set at 0.05
N/A
Examiners formally calibrated / difference
among groups at each time point was sought
using ANCOVA adjusting for baseline values.
/ If significant differences
were found among the four groups,
significance of differences between pairs of
treatment groups was determined and the
Bonferroni adjustment was used to adjust for
multiple comparisons. / power calculation
with reasonable values for SD and clinically
signficant results
5.02
1.5
15
(read off graph)
4.0
Judged
(read off graph) to be SD
1.2
although
stated SE
1.13
Not given
16
3.92
0.97
15
(read off graph)
3.5
(read off graph)
1.0
Judged to be
SD although
stated SE
0.46
Not given
N/A
15
(read off graph)
3.6
(read off graph)
1.1
15
(read off graph)
3.1
Judged
1.1
although
stated SE
0.55
Not given
16
(read off graph)
2.8
(read off
graph) 0.6
15
(read off graph)
2.7
(read off graph)
0.8
Judged to be
SD although
stated SE
0.11
Not given
N/A
CAL, Moderate sites
(baseline PD 4 to 6 mm).
15
(read off graph)
5.5
(read off graph)
1.3
15
(read off graph)
4.0
Judged
1.4
although
stated SE
1.52
Not given
16
(read off graph)
4.9
(read off
graph) 0.5
15
(read off graph)
4.0
(read off graph)
0.9
Judged to be
SD although
stated SE
1.01
Not given
N/A
CAL, Deep sites
(baseline PD >6 mm).
15
(read off graph)
7.8
(read off graph)
1.1
15
(read off graph)
5.1
Judged
1.1
although
stated SE
2.56
Not given
16
(read off graph)
7.8
(read off
graph) 0.6
15
(read off graph)
6.4
(read off graph)
1.5
Judged to be
SD although
stated SE
1.32
Not given
N/A
CAL, Shallow sites
(baseline <4 mm).
Mascarenhas
2005
6 months
Oteo 2010
CAL
6 months
3 months
1, 3 months
clinical attachment level (CAL), and
bleeding on probing (BOP) was
assessed for all teeth / CAL
measured at six sites per tooth
PPD and recession (REC) in
millimetres
at six sites per tooth in all teeth,
excluding third molars. CAL
calculated as the sum of PPD and
REC
15 patients
SE
(Not stated,
dropouts, but the
(sites>6mm)
means are given
estimated off
only for those who
Figure 2 as 0.4
completed the
study) = 23
Use these for
SD calculations
for all txs
-0.19
Sites>6mm:
-1.7
3.46mm
0.18
15
2.7
0.18
SE
0.96
SD
15
CAL (all sites)
Not reported
5.74
3.42
Not reported
17
Caries
data
full mouth not noted how many
25
1.37
Mean SD (or
SE) gain,
CONTROL
all data:
estimated off
figure 1 as 0.1
(read off
figure, finalbaseline)
0.88
7.21
Mean gain
CONTROL
(baselinefinal)
(Not stated,
dropouts, but
the means are
given only for
those who
completed the
study) = 25
3 and 6 months
17
SD or SE?
17
12 month data are the
changes in AL from
baseline
Not reported
Control SD
Control
Control SD or
Control mean
or SE (list
sample size
SE (list value)
at end of test
value)
at end on test
at end of test
period
Baseline
period
period
Not described
12 months
5 and 13 weeks
Test mean
Baseline
0.76mm
0.12mm
14
all data:
estimated off
figure 1 as 0.1
(read off
figure, finalbaseline)
3.03
0.56
23
Not reported
Not reported
SE
(sites>6mm)
estimated off
Figure 2 as 0.4
-0.15
Sites>6mm:
-1.2
3.56
0.31
13
3.32
0.33
SE
Use these for SD
calculations for
all txs
0.28mm
0.14mm
N/A
Data were first averaged within each
patient, and then patient means were
analyzed between treatment groups to
determine baseline comparability of the two
groups. Differences between study drug and
control groups were performed using the
Student t test
Intra-examiner calibration was performed
twice, before and during the study / evaluating
the normality of the distribution / ANCOVA
was selected to compare both groups, either
at baseline or in changes baseline follow-up
visits (inter-group comparison), including
baseline values of the examined variable,
smoking and
gender as cofactors / Bonferroni
correction was used / PPD primary outcome
and used for power calculations
Baseline versus 6 months Placebo 0.28 0.14
0.00 0.57 0.016 Baseline CAL, smoking
Test 0.76 0.12 0.52 1.01
Full mouth:
1.02
Sampaio 2011
CAL (distance in mm
from the cementoenamel
junction to the bottom of
the sulcus/pocket)
12 months
6 months
measured at six
sites per tooth in all teeth,
excluding
the third molars./ The PD and CAL
measurements were recorded to
the
nearest millimetre using a North
Carolina periodontal probe
Full mouth:
1.62
Full mouth:
1.04
Initially shallow Initially shallow
sites (PD≤3
sites (PD≤3
mm):
mm):
0.17
0.94
20
5.51
0.94
19 but 20 analyzed
using LOCF
4.44
0.77
SD
Initially deep
-
Full mouth:
1.65
Initially shallow Initially shallow
sites (PD≤3 sites (PD≤3 mm):
mm):
1.10
0.17
20
Initially
Initially
intermediate
intermediate
sites (PD 4- 6 sites (PD 4- 6
mm):
mm):
- 1.14
1.16
Initially deep
July 2015
-
5.74
0.83
19 but 20
analyzed using
LOCF
4.69
0.89
SD
Initially
Initially
intermediate sites
intermediate
(PD 4- 6 mm):
sites (PD 4- 6
1.31
mm):
-1.15
Initially deep
sites (PD≥7mm):
Initially deep
1.70
N/A
power based on identying 1 mm difference in
CAL in sites with initial PD >= 7 mm and
assuming SD of 1 mm / The inter-examiner
variability was 0.25mm for PD and
0.29mm for CAL. The mean intraexaminer
variability was 0.22mm (PD) and 0.27mm
(CAL) for the first examiner (M. R.) and
0.23mm (PD) and 0.26mm (CAL) for the
second examiner (E. S.). One examiner
carried out all clinical measurements in a
given subject and treatment was performed by
the second clinician / Intention-to-treat
analyses were performed in these two
subjects (their 6-month data were carried
forward). / also looked at change in CAL over
time intervals by pocket depth
Page 141
Systemic antimicrobials: azithromycin + SRP -Updated literature
Time period for
No. Sites treated
data presented in
per mouth / No.
sites averaged per
close to 9 months
tooth
as possible)
Citation:
Author, Year
Outcome measure
Han, 2012
CAL
6 months
Martande, 2014
CAL
12 months
July 2015
Test
Test SD or
Mean
Mean SD
Test SD or SE
sample
Test mean at
SE (list
difference
(or SE)
(list value)
value) at SD or SE?
Baseline
of test
period
end of test
baseline)
TEST
period
period
Test sample
size
Baseline
Test mean
Baseline
not stated
18
5.68
0.7
14
not reported
not reported
SD
1.55
not stated
35
7.69
1.02
35
4.97
1.18
SD
2.71
Control
Control SD
Control
sample
or SE (list
mean at end
size at end
value) at SD or SE?
of test
on test
end of test
period
period
period
Mean
difference
CONTROL
(finalbaseline)
Control
sample
size
Baseline
Control
mean
Baseline
Control SD or SE
(list value)
Baseline
0.5
18
5.32
1
14
not reported
not reported
SD
1.54
0.4
not reported
None
1.15
35
7.63
1.42
35
5.91
1.09
SD
1.71
1.29
not reported
None
Mean SD (or
SE)
Caries data
difference,
CONTROL
Page 142
Systemic antimicrobials: clarithromycin + SRP - Study characteristics
Special population?
Citation:
(e.g. smokers) and other data regarding
Country
Author, Year
inclusion - exclusion criteria for patients
and teeth
Severity of
disease (e.g.
refractory, mild,
moderate)
Control
Test subject
subject age
age (mean,
(mean,
median,
median,
range as
range as
described)
described)
Control
Control
Dose/ duration/
applicable
Was standard
Trial design
Duratio
Test (typically
counseling
(split mouth /
n of
adjunct)
timing including simultaneous/ mentioned as part of parallel group
study
before/ after
control treatment? / cross over)
No
Pradeep 2011
India
Systemically healthy patients having at least
20 natural teeth with a PD of ≥ 5 mm and
CAL of ≥ 3 mm in at least 30% sites were
recruited / Patients with any antimicrobial
therapy or non steroidal anti-inflammatory
drugs or steroidal therapy or patients with
any periodontal therapy in the preceding 6
months, having known or suspected allergy
to macrolide group, smokers (current or
past), or subjects having tobacco in any
other form, alcoholics, and pregnant or
lactating females were excluded from the
study
Chronic
periodontitis
35.2 ± 6
years
37.3 ± 5.7
years
SRP +
placebo
placebo 500 mg b.i.d.
for 3 days / SRP
(Ultrasonic) was
performed at baseline
and at 6 months (as
SRP+
prophylactic
systemic
measure during
Clarithromycin
maintenance phase),
until the root surface
was considered
thoroughly smooth and
clean by the operator.
500 mg b.i.d. for 3 days
No anti-plaque agent
was prescribed
after treatment,
however home care
oral hygiene like
brushing
twice a day and
rinsing after every
meal was
recommended
Parllel group
9
months
No adverse reaction was observed in any
subject from the test group, and no patient
reported any discomfort (except for
unpalatable taste and mild gastric
intolerance as reported by 2 patients).
Systemic antimicrobials: clarithromycin + SRP - Outcomes data
Citation:
Author, Year
Outcome measure
Reduction in CAL
compared to Baseline,
mm
Pradeep 2011
UNC-15
graduated periodontal
probe was used to
standardize the
measurement of PD
and CAL
July 2015
Other time
Time period for
periods for
Test sample
data presented
which data mouth / No. sites averaged
size
in this
are
per tooth
Baseline
abstraction
available
6 months
NOTE: SRP
repeated at 6
months so 9month data
ineligible
CAL were assessed in all
patients for all the teeth
(except 3rd molars and teeth
with
orthodontic appliance) and in
all quadrants at six locations
1, 3, 6, and
around the tooth (mesio9 months buccal, buccal, disto-buccal,
mesiolingual,
lingual, and disto-lingual) as
per UCLA charting. The PD
and CAL values were
estimated to their nearest
millimetre
Test mean
Baseline
Test SD or SE Test sample
(list value)
size at end of
Baseline
test period
Test SD or SE
Test mean at
(list value) at SD or
end of test
end of test
SE?
period
period
Mean gain
Control SD
Control
Control SD or
Mean gain
Mean SD (or Control sample
Control mean
TEST
Control mean or SE (list sample size
SE (list value)
CONTROL
SE) gain,
size
at end of test
SD or SE?
(BaselineBaseline
value)
at end on test
at end of test
(baselineTEST
Baseline
period
final)
Baseline
period
period
final)
Mean SD (or
SE) gain,
CONTROL
Caries
data
Subject based analysis
20
Not reported
Not reported
18
Not reported
Not reported
SD
1.81
0.36
20
Not reported Not reported
19
Not reported
Not reported
SD
0.86
0.23
N/A
90% power; 2 sided at 90%
power, with alpha error of 5%
and standard deviation (SD)
of S1 = 0.010, S2 0.1093 with
a mean difference of 0.091
and an effect size of 1.527
r = 0.92 for duplicate CAL
measurements
Page 143
Systemic antimicrobials: moxifloxacin + SRP - Study characteristics
Citation: Author,
Year
Guentsch 2008
Country
Control
Special population?
Test subject
Severity of disease
subject age
age (mean,
(mean,
median, range
moderate)
median, range
as described)
as described)
Germany
No
attachment loss >=5 mm at >30%
of sites and age >=35 years. / no
systemic condition / at least 5
pockets >= 5mm in different
quadrants / radiographic evidence
of moderate to advanced
periodontal destruction / no
antibiotics, steroids, NSAIDs
within previous 6 months / no
peridontal treatment in previous
12 months / not pregnant or
nursing / Less than 35% of the
subjects were active smokers
Severe chronic
periodontitis
Control
Dose/ duration/ frequency/ timing if
applicable
Control
Dose/ duration/
Test (typically
frequency/ timing
adjunct)
including
after
mentioned as part of control
treatment?
Trial design
parallel group
study
/ cross over)
Treatment started with chlorhexidine rinsing
Before the onset
(0.12%) for 1minute. Subgingival depuration
of the study, the plaque index had
and root planing for disrupting the subgingival
to be <35% after the hygiene
biofilm were performed in all four quadrants
phase, which included
under local anesthesia as a fullmouth
systemically
supragingival calculus removal
procedure within 24 hours by the same
SRP+Systemic
mean age of 49.6 –
administered MOX, 400
and oral hygiene instructions /
SRP No Placebo
experienced periodontist (one calibrated
moxifloxacin at
Parallel group
9.4 years at 12 months (92 pts)
mg once daily for 7 days each center performed the tx in the
periodontist at each center). SRP was
antibiotic dose
(MOX group).
same standardized manner;
performed with manual instruments# on all
subjects received OHI from
teeth. An ultrasonic instrument** was only
experienced periodontist / all pts
used in the furcation areas. SRP was
received SPT and reinforcement of
completed within 120 minutes. The endpoint
OHI at 3-month intervals
of SRP was a tactile smooth root surface.
None of subjects in antibiotic
groups reported any adverse
event at any time point
associated with the therapy
12 months
They dropped out subjects who
needed to be retreated. - a lot
more in the control group
Systemic antimicrobials: moxifloxacin + SRP - Outcomes data
Citation: Author,
Year
Outcome measure
Time period for
data presented in
this abstraction
Guentsch 2008
CAL
To nearest mm at 6 sites per tooth
12 months
July 2015
Other time
periods for which mouth / No. sites averaged
data are available
per tooth
3 and 6 months
full mouth not noted how
many
Test sample
size
Baseline
Test mean
Baseline
37 (people)
5.5
Test SD or
Test SD or
Test sample Test mean at SE (list
SE (list
size at end of end of test value) at
value)
test period
period
end of test
Baseline
period
0.94
35
3.58
0.51
SD or
SE?
Mean gain
TEST
(Baselinefinal)
Mean SD (or SE) gain,
TEST
Control sample
size
Baseline
Control
mean
Baseline
SD
1.79
0.52
28
5.15
Control SD or
Control SD or
Control sample Control mean at
SE (list value)
SE (list value) size at end on test
end of test
SD or SE?
at end of test
Baseline
period
period
period
0.55
21
3.61
0.57
SD
Mean gain
CONTROL
(baseline-final)
Mean SD (or
SE) gain,
CONTROL
Caries data
1.48
0.53
N/A
Calibration, reliability, power calculations;
normal distributions verified with clinical data
Page 144
Systemic antimicrobials: tetracyclines + SRP - Study characteristics
Citation: Author,
Year
Al-Joburi, 1989
Guentsch 2008
Lindhe 1983
Ng, 1998
Ramberg, 2001
July 2015
Country
Special population?
(e.g. smokers) and other data regarding inclusion - exclusion
Canada
1. At least 35 years of age.
2. Both clinical and radiographie evidence of periodontal disease.
3. At least two sites with probing depth of at least 7 mm.
4. Presence of at least 15 teeth.
5. Absence of other serious or complicated oral pathosis.
6. No periodontal therapy within the past 6 months.
7. No antibiotic therapy within the past 6 months.
8. No contra-indications to participation (including
hypersensitivity to the medications).
9. Not pregnant or nursing.
Severity of disease
moderate)
Advanced adult chronic
perio
Presence of at least 2
sites with probing depth
of at least 7 mm
Severe chronic
periodontitis
Sweden
The patients were in good general health, none
of the women was aware of being pregnant, no
patient had received antibiotics in the previous
6 months and none had a history of allergy to
tetracycline. Each of the participants had at
least 20 remaining teeth and 4 pairs of diseased
sites (selected sites) around contralatera] premolars
and incisors where pockets could be
probed to >6 mm and where >4fl% of the
alveolar bone had been lost.
disease. At least 20
remaining teeth and 4
pairs of diseased sites
around contralateral
premolars and incisors
where pockets could be
probed to ≥6mm and
where ≥40% of the
alveolar bone had been
lost
USA
15 current smokers, 17 non-smokers, not asked about past
smoking / 1) radiographic bone loss greater than 50% in at least 2
matching tooth types per subject and 2) periodontal probing depth
≥5 mm in 1 or more sites in at least 2 matching tooth types.
Exclusion criteria included: 1) systemic diseases that may affect
periodontal status of the patient; 2) serious medical complications
that may affect the treatment provided; 3) known side effects to
either doxycy-cline or Ibuprofen; 4) periodontal therapy within 6
months from the onset of the study; and 5) antibiotic or nonsteroidal anti-inflammatory drug therapy within the last 6 months.
Smokers were included but their data was not tracked separately.
generalized periodontitis
Sweden
Sample not split: average age
of those completing trial was
46 +/- 0.9 years
Control
Control
Dose/ duration/ frequency/ timing if applicable
Test (typically
adjunct)
SRP with placebo
SRP started at baseline appt and completed in 2
sessions of 3 hours each performed within 1 week
of each other / Placebo capsules every 6 hours for
14 days
SRP +
tetracycline
Dose/ duration/
frequency/ timing
including simultaneous/
before/ after
tetracycline; 250 mg
capsules every 6 hours for
14 days
14 days
mentioned as part of control
treatment?
No
Trial design
(split mouth /
parallel group /
cross over)
Parallel group
Duration of
study
24 weeks
Adverse reactions to drugs were
assessed at 1- and 2-week visits by
means of a questionnaire and blood
analyses
1 tetracycline group severe diarrhea
14 days
No
attachment loss >=5 mm at >30% of sites and age >=35 years. /
no systemic condition / at least 5 pockets >= 5mm in different
quadrants / radiographic evidence of moderate to advanced
periodontal destruction / no antibiotics, steroids, NSAIDs within
previous 6 months / no peridontal treatment in previous 12 months /
not pregnant or nursing / Less than 35% of the subjects were active
smokers
Germany
Test subject
Control subject
age (mean,
age (mean,
median,
median, range
range as
as described)
described)
mean age of 49.6 –
9.4 years at 12 months (92
pts)
37-52 years
of age
37-52 years of
age
range:32-72
60% were smokers in test, 56% in control.All women. tetracycline
on the outcome of periodontal therapy, 35 adult subjects, 19 female
and 16 male, aged between 24 and 60 years were included in a test
group. They were recruited from a larger group of patients who in
1982 – 1984 were referred to the Department of Periodontology,
Helsingborg, Sweden for treatment of advanced periodontal disease.
Advanced Chronic
80 age and gender matched subjects from the same pool were
Periodontitis. PPD
Mean: 41.2
during the corresponding time interval recruited for a control group stratified: those <3 mm, (range:24-60)
(42 female and 38 male). In order to be included in the study a
4-6mm, and >7mm
subject had to be ±20 years of ge and have at least 16 teeth out of
which at least 2 must be molars. Subjects were excluded (i) with
systemic conditions which required antibiotic coverage for nonsurgical periodontal procedures, (ii) were pregnant, (iii) allergic to
tetracycline or (iv) had taken antibiotic during the previous 6 months.
Mean:42.1
(range:23-66)
Treatment started with chlorhexidine rinsing
(0.12%) for 1minute. Subgingival depuration and
root planing for disrupting the subgingival biofilm
were performed in all four quadrants under local
anesthesia as a fullmouth procedure within 24
hours by the same experienced periodontist (one
SRP No Placebo
calibrated periodontist at each center). SRP was
performed with manual instruments# on all teeth.
An ultrasonic instrument** was only used in the
furcation areas. SRP was completed within 120
minutes. The endpoint of SRP was a tactile smooth
root surface.
SRP+Systemic
doxycycline at
antibiotic dose
Before the onset
of the study, the plaque index had to
be <35% after the hygiene phase,
which included supragingival calculus
orally administered
removal and oral hygiene instructions /
DOX,i 200 mg on the first
each center performed the tx in the
day followed by 100 mg/ day
same standardized manner; subjects
for 9 days (DOX group);
received OHI from experienced
periodontist / all pts received SPT and
reinforcement of OHI at 3-month
intervals
Parallel group
12 months
None of subjects in antibiotic
groups reported any adverse event
at any time point associated with
the therapy
They dropped out subjects who
needed to be retreated. - a lot more
in the control group
SRP by quadrant
SRP in 2 quadrants.
Tetracycline
hydrochloride
Tetracycline daily for first 2
weeks 250 mg 4x per day.
In the final 48 weeks, 250
mg once a day
yes
parallel
50 weeks
no
SRP+ placebo
Scaling and root planing was performed
under local anesthesia using ultrasonic and hand
instruments; placebo one capsule per day
SRP+DOXY
200mg doxycycline hyclate
tablet orally the first day,
100mg per day for 6 weeks
no
Parallel group for
this part of study
6 months
This study did not collect data on
adverse events
SRP
4-6 sessions of scaling and root planing without
antibiotic. 2% Chlorhexidene rinses b.i.d. during
basic therapy (assumed to be 3 weeks)
SRP plus
systemic
tetracycline
250mg tetracycline
hydrochlorine (Tetracyklin
NM Pharma) 4x a day for 3
weeks. SRP was done
during this 3 week period.
Chlorhexidene rinses b.i.d.
during basic therapy
(assumed to be 3 weeks)
all subjects received oral hygiene
instruction (OHI)
Parallel group
13yrs
Not reported
Page 145
Systemic antimicrobials: tetracyclines + SRP - Updated literature
Citation:
Author, Year
Country
Special population?
patients and teeth
Test subject
age (mean,
median, range
as described)
Control subject
age (mean,
median, range
as described)
Control
Control
Test (typically
adjunct)
Tsalikis, 2014
Greece
Type 2 diabetes. Excluded:
Type 1 diabetes, smoker,
pregnant/lactating
Moderate to severe periodontal
distase
62.9 +/- 10
57.94 +/- 8.22
Placebo and SRP
"Same instructions" as test. Assume
this is 2 pills on day 1, and then 1 pill
daily for 20 days
SRP and DOX
July 2015
Was standard
Trial design
counseling
study
after
control treatment?
/ cross over)
200 mg loading dose and 100 mg for 20
days
yes
parallel
6 months
not reported
Page 146
Systemic antimicrobials: tetracyclines + SRP - Outcomes data
Citation: Author,
Year
Outcome measure
Time period for data
presented in this
abstraction
Other time periods
for which data are
available
No. Sites treated per mouth /
No. sites averaged per tooth
Test sample size Test mean
Baseline
Baseline
Pockets 1-3 mm deep
Pockets 4-6 mm deep
Al-Joburi, 1989
24 weeks
2, 18, 12 weeks
2 sites per patient / Williams
96 total patients to
probe to nearest mm / according
start; 32 per group
to Clark et al procedure
Pockets greater than 7 mm deep
Test SD or
SE (list
value)
Baseline
CAL:7.25m
m
0.46
CAL:9.06m
m
0.26
Test sample
size at end of
test period
Test mean at
end of test
period
Test SD or
SE (list
value) at
end of test
period
7.06mm
0.55
8.00mm
0.27
28 patients
CAL:10.58
0.25
SD or
SE?
Mean gain
TEST
(Baseline-final)
Mean SD (or SE) gain,
TEST
0.26
Control SD or SE
Control sample size Control mean at
(list value)
at end on test period end of test period
Baseline
CAL:7.50mm
0.84
9.11mm
0.22
96 total patients to
start
SE
8.79 mm
Control sample size Control mean
Baseline
Baseline
Control SD or
SE (list value)
at end of test
period
7.80mm
0.82
8.09
0.21
24 patients
10.75mm
0.29
SD or SE?
Mean gain
CONTROL
(baseline-final)
Mean SD (or SE)
gain, CONTROL
Caries data
ANOVA used to test comparability of groups if
homoscedasticity of residual variances; data at
baseline used as regressor if relationship
observed if homogeneity of slopes; data not fit for
ANOVA tested with X2; Type I error at 5%
SE
9.21
0.34
Guentsch 2008
CAL
To nearest mm at 6 sites per tooth
12 months
3, 6, 12 months
full mouth not noted how many
37 (people)
5.64
0.91
36
3.9
0.86
SD
1.59
0.61
28
5.15
0.55
21
3.61
0.57
SD
1.48
0.53
N/A
Calibration, reliability, power calculations; normal
distributions verified with clinical data. ANOVA
repeated measures - dropped out those who did
not respond - appears that baseline data only
included those who finished
Lindhe 1983
CAL 1/2 mouth
50 weeks
10, 20 30 50 weeks
1/2 mouth
7
7.1
0.5
7
nr
nr
se
1.7
0.3
7
7.4
0.5
7
nr
nr
se
1.4
0.3
no
t-test on difference, anova
Ng, 1998
CAL
6 months
1 site per treatment combination
3 weeks, 6 weeks, 12
(many arms in trial); all teeth
weeks, 24 weeks
matched according to tooth type
in both groups
Ramberg, 2001
PAL with stents
1 year
3, 5 and 13 year data
Supportive periodontal therapy 3is available in graph
4X/yr, for 13 years
only
July 2015
8
35people
CAL:7.8
CAL:1.2
8
28 people at the
end of 13 years.
not reported not reported Sample size at
1 year not
reported
CAL:7.4
CAL:0.5
SD
Not reported
Not reported
8
CAL:9.0
CAL:1.9
8
CAL:9.9
CAL:0.8
SD
Not reported
Not reported
Not reported
experimental unit was the subject in all statistical
analyses. These data were adjusted by Duncan's
multiple range test for multiple comparisons.
Within each treatment group, data from baseline
and 24 weeks were compared and analyzed by
Student t-test. The data of the with-scaling and
without-scaling were also compared and analyzed
by Student t-test. Statistical significance was
accepted at probability level of ≤0.05 for all tests.
not reported
not reported
SD
0.47mm
±0.6mm (SD)
80people
not reported
not reported
61 people people at the
end of 13 years.
Sample size at 1 year
not reported
not reported
not reported
SD
0.16mm
±0.5mm (SD)
N/A
No description
Page 147
Systemic antimicrobials: tetracyclines + SRP - Updated literature
Citation:
Author, Year
Outcome measure
Tsalikis, 2014
CAL
July 2015
Time period for
No. Sites treated
data presented in
per mouth / No.
sites averaged per
close to 9 months
tooth
as possible)
6 months
not stated
Test sample
size
Baseline
Test mean
Baseline
35
3.73
Test
Test SD or
Mean
Mean SD
Test SD or SE
sample
Test mean at
SE (list
difference
(or SE)
(list value)
value) at SD or SE?
Baseline
of test
period
end of test
baseline)
TEST
period
period
0.88
31
3.02
0.67
SD
NOT
REPORTED
NOT
REPORTED
Control
sample
size
Baseline
Control
mean
Baseline
Control SD or SE
(list value)
Baseline
35
3.77
1.24
Control
Control SD
Control
sample
or SE (list
mean at end
size at end
value) at SD or SE?
of test
on test
end of test
period
period
period
35
2.87
0.89
SD
Mean
difference
CONTROL
(finalbaseline)
Mean SD (or
SE)
Caries data
difference,
CONTROL
NOT
REPORTED
NOT
REPORTED
not reported
None
Page 148
Systemic Antimicrobials- Review authors’ judgment of each risk of bias item as low, unclear, or high for each included study
Selection bias
Domain:
Random sequence
generation
Citation: Author,
Year
Support for
judgment
Review
author's
judgment
Performance bias
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
same except for the
intervention?
Detection bias
Attrition bias
Reporting bias
Masking of outcomes
assessment
follow-up)
>20% high
Selective reporting
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review author's
judgment
"if indicated OHI"
High
no mention of
examiner
blinding
High
none lost
Low
Review author's
judgment
Support for
judgment
Review author's
judgment
AMX/MET
Berglundh, 1998
randomly
created two
different samples
assigned sample
to tx
Cionca 2009
Computer
generated table
Flemmig 1998
NR
High
Not described
unclear
high
Low
The treatment
group was
concealed from
the patient,
clinical examiner
(NC), therapist
(GU), and
statistician (AM)
Low
No differences
noted
Low
The treatment
group was
concealed from
the patient,
clinical examiner
(NC), therapist
(GU), and
statistician (AM)
Low
47/51
completed
(8% lost)
Low
unclear
no mention of
masking or
blinding of
examiner or
therapist
unclear
yes
low
no mention of
examiner
blinding
unclear
10 out of 48
high
Low
Low
neutral package
containing the
test or placebo
medication,
identical in
appearance and
only
marked with the
subject number
Low
The treatment
group was
concealed from
the patient,
clinical
examiner
(NC), therapist
(GU), and
statistician
(AM)
unclear
alternate
assignment
high
NR
no evidence of
clinical trial
registration
no mention of
masking or
blinding of
examiner or
therapist
blind, placebo
used
Goodson, 2012
"randomly" &
"computer
generated
number"
Low
Not described
Unclear
not placebo
controlled
high
therapist and
statistician were
given treatment
identity.
high
oral hygiene
reinforced if
necessary all sites
with PPD >=5 mm
and BOP SRP
high
Designated
clinical
examiners were
blinded
low
44 out of 231
or 19%
Unclear
Mombelli 2005
not clearly
randomized
High
Not specifically
addressed
Unclear
Placebo
capsules and
gels
Low
not clearly stated
Unclear
Yes
Low
Implied but no
stated
Unclear
2/16 lost
(12.5%)
Unclear
Low
allocation
distributed in
numbered
opaque
envelopes, not
known by
randomizer
Unclear
Riberiro, 2009
randomized
using computer
generated list
Low
randomization
not broken until
all data
collected
Low
allocation not
known until all
data collected
Low
all patients given
SRP and either
placebo or
antibiotics
Unclear
PAL reported but
not PD or other
perio measures
Low
blinded, and
duplicate
measurements
Low
3/28 excluded
because they
did not show
up to all
appointments
No bias detected
Low
none
low
Clinical trial
registration > 5
years after trial
completion No a
priori
hypotheses
no evidence of
clinical trial
registrationNo a
priori
hypotheses
reported on
primary&second
ary outcomes
HIgh
Unclear
Low
Metronidazole
Palmer et al. Brit
Random Number
Dent J
Table
1998;184:548-552.
Low
no details
Unclear
Not reported;
no placebo pills
High
Not reported
High
all patients given
SRP
Low
Single blind and
randomized
Low
93% (84/90)
pts completed
the 6 month
study
Low
Reported primary
and secondary
outcomes, but no
baseline data for
CAL
Unclear
Palmer et al. JCP
1999;26:158-163.
Random Number
Table inferred
from Palmer
1998
Low
no details
Unclear
Not reported;
no placebo pills
High
Not reported
High
all patients given
SRP
Low
Single blind and
randomized
Low
93% (84/90)
pts completed
the 6 month
study
Low
Reported primary
and secondary
outcomes, but no
baseline data for
CAL
Unclear
Haffajee 2007
Random number
table
Low
Assignment by
clinic cocoordinator
Unclear
No - single
blinded
High
No-single blinded
High
Yes
Low
Masked
Low
67/98 subjects
had complete
data for all
monitoring
visits; ITT
used with
LOCF; if only
baseline data,
subject
excluded
High
AL at 12 months
for pockets with
baseline PD>6
mm primary
outcome
measure
Low
Gomi 2007
No details given
Unclear
No details given
Unclear
No details but
likely not
High
No details but
likely not
TBI based on need
Unclear
Not stated
Unclear
No losses
Low
No bias detected
Low
Masked
Low
67/98 subjects
had complete
data for all
monitoring
visits; ITT
used with
LOCF; if only
baseline data,
subject
excluded
High
AL at 12 months
for pockets with
baseline PD>6
mm primary
outcome
measure
Low
Azithromycin
High
Haffajee 2007
Random number
table
Low
Assignment by
clinic cocoordinator
Unclear
No - single
blinded
High
No-single blinded
High
Yes
Low
Mascarenhas 2005
Selecton from a
bag
Low
Masked, but no
details given
Unclear
Not masked
High
Randomized after
SRP
Low
Yes
Low
Examiner
masked
Low
3.2% loss
Low
No bias detected
Low
Oteo 2010
computergenerated
randomization
list
Low
Identical pills,
treatment
assignment not
revealed until
after study
Low
treatment
assignment not
revealed until
after study
low
2/14 lost in
placebo
(14%); 0 in
test group;
2/29 total (7%)
Low
No bias detected
Low
Low
All examiners and
study personnel
masked
Low
Examiners and
statisticians had
no knowledge of
assignments
Low
2/40 lost = 5%
Low
No bias detected
Low
High
Mentions double
masking so this
is the only
possiblity
although not
described
Low
No losses
Low
Data interpolated
off graph and not
provided
explicitly
Unclear
Low
Assessor
masked
Low
3/40 lost 7.5%
Low
No bias detected
Low
High
in control group subjects who did
not resond were
dropped out for
retreatment-thus
under reporting
more severe
subjects no
intent to treat
data shows up
in baseline data
where these
retreat subjects
were not
included
High
Low
No bias
detected, but did
not report the
distribution of the
pockets in the
study - which
could inlfuence
values.
Unclear
High
Sampaio 2011
computergenerated table
Low
Sealed envelopes
Low
Opaque plastic
bottles; code
breaking after
statistical
analysis
Low
Identical pills
Low
Capsules
identical
Unclear
Unclear how this
can be double
masked?
Low
Yes
Low
Yes
No differences
noted
Low
Yashima 2009
No details given
Unclear
No details given
Unclear
Masking not
possible; no
placebo
described yet
stated "double
blind"
Pradeep 2011
computer
generated list
prepared by an
independent
study
coordinator
Low
No details given
Unclear
Yes
Unclear
No placebo,
patients taking
antibiotics
"extensively
informed about
the intake of
the prescribed
medication"
Unclear
Double-blind
but no other
details; All
capsules of
identical
appearance
High
No
High
Since no placebo,
only tx groups
received extensive
info about the
medications
Unclear
Unclear
double blinded but
no details
Unclear
Yes
Low
SRP performed
before treatment
group
assignment,
examiners all
blinded to
treatment group
Low
all patients given
SRP and either a
dose or placebo
Unclear
No - different SRP
methods
Clarithromycin
Low
Yes
Moxifloxacin
Guentsch 2008
randomization
performed
independently at
each center, no
other details
Unclear
No details given,
but control
patients not given
placebo
High
No
High
Since no placebo,
only tx groups
received extensive
info about the
medications
Unclear
Yes; masked to
tx allocation
Low
7/28 in control
and 1/37 in
treatment
dropped out
(in control
group,
patients who
needed further
treatment were
dropped)
Low
Double blind;
assume clinician
but not explicitly
stated
Unclear
79/96 pts
completed
study (18%
lost)
Yes; masked to
tx allocation
Low
7/28 in control
and 1/37 in
treatment
dropped out
(in control
group,
patients who
needed further
treatment were
dropped)
High
in control group subjects who did
not resond were
dropped out for
retreatment-thus
under reporting
more severe
subjects no
intent to treat
data shows up
in baseline data
where these
retreat subjects
were not
included
Low
double blinded
but no details
Unclear
no info.
Assumed no
loss
Unclear
No bias detected
Low
Low
examiners all
blinded to
treatment group
assignment
Low
reported on
primary&second
ary outcomes
Low
high
only subjects
who remained in
the study the
entire 13 year
period were
included in the
analysis;
selected different
teeth in each did
not discuss how
selected
High
Tetracyclines
Al-Jaburi 1989
Unclear
No details given
Guentsch 2008
randomization
performed
independently at
each center, no
other details
Unclear
No details given,
but control
patients not given
placebo
Unclear
No placebo,
patients taking
antibiotics
"extensively
informed about
the intake of
the prescribed
medication"
Lindhe 1983
randomized but
no method
reported
unclear
not reported
Unclear
double blinded
but no details
Ng,1998
Ramberg, 2001
July 2015
Described as
random but
details not given
randomized but
no details
no details
Unclear
Unclear
No details
provided
no details
Unclear
Unclear
patients given
placebo if not
an intervention
no placebo
Unclear
High
Double blind but
no details
no details
regarding
masking
Unclear
High
Yes; no other
differences
described
yes
low
no details
Low
High
none lost
7/35 in test
group and
19/80 in
control group
lost to follow
up. Greater
than 20% loss
to follow-up
Page 149
Systemic Antimicrobials- Updated literature
Selection bias
Domain:
Random sequence
generation
Performance bias
Were the groups
treated the same
except for the
intervention?
Detection bias
Attrition bias
Reporting bias
Masking of outcomes
assessment
Incomplete outcome
lost to follow-up)
≤10% low; 11-20%
unclear; >20% high
Selective reporting
Citation:
Author, Year
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Miranda, 2014
AMX/MET
computer
genrated Table
low
not reported
unclear
Placebo Pill
low
Clinician was
blinded
low
yes. All
received OHI.
low
evaluator was
blinded
low
up to 15%
LOSS TO
FOLLOWUP
low
reported all
data
low
low
Codebook
manager kept all
patient and
allocation data
througout the
study, securing
masking of the
clinical research
staff
low
Codebook
manager kept
all patient and
allocation data
througout the
study, securing
masking of the
clinical
research staff
low
Codebook
manager kept
all patient and
allocation data
througout the
study,
securing
masking of the
clinical
research staff
low
up to 2%
LOSS TO
FOLLOWUP
low
reported all
data
low
low
low
evaluator was
blinded
low
22% loss to
follow-up
high
all data
reported
low
low
evaluator was
blinded
low
0 loss to followup
low
all data
reported
low
low
Examiners
were not
aware of the tx
low
12% Loss in
tx group. No
loss in control
unclear
reported all
data
low
Preus, 2013
Metronidazole
Computer
generated
sequence
Han, 2012
Azithromycin
computergenerated
randomization list
Martande, 2014
Azithromycin
computer
genrated
Tsalikis, 2014
Tetracyclines
Randomization
software
July 2015
low
Placebo Pill
low
randomization list
kept by one of
the oughtus utill
all tx and
evaluatin were
completed
low
pts masked.
Placebo and tx
pill had exact
same
appearance
low
clinician,
evaluater and
biostatistician
were blinded
low
not reported
unclear
pts masked.
Placebo and tx
pill had exact
same
appearance
low
Clinian was
blinded
low
low
"randomization
list was kept by
one of the
authors until
patients were
eligible for the
study
low
Upon
completion of
the tx (SRP),
subjects were
allocated to two
groups
according to
the
randomization
list
low
unclear
Placebo Pill
low
yes. All
received OHI.
all received
OHI and
supragingival
plaque and
calculus
removal at
eval visits
Yes. All
received OHI
and re SRP
at all
evaluation
visits
Yes, all
receivewd
OHI
Page 150
Chlorhexidine chip +SRP - Study characteristics
Citation:
Author, Year
Azmak 2002
DIMITRA,
2010
Gonzalez
2011
HEASMAN,
2001
Paolantonio, J
Perio 2008a
(all data)
Paolantonio
et al. J Biol
Regulat
Homeostatic
Agents, 2008b
July 2015
Special population?
patients and teeth
Severity of disease
moderate)
Turkey
No
Moderate to severe
chronic periodontitis (68mm)
Greece
Inclusion: CAL ≥5mm; 4
teeth with pocket depth ≥5
and ≤ 7mm; at least 20
teeth; no antibiotics for
previous 3 months; no
allergies to antibiotics; no
perio tmt previous 12 months
systemic pathogies;
Exclusion: no pregnant or
lactating women. Smoking
status recorded.
Germany
Inclusion: Systemically healthy
individuals aged >35 and <65
years w ere enrolled if they had
≥12 teeth w ith PD ≥5 mm w ith
BOP. Exclusion criteria w ere: 1)
systemic antibiotic therapy w ithin
the past 6 months, 2) hx of allergy
to CHX, 3) perio tmt w ithin the past
6 months, 4) pregnancy, and 5)
heavy smokers (>10 cigarettes
per day).
UK
Recall (maintenance) patients.
Inclusion criteria: signed
informed consent; min of 10
natural uncrow ned teeth; a min of
1 pocket/quadrant w ith a pocket
probing depth (PPD) of at least 5
mm w ith persistent BOP; nonsurgical phase of therapy completed at least 3 months prior to
bas line. Exclusion criteria: early
onset periodontitis; any teeth w ith
furcation involvement; systemic
antimicrobial therapy w ithin 2
months prior to entry; hx of allergy
to CHX; smoking; hx of perio
surgery; perio tmt less than 3
months prior to the baseline visit.
Italy
Non-smokers, at least two
teeth with PD≥5mm.
Exclusion criteria: smoking,
pregnancy, allergy to CHX,
systemic antimicrobial
and anti-inflammatory drug
therapy within 3 months prior Moderate to advanced
to the study, periodontal
perio (at least two sites
treatment undertaken <6
5 mm or greater)
months prior to the
preliminary visit, or the
presence
of a removable prosthesis;
furcation sites and teeth with
a fixed prosthesis.
Country
Test subject age Control subject
(mean, median,
age (mean,
range as
median, range as
described)
described)
36-62
36-62
Control
Dose/ duration/
applicable
Test
(typically
adjunct)
SRP of entire
mouth. One
isolated mesial
interproximal pocket
with probing depth of
6-8mm and BOP
served as the
control site
n/a
CHX chip +
SRP
Chiorhexidine chip (2.5mg
chlorhexidine gluconate in
gelatin) was placed in four
pre-selected pockets with
Periochip®
probing depth and probing
CHX + SRP attachment level ≥ 5 mm and
≤ 7mm with a blunt
instrument by the same
clinician who performed
SRP.
Generalized Chronic
periodontitis
Mean = 46.35,
Mean = 48.75
±7.31 (range 36-64 ±10.15± (range 37years)
75 years)
SRP
Full mouth SRP w as
performed in tw o
quadrants under local
anesthesia, in tw o
sequential visits, one day
apart / Mechanical
instrumentation included
ultrasonic instrumentation
follow ed by hand
instruments (Gracey
curettes SG 3/4, 11/12,
13/14, Hu-Friedy, Chicago,
IL, U.S.A.). / Duration of
instrumentation for each
visit ranged betw een five
and 10 minutes per
tooth.
Specific age data are
Specific age data are
not provided; just
not provided; just
stated individuals
stated individuals w ere
w ere aged >35 and
aged >35 and <65
<65 years; 24
years; 24 recruited,
recruited, equal # of
equal # of men and
men and w omen;
w omen; equal-->12
equal-->12 per group
per group w ith equal #
w ith equal # of men
of men and w omen.
and w omen.
SRP plus placebo
chip
Prophy plus CHX or
Placebo chip for 10
days. Then SRP plus
CHX or Placebo chip
again. 12 sites with ≥
5mm were selected
for the intervention
sites
Periochip®
2.5 mg CHX
gluconate
SRP
Supragingival ultrasonic
scaling and a prophylaxis
of all teeth w ere
performed and all target
sites w ere root planed
under local anaesthesia
for a maximum of 5 min for
each tooth. Target sites
w ere randomised at split
mouth level (left side/right
side) to one of the 2
treatment groups; SRP
alone, SRP + PerioChip.
Follow ing debridement,
target sites w ere irrigated
gently w ith cold saline and
then left for 10 min to
achieve haemostasis prior
to placement of
PerioChips.
SRP +
PerioChip
Moderate to severe
42.6 (sd 12.6) Range 34-59 years
aged 33-65
SRP only
SRP at baseline visit
under local anesthesia
for entire mouth; 2nd
session within 48
hours. Each
SRP +
appt=2hrs; hand
PerioChip at
instrum-Gracey's.
one site
SRP performed
carefully for 5 minutes
at the experimental
sites.
SRP only
Screening visit 2 wks
prior to baseline appt.
During screening visit
all pts. received
supragingival scaling,
OHI and PD
measurements at 4
sites around each
tooth (Mesial-, Midand Disto-Buccal and
Mid-Lingual/Palatal).
Control Tx consisted
of SRP only using
Gracey curettes.
82 systemically healthy pts.
(49 females & 33 males).
Inclusion criteria: minimum
of 10 natural teeth and
periodontal disease
characterized by 2 or more
natural teeth with PD ≥ 5
Italy
Mean age not
Mean age not
mm and BOP. Exclusion
Moderate and Advanced reported. Range
reported. Range
criteria: smoking,
Chronic Periodontitis for all pts. Was 31- for all pts. Was 31pregnancy, allergy to
63 yrs.
63 yrs.
CHX, systemic
antimicrobial or antiinflammatory drug
therapy within 3 mo. prior
to study, and periodontal
Tx undertaken < 6 mo.
prior to baseline visit.
Was standard
Trial design (split
counseling mentioned
timing including
mouth / parallel
as part of control
group / cross over)
treatment?
after
Control
SRP (of entire mouth) + CHX
chip placed in one isolated
mesial interproximal pocket
with probing dept of 6-8mm
and BOP
Duration of
study
Adverse events
reported
Yes
split mouth
6 months
Did not seek or
report adverse
events
All patients received detailed
oral hygiene instructions and
interdental toothbrushes
w ere providedw ith identical
nylon, soft, multitufted TB
and fluoride toothpaste. TBs
w ere replaced every3
months. Subjects instructed
not to use an anticeptic
mouthw ash throughout the
study.
Parallel group
6 months
No adverse effects
resulting from CHX
placement, such as
discomfort, pain or
swelling, as reported
by patients, were
recorded.
6 months
Not reported
Prophy plus CHX or Placebo
Parallel group
chip for 10 days. Then SRP
Yes, repeated
Randomized, doubleplus CHX or Placebo chip
instructions in OHI were masked, placeboagain. 12 sites with ≥ 5mm
given.
controlled clinical
were selected for the
trial
intervention sites
PerioChip (2.5mg
chlorhexidine gluconate in
gelatin) placed at baseline
Not reported
Split mouth
6 months
Yes, 1 person
reported nontreatment aphthae of
buccal mucosa
CHX at time of SRP;
Yes, OHI given. No
flossing after placement
of CHIP for 10 days; no
chemotherapuetic
mouthrinses or oral
irrigation during study.
At 3-month visit,
supragingival scaling +
OHI
split mouth
6 months
Did not seek or
report adverse
events
OHI at screening visit
Split mouth
6 months
Not Reported
SRP + CHX 1 CHX chip per test site at
chip
time of SRP
Page 151
Chlorhexidine chip + SRP - Outcomes Data
Citation:
Author, Year
Azmak 2002
Outcome measure
CAL
DIMITRA,
2010
Probing Attachment
Level (PAL)
Gonzalez
2011
Main outcome
variable was the
change over time of
the microbiologic
data within both
groups. CAL change
over time was a
secondary outcome.
HEASMAN,
2001
Time period for
data presented
in this
abstraction
6 months
Other time
periods for
which data are
available
mouth / No. sites
averaged per tooth
Test sample size
Baseline
1 and 3 months
Two interproximal sites (one
tx and one control) from
mesial surfaces of anterior
teeth that were 6-8mm. So
two sites per mouth, and one
site (mesial) per tooth.
22 individuals,
one pocket per
individual
6 months
Baseline, 3 and 6
months
Clinical data measured for all
teeth in dentition, although
chip only at 4 pockets. /
PAL measured at 6 sites per
tooth /
6 months
Day 0, prior to
Chip placement
on day 14, 10
days prior to
SRP; 1, 3 & 6
months
12 teeth w ith the deepest
periodontal pockets (PD ≥5 mm)
w ere selected (test teeth) for one
of the tw o treatments: CHX or
placebo chips. If more than one
site w ith PD ≥5 mm w as present in
a single tooth, a maximum of tw o
chips per tooth w ere inserted.
144 total teeth per group
27
12
Test mean
Baseline
8.83
6.47
Test SD or SE
(list value)
Baseline
1.34 SD
±0.85
Not reported;
Not reported;
graphic display of
graphic display
Box plots with
of Box plots with
percentiles
percentiles
Estimate 4.9
Test sample size
at end of test
period
Test mean at
end of test
period
20
Figure 2 presents
improvement of
CAL in graph, no
raw data.
Improvement
estimated at 1.75
mm, but this is
eye-balling it
25
12
4.5-5.5 (25th and
75th percentiles)
5.07
Test SD or SE
(list value) at
end of test
period
SD or SE?
Unclear
Not stated;
assumed SE
for difference
±1.05
Not reported;
graphic
Not reported;
display of Box
graphic display of
plots with
Box plots with
percentiles
percentiles
Estimate 3.6
SD
not reported
4.5-4.5 (25th
and 75th
percentiles)
Mean gain
TEST
(Baselinefinal)
Mean SD (or
Control
SE) gain,
sample size
TEST
Baseline
Figure 2
presents
improvement of
CAL in graph,
22 individuals,
no raw data.
Estimate: 0.2 one pocket per
Improvement
individual
estimated at
1.7 mm, but
this is eyeballing it
Not reported
Not reported
Data
text indicates presented in
1.17mm gain figure 2 only.
in attachment Raw data not
reported
29
12
Control
mean
Baseline
8.72
6.38
Control SD or
Control SD or
Control sample
Control mean at SE (list value)
SE (list value) size at end on test
end of test period at end of test
Baseline
period
period
0.84
1
Not reported; Not reported;
graphic
graphic display
display of
of Box plots
Box plots
with percentiles
with
percentiles
4.2-6.1 (25th
and 75th
Estmate=5.0
percentiles)
20
25
12
Figure 2 presents
improvement of
CAL in graph, no
raw data.
Estimate: 0.2
Improvement
estimated at 1.6
mm, but this is eyeballing it
4.98
Not reported;
graphic display of
Box plots with
percentiles
Estmate=4.5
±1.37
Not reported;
graphic display
of Box plots
with percentiles
SD or SE?
Mean gain
CONTROL
(baseline-final)
Mean SD (or SE)
gain, CONTROL
Caries data
Not stated;
assumed SE
for difference
Figure 2 presents
improvement of
CAL in graph, no
raw data.
Improvement
estimated at 1.70
mm, but this is
eye-balling it
Unclear
not reported
Changes in CAL are based on visual estimates based on figure 2
NA
The subject (not the site) was chosen as the observational
statistical unit, and a probing depth (PD) difference of 2 mm
was chosen as a clinically desirable primary outcome. To detect
differences with a signif level (alpha) of 0.05 (two tailed), power of
80% (type beta) and an expected standard deviation of the afterbefore differences =2, a sample size of at least 25 in each group
is required. To check differences between groups across all time
points the general linear model, repeated measures procedure
was appliped with the patient as the observational unit. ANOVA
was also
implemented at each time point.
NA
Because the parameters of interest were not normally distributed,
the median, quartiles, maximum, and minimum were used for
description of data distribution. Summarizing data of discrete
variables and relative frequencies were computed separately by
group. Because normal distribution could not be assessed, the
change over time within groups and among the treatments was
analyzed by means of the Wilcoxon-Mann-Whitney test. Results
are shown in the form of tables and box plots. 144 test teeth in
each group.
Data were analysed on an intention-to- treat basis with the subject as
the unit of statistical analysis. The protocol-defined primary outcome
variable was the reduction of PPD from baseline. At the 1, 3 and 6
month visits, the change from baseline for PPD, BI and CAL for each
site was calculated. A mean value was calculated for each treatment
(split- mouth) and an overall mean of the differences from baseline
was calculated for each treatment. Summary statistics were
determined and 2 sample t-tests undertaken to identify statistically
significant differences between the treatments (at p=0.05). In
addition, the proportion of sites within a patient showing an
improvement from baseline of PPD of >1 and >2 mm were recorded.
The distribution of the scores at the 6 month visit was compared
across the treatments using nonparametric, Cochran-MantelHaenszel row means test.
SD
not reported
3.5-5.0 (25th
and 75th
percentiles)
Not reported
text indicates
0.79 mm gain in
attachment
Not reported
not reported
CAL
6 months
24 subjects; 135 PerioChips
were placed (87 at molar
26 (served as
1, 3 and 6 months sites) and 165 control sites
their own control)
(102 molar sites) were
identified
14.23
SE, 0.19
24
Not reported
Not reported
SE
gain, 0.43
0.15
26 (served as
their own
control)
14.14
0.16
24
Not reported
Not reported
SE
0.15
0.09
NA
RAL (Relative
Attachment Level), all
data
6 months
2 interproximal sites (one tx
and one control)
not reported
n/a
unclear. Assumed
to be 116
Not reported
Not reported
SE
changes in
RAL for all
sites at 6
months
approximately
1.1mm
0.1
116
not reported
N/A
unclear. Assumed
to be 116
Not reported
Not reported
SE
Figure 4a
presents changes
in RAL for all
sites estimated to
be 0.6mm
0.1
not reported
Figure 4b
presents
changes in
RAL for sites
7mm or greater
at 6 months
approximately
1.2mm
0.2
Paolantonio, J
Perio 2008a
(all data)
116
1, 3, 6 months
RAL (Relative
Attachment Level) , 7
mm or greater data
Paolantonio
et al. J Biol
CAL, PD, BOP and
Regulat
GCF Acid Phosphotase
Homeostatic
Levels
Agents, 2008b
July 2015
2 interproximal sites (one tx
and one control)
6 months
6 months
Baseline and 6
months
116
not reported
2 test teeth per mouth.
82 pts. X 2 sites
Number of sites per tooth not (2 teeth) = 164 8.7 ± 1.4 (mm)
reported.
test sites
n/a
unclear. Assumed
to be 116
Not reported
Not reported
SE
± 1.4 mm
82 patients, 164
Test Sites
7.3 ± 0.54 (mm)
± 0.54 mm
Not reported
116
Not reported,
82 pts. X 2
Estimated from but estimated sites (2 teeth)
Figure: 1.1
from
= 164 test
figure:0.1mm
sites
not reported
8.8 ± 2.1
(mm)
Table 2 has data on % gain in RAL from baseline categorized into greater than
or equal to 2mm, 1mm, or less than or equal to 0mm.. Abstract states that
changes in RAL betw een control and tx group w as 0.64mm at 6 months
(p<0.001)
Parametric methods w ere used w hen appropriate after havingtested the
normality of the data, using the Shapiro-Wilk test and Q-Q normality plots; the
equality of variance among the data sets also w as tested using the Levene
test and Q-Q normality plots of the residuals.
A multivariate three-w ay analysis of variance (three-w ay MANOVA) w as
performed to assess the differences in PD and RAL. The three factors w ere
time and treatment (as repeated factors) and investigator/study site (as an
independent factor). A paired-sample t test w as used, w hen appropriate, for
pairw ise comparisons.
N/A
unclear. Assumed
to be 116
Not reported
Not reported
SE
Figure 4b
presents changes
in RAL for sites
7mm or greater at
6 months
approximately
0.7mm
0.1
not reported
± 2.1 mm
82 patients, 164
Sites
7.9 ± 1.41 (mm)
± 1.41 mm
Not reported
Not reported, but
estimated from
figure: 0.5 mm
Estimated from
Figure: 0.1
Not Reported
An additional analysis included calculation of the clustered PD and RAL
changes at 3 and 6 months w ith respect to the baseline scores. These
clustered changes w ere set as ≤0 (no reduction/gain), 1, and ≥2 mm. These
clusters w ere considered ordinal data, and the corresponding significances
of the differences
betw een the treatments (for each of the 3- and6-months time-point changes)
w ere evaluated w ith the Wilcoxon test.
Parametric methods use when appropriate after having tested
normality of data by means of a Shapiro-Wilk test and by Q-Q
normality plots. Changes in clinical parameters between
baseline and 6 months were analyzed within Tx groups using
Student's t-test for paired samples. The same analysis was used
to determine significant difference bgetwee test and control
groups a baseline and 6 months. Bonferroni corrections were
applied to adjust p values in the pairwise comparisons.
Page 152
Chlorhexidine chip + SRP - Review authors’ judgment of each risk of bias item as low, unclear, or high for each included study
Random sequence
generation
Citation:
Author, Year
Azmak 2002
Support for
judgment
flip of a coin
Review
author's
judgment
Allocation
concealment
Support for
judgment
low
Not reported
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Unclear
Blinding
claimed, but not
described in
detail. It is likely
that personnel
were aware of
the site they
were placing
chip in
High
unclear
Blinding
claimed, but
not described
in detail.
Unclear
only the
examiner was
described as
blinded
High
only the
examiner was
described as
blinded
Review
author's
judgment
Unclear
Were the groups
treated the same
except for the
intervention?
Masking of outcomes
assessment
Review
author's
judgment
Support for
judgment
low
Blinding claimed,
but not described in
detail. It is unclear
if person conducting
evaluation was the
same as the person
placing the chip
Yes
Support for
judgment
both groups
were treated
similarly
Review
author's
judgment
follow-up)
≤10% low; 11-20%
unclear; >20% high
Support for
judgment
Selective reporting
Review
author's
judgment
Support for
judgment
Review author's
judgment
Unclear
Unclear
2 drop outs
due to use of
antibiotics
Low
all data was
reported, but
in graphs
rather than
raw data;
limited
information
provided on
clinical
parameters
Low
Outcome
measurements by
blinded examiner
Low
6 of 56 lost
(11%);
although half
intentionally
excluded
because nonoptimum OHI
unclear
No bias
detected
Low
DIMITRA, 2010
Random tables
Low
Kept by 1
investigator
until patients
were eligible
for study
GONZALES,
2011
Number
assigned in
sequence of their
presentation;
randomly
allocated-doesn't
say how;
Unclear
Not
described
Unclear
Not described;
just said
study was
double
masked
Unclear
1 person
examined and
was blinded
Low
Yes
Low
Outcome
measurements by
blinded examiner
Low
Not reported;
assumption is
0
unclear
No bias
detected
outside of not
describing/rep
orting previous
areas.
Unclear
HEASMAN,
2001
Target sites
were randomized
at split mouth
level
Unclear
Not
described
Unclear
Not described
Unclear
2 calibrated
examiners
Unclear
Yes
Low
Periochip placed by
clinician when
examiners not
present
Low
2 of 26 lost
Low
No bias
detected
Low
Paolantonio,
2008a
coin toss
low
Not reported
unclear
not described
Unclear
Not reported
Unclear
yes
low
Examiner was
masked
Low
None reported;
assumption is
0
Unclear
Raw data, SD
and loss to
follow-up not
reported
high
High
Intervention
(but not
control group)
told not to
use dental
floss for 10
days after
placement of
chlorhexidine
chip.
high
Examiner unaware
of attribution of sites
Low
No losses
Low
Mistakes in
reporting
High
Paolantonio
2008b
No details given
July 2015
Unclear
No details
given
Unclear
Not blinded
(single blind)
High
Not blinded
(single blind)
Page 153
Locally-delivered antimicrobials: doxycycline hyclate gel + SRP - Study characteristics
Citation:
Author,
Year
Country
Special population?
(e.g. smokers) and other data regarding inclusion - exclusion
Severity of disease
moderate)
Control
Test subject
subject age
age (mean,
(mean,
median,
median,
range as
range as
described)
described)
Control
Control
Dose/ duration/
applicable
including simultaneous/ before/ after
Agan 2006
Turkey
2 or more tooth sites with PD >= 6mm and CAL >= 3mm and BOP.
No antimicrobial therapy within 6 months of BL. Study also included
AgP but subjects reported separately from CP.
Advanced chronic
periodontitis
Mean 55
Same as
years, range test: Split41-49. SD not
mouth
given
design
SRP
SRP under local
anesthesia with hand
instruments, limited to
10 min per tooth / Single
visit
doxycycline
hyclate+SRP
Single subgingival application of doxycycline
hyclate 10% gel, covered with dressing for 1
week. / Total dose not specified. Gel to fill
pocket.
OHI given to all
subjects
Split-mouth
6 months
None reported by subjects (mentioned in
discussion)
Machion
2004
Brazil
SMOKERS. 1) patients diagnosed w ith chronic periodontitis, show ing a minimum of
four periodontal pockets (probing depth [PD] ‡5 mm and bleeding on probing [BOP])
located on anterior teeth (canines and incisors); 2) patients w ho smoked ‡10
cigarettes/day for a minimum of 5 years; Exclusion: Exclusion criteria w ere as
follow s: 1) patients w ho received scaling and root planing w ithin a period of 6
months prior to the study; 2) patients show ing the presence of periapical or pulpal
alterations on qualifying teeth; 3) patients w ith a compromised heart condition or any
systemic disorder that w ould require prophylactic antibiotic cover; 4) patients w ith a
history of allergy to doxycycline hyclate or other tetracycline; 5) patients w ho used
systemic or subgingival antimicrobials w ithin a period of 6 months prior to baseline
examination; and 5) patients undergoing drug therapy that could affect the clinical
features of periodontitis or the response to periodontal treatment.
40.45+/-4.47 42.00+/-4.38
SRP plus saline
irrigation
SRP followed by
irrigation with saline /
instrumentation
continued until root
smooth and clean
SRP+local doxycycline
(Atridox, CollaGenx, Ft.
Collins, CO)
10%
No
Parallel
6 months
No adverse reactions from any of the patients in
test group
Machion,
2006
same as
above
same as above
same as above
same as above
same as above
same as above
same as above
same as above
same as
above
2 years
no
12 months
Not described
same as
above
same as
above
Was standard Trial design
counseling
(split mouth
Duration of
mentioned as part / parallel
study
of control
group /
treatment?
cross over)
Patients were
enrolled for initial
Patients with Type I Diabetes Mellitus
Martorelli
2004
Brazil
No other systemic disease / no antimicrobial tx in past 6 months /
Each patient contributed two sites which were used for
measurements. Sites included were required to have (1) probing depth
(PD) X5.0mm and (2) bleeding and/or suppuration on probing
Advanced periodontal
disease
Subjects age 35-55 years
therapy which
Scaling and root planing plus
experimental doxycycline
included oral
SRP + placebo gel
hyclate gel (methocel
hygiene instruction,
(Farmacia Escola Comunitaria
supragingival
"Patients seen at 6
Split mouth,
(FAQFAR), University of
ultrasonic
weeks, 3, 6, 9, and Gel placed immediately
ItaJai, Brazil) w ith 10%
Gel placed immediately after SRP procedures
2 sites per
instrumentation and
12 months for
after SRP procedures doxycycline hyclate (MASE
person
appointments for fullperiodontal
Produtos Quirnicos e
mouth
scaling
and
maintenance" which
Farmaceuticos Ltda.,
root planning under
was not described
Cambuci, Sao Paulo, Brazil)
test group)
anesthesia prior to
the experimental
phase.
July 2015
Page 154
Locally-delivered antimicrobials: doxycycline hyclate gel + SRP - Outcomes data
No. Sites treated
Time period for
Other time
per mouth / No.
data presented in periods for which
sites averaged per
this abstraction data are available
tooth
Citation:
Author,
Year
Outcome measure
Agan 2006
CAL
6 months
RAL gain measured at six sites
per tooth, mm
All pockets
6 months
Machion
2004
7 days, 1 and 3
months
presumably 2 sites
in each group (one
site each of test
and control) in each
of 10 subjects
mean of 7.3 sites
per patient, total of
314 sites, six sites
per tooth
Test sample
size
Baseline
Test
mean
Baseline
Test SD or Test sample
SE (list
size at end
value)
of test
Baseline
period
Test mean
at end of
test period
Test SD or SE
(list value) at
end of test
period
SD or SE?
Mean gain
Mean SD
Control
TEST
(or SE)
sample size
(Baselinegain, TEST
Baseline
final)
Control mean
Baseline
Control
Control
Control SD or SE
sample
Mean gain Mean SD
Control SD or
mean at
(list
size at
CONTROL
(or SE)
SE (list value)
end of value) at SD or SE?
end on
(baselinegain,
Baseline
test
end of
test
final)
CONTROL
period
test
period
period
Caries
data
8.27
1.14
(appears to
be SD for
sites)
(N=20)
10
NR
NR
NR
1.56
NR
10
8.72
0.94 (appears
to be SD for
sites) (N=20)
10
NR
NR
NR
1.44
NR
NR
"Tests w ere subjected to each treatment
protocol on a patient-level basis." Changes
form BL w ere analyzed by the repeated
measures analysis of covariance.
Intergroup differences tested using
Bonferroni-corrected Wilcoxon signed rank
test and considered P < 0.01 as significant.
24
not
reported
not
reported
22
1.63
0.93
SD
1.63
0.93
24
not reported
not reported
21
1.04
0.71
SD
1.04
0.71
N/A
Examiner calibrated
24
not
reported
not
reported
22
1.37
1.02
SD
1.37
1.02
24
not reported
not reported
21
1
0.75
SD
1
0.75
N/A
Examiner calibrated
24
not
reported
not
reported
22
2.54
1.27
SD
2.54
1.27
24
not reported
not reported
21
1.29
0.95
SD
1.29
0.95
N/A
Examiner calibrated
n.a.
n.a.
19
n.a.
n.a.
n.a.
1.31
0.95(SD)
n.a.
n.a.
16
n.a.
n.a.
n.a.
0.99
0.85(SD)
7.2
0.4
11
4
0.4
SE
6.6
0.5
11
5.6
0.6
SE
Not
reported
Not reported
10 subjects
although data
presented for
sites (N=20)
45 days, 3 months
RAL gain, mm
5-6 mm pockets (moderate)
6 months
RAL gain, mm
deep pockets
6 months
Machion,
2006
RAL gain measured at six sites
per tooth, mm
All pockets. (site specific data
also available, but in graphic
form)
12 month
Martorelli
2004
CAL = the distance from CEJ
(cemento enamel junction) to the
base of the pocket [Each patient
contributed two sites which were
used for measurements. Sites
included were required to have
(1) probing depth (PD) =>5.0mm
and (2) bleeding and/or
suppuration on probing.]
9 months
July 2015
same as above
total of 236 sites,
six sites per tooth
Twenty-two paired
periodontal defects
6 weeks, 6, and 12 =>5.0mm in the
months
maxillary incisor or
canine areas of 11
patients
11
11
N/A
Page 155
Locally-delivered antimicrobials: doxycycline hyclate gel + SRP - Review authors’ judgment of each risk of bias item as low, unclear, or high for each included
study
Domain:
Selection bias
Random sequence
generation
Citation:
Author, Year
Agan 2006
July 2015
Support for
judgment
Mouth sides
randomized by
coin flip
Review
author's
judgment
Low
Performance bias
Support for
judgment
Not specified
Detection bias
same except for the
intervention?
Review
author's
judgment
Support for
judgment
Review author's
judgment
Support for
judgment
Review
author's
judgment
Review
author's
judgment
Support for
judgment
Unclear
Termed "Blind" by
authors but probably
for lab assessments
only
Unclear
Not described
Unclear
Yes
Low
Not specified
Review
Support for
author's
judgment
judgment
Unclear
Machion 2004 No details given
Unclear
No details given
Unclear
No
Unclear
All SRP done
by same
masked
operator
low
Yes
Low
masked
Low
Martorelli, 2004
unclear
n.d.
unclear
"patient blind"
low
"operator
blind"
low
Yes
low
n.d.
unclear
n.d.
Attrition bias
Incomplete outcome
Masking of outcomes
lost to follow-up)
assessment
≤10% low; 11-20%
unclear; >20% high
0/10 lost
43/48
completed
study (10%
lost); sites of
both groups
excluded if
>= 2 mm AL
at any time
point; 3 sites
from control
and 1 from
test
excluded out
of 314 sites
No losses
noted
Reporting bias
Selective reporting
Review
author's
judgment
Review author's
judgment
Low
No bias detected
Low
Low
No bias detected
Low
low
good data report
low
Page 156
Locally-delivered antimicrobials: minocycline microspheres + SRP - Study characteristics
Citation:
Author,
Year
Country
Special population?
Severity of disease
(e.g. smokers) and other data regarding inclusion - (e.g. refractory, mild,
exclusion criteria for patients and teeth
moderate)
Control
Test subject
subject age
age (mean,
(mean,
median,
median,
range as
range as
described)
described)
Control
Control
Dose/ duration/
applicable
No
Henderson
2002
Skaleric
2004
at least two pairs of
adjacent 6-9mm pockets; each pair located on
adjacent teeth in an interproximal space, on opposite
New Zealand
sides of the mouth. Each study site was required to
have at least 3mm loss of attachment. / no perio tx at
least 6 months prior / no antibiotics for prior 3 months /
other disease restrictions / 6/15 subjects were current
smokers, 6-40 cigarettes/day over 15-30 years
Slovenia
Type I diabetics (poorly controlled) / 7 smokers in test
group and 3 in control group but stated p=0.18 /
HbA1c 7.5% and adult periodontitis, as detertmined by
the presence of four teeth in at least 2 quadrants with
5 mm periodontal pockets, two of which had 6-9 mm
pockets and BOP / no systemic antibiotics for prior 3
months / no antiinflammatories prior 1 month / several
co-morbidity restrictions. No Type II diabetics
Moderate to severe
Adult periodontitis
SRP with ultrasonic
and hand
mean age of 46.3 years(35instruments + OHI.
69 years range)
Local anesthesia
when needed
42
41.6
SRP
No
Van Dyke
2002
U.S.
at least two teeth
having one site each with pocket depth (PD) >=6mm
and with prostaglandin E2 (PG E2) levels > 66.2ng/ml
in gingival crevicular fluid.
Moderate to severe
periodontitis
Not stated
Not stated
SRP
Single 90-minute
session
Completion within 48
hours / The use of hand
curettes, ultrasonic
instruments and local
anesthesia were
permitted / a timed (20
minute) supragingival
cleaning at 12 weeks for
both groups
For those patients
receiving no Tx or SRP
only irrigation
of ,the surrounding test
area was performed
using sterile wvater or
saline to ensure patient
blinding.
Test (typically
adjunct)
including simultaneous/ before/ after
Was standard
Trial design
counseling
(split mouth
Duration of
mentioned as part / parallel
study
of control
group /
treatment?
cross over)
OHI given to all pts
following baseline
SRP was followed by a single application of I
exam / consisting of
mg of minocycline in the form of Minocyctine
SRP+Local
tlie
Periodontal Therapeutic System) (MPTS) into
minocycline
Bass toothbrushig
one of the four sites selected at random by
Split mouth
microencapsulated
methaod and
another clinician, who also randomly selected
microspheres (Arestin)
interproitial cleaning
one of thle two sites on the opposite side of
with the use of floss
the mouth to be design ated the Remote site.
and/or interproximial
brushes.
SRP+Local Arestin
(minocylcine
microspheres)
containing 1 mg
minocycline
SRP+ Local Arestin
(minocylcine
microspheres)
containing 1 mg
minocycline
All pockets >= 5 mm at baseline after SRP
and bleeding subsided / and at 12 weeks. 4
mg of dry powder - 1mg of minocycline and
3mg of polymer
Treatment was applied to any,
of six pockets >= 5mm in the two chosen
study teeth.
No
No
6 months
Not assessed
Parallel group 24 weeks
Not described
Parallel
6 months
An SRP + MPTS patient experienced tw o adverse events
(AEs) - a black hairy tongue ruled to be possibly dtug
related by the investigator and abscess formation at study
sites w ith oedema, w hich w as not considered to be related
to study medication. There w ere three AEs reported in the
no Tx group: toothache in a tooth adjacent to a study tooth,
ulcerative stomatitis, and melena. They w ere not related to
study medication. An SRP patient reported an event of
myalgia, and SRP patient reported an event of a
gramulomatous lesion, and an MPTS patient reported an
event of toothache in a non-study tooth, and SRP + MPTS
patient reported an event of rhinitis, and an MPTS patient
reported an event of headache.
Regarding the gingival margin, the SRP + MPTS group tended
to display the! least redness and sw elling at 14 days and
one month. The same trend w as obsetved at six months,
but to a lesser degree
There w as no significant difference in intensity and extent
of tooth staining at any assessment point among the
treatment groups. There -w ere no abnormal clinical
chemistry or haemnatological results observed in the study
for any of
the groups.
NDA 50-781:
103A
USA
At least 4 teeth with PD 6-9 mm and BOP; smokers
not excluded
48.6 (10.1)
48.0 (10.0)
SRP
No details given
NDA 50-781:
103B
USA
At least 4 teeth with PD 6-9 mm and BOP; smokers
not excluded
49.6 (10.2)
47.4 (9.5)
SRP
No details given
(Williams et
al 2001)
USA
July 2015
30+ years of age, in good general health, no perio
treatment within 6 months or antibiotics within 3
months, No medications that "could affect periodontal
status or healing"
periodontitis (4+ teeth
with pockets 6-9 mm)
47.7 years
49.1 years;
SRP alone
group
scaling and root
planing alone
Once at baseline. Not
time limit. No apparent
maintenance therapy at
3 or 6 months (in either
test or cotrol groups)
SRP+Arestin
(minocycline
minospheres)
SRP+Arestin
(minocycline
minospheres)
No details given
Not described
No details given
Not described
minocycline
microspheres inserted 1 mg minocycline in each pocket at baseline,
in all pockets >= 5mm 3 and 6 months. At basleine, placed after
at baseline. Product
instrumentation. At 3 and 6 month visits,
reapplied to test sites
placed after probing.
at 3 and 6 months.
Not specified.
Parallel arm
9 months
Most common treatment emergent AEs: periodontities, ; stat
sig difference in treatment emergent Aes w ith test vs
control. Non drug-related, serious AEs w ere: body pain,
tachycardia, myocardial infarction, colitis, pancreatitis,
asthma, urinary incontinence, uterine disorder, accidental
injury, carcinoma, hernia, viral infection, emolus, elective
surgery, prostatic carcinoma.
Adverse events were reported by 62.4% and
68.3% of patients in cntrol and combination
therapy groups respectively. The incidence of
these adverse events was similar among
treatment groups. The most common adverse
events are listed in Table 4, and included
headache, dental infection, increased
periodontitis, tooth sensitivity, tooth caries, dental
pain, gingivitis, and stomatitis. No clinically
significant changes in vital signs or oral hard or
soft tissues were noted in these studies.
Page 157
Locally-delivered antimicrobials: minocycline microspheres + SRP - Outcomes data
Citation:
Author,
Year
Outcome measure
Time period for
data presented in
this abstraction
Other time
periods for which
Test sample size
mouth / No. sites
data are
Baseline
averaged per tooth
available
6 months
1 site per mouth tx with
test; two control sites,
one adjacent and one
remote
15
Not
reported
Not
reported
Not reported
1 site per mouth tx with
test; two control sites,
one adjacent and one
remote
15
Not
reported
Not
reported
Not reported
all periodontal pockets
5' mm or deeper treated
with minocycline; CAL
measured at 6 sites per
tooth
10 patients
6.89mm
1. 36
Not stated
3.8
six sites on two teeth
selected for the
study. The two teeth
were selected based
upon the presence in at
least one of the sites
(in each tooth) of A PD
6mm and GCF levels of
PGE 2 > 66.2ng/ml.
Although treatment was
administ’d only at sites
≥5mm on the study
teeth, clinical indices
were monitored at all
six sites.
12
11.01
not given
12
12
11.01
not given
12
11.01
Not described
121
5.56
Test
mean
Baseline
Test SD or Test sample
SE (list
size at end
value)
of test
Baseline
period
Test mean
at end of
test period
Test SD or SE
(list value) at
end of test
period
SD or SE?
Mean gain
Mean SD
TEST
(or SE)
(Baselinegain, TEST
final)
Control
sample size
Baseline
Control mean
Baseline
Control SD or
SE (list value)
Baseline
Control
Control
Control SD or SE
sample
mean at
(list
size at
end of value) at
end on
test
end of
test
period
test
period
period
SD or SE?
CAL gain, mm
Pocket depths were recorded using a
manual probe with 1mm increments and
wvith a tip diameter of 0.5mm. The
measurements were made to the
nearest
Henderson
millimetre. Sites were rounided down if
2002
the
reading fell1 between two, millimetre
markings.
Frequency and percentage of CAL gain
>/= 2 mm
Skaleric
2004
3 months
6 months
CAL attachment level (although states
"loss" it is judged to be "level"), mm
24 weeks
6, 12, 18 weeks
measurements at 6 sites per tooth
excluding 3rd molars
Not reported
Not reported
SD
2.1
1.5
6 months
Change in CAL (baseline given), mm
6 months
Van Dyke
2002
>=5 but <6 mm SITES
Months 1 and 3
6 months
>=6 mm SITES
NDA 50-781:
103A
CAL at baseline, and CAL gain at 9
months
NDA 50-781:
103B
CAL at baseline, and CAL gain at 9
months
(Williams et
al 2001)
CAL (paper's primary outcome was PD.
BOP was a secondary outcome. CAL
was listed as a safety outcome)
July 2015
9 months
9 months
9 months
None
None
Not described
Treated all sites >=
5mm; PD
3 and 6 months
measurements at 6
after randomization sites per tooth recorded
in whole mm using
round-down procedure
128
249
5.21
Caries
data
With Only 15 patients, the power of this
study is low and therefore clinical differences
between sites would have to be
proportionately greater to show
Not
statistical significance. It is therefore nor
Adjacent
reported
surprising that for the majority of clinical
Adjacent
site, CAL
mneasurements, statistiqaliv
site, CAL
gain:
significant diffcrences betwveen treatments
gain:
(1.4)
were not shown. This may be due to no truse
1.4 (1.4)
difference, with the
null hypothesis being correct, or because the
number of subjects was too small to show
Remote site: 8/15 (53%)
Not
any difference. numbers don't add up for
Adjacent site: 6/15 (40%) reported
"remote" sites: should be n=30.
Remote
Remote site,
site, CAL
CAL gain
gain
(1.3)
1.3 (1.3)
15
Not reported
Not reported
Not
reported
Not
reported
Not
reported
SD
N/A
15
Not reported
Not reported
Not
reported
Not
reported
Not
reported
N/A
1.3
SD
10 patients
7.7
1.26
Not
stated
5.78
1.38
SD
Not
reported
Not reported
N/A
1.02
0.26
SE
1.02
0.26
12 (10 included
in this mean)
11.11
not given
12
0.54
0.18
SE
0.54
0.18
N/A
11
0.94
0.3
SE
0.94
0.3
12 (10 included
in this mean)
11.11
not given
9
0.6
0.28
SE
0.6
0.28
N/A
not given
11
1.1
0.29
SE
1.1
0.29
12 (10 included
in this mean)
11.11
not given
10
0.45
0.2
SE
0.45
0.2
N/A
1.07
121
Not reported
Not reported
SD
1.01
0.82
124
5.63
1.06
123
Not
reported
Not
reported
SD
0.98
0.88
Not
reported
Reviewer analysis with some modifications
from the submitted data by manufacturer
126
Not
reported
Not
reported
1.01
Not
reported
Reviewer analysis with some modifications
from the submitted data by manufacturer
11/15 (73%)
ALL TREATED SITES
Mean gain Mean SD
CONTROL
(or SE)
(baselinegain,
final)
CONTROL
1.6
Study
103A: 5.56 SDs: 1.07
mm;
(A); 1.60
Study
(B)
103B: 5.21
128
237
Not reported
Not reported
SD
1.09
1.01 mm
(A); 1.09
mm (B)
1.03
SDs: 0.82
(A); 1.03 (B)
126
250
5.23
5.63 mm: Study
103A; 5.23 mm:
Study 103B
1.71
1.06 mm (A);
1.71 mmm (B)
SD
0.99
0.98 (A);
0.99 (B)
32
Primary, seconday and subgroup analyses
(12.9%)
predetermined. Used patient as the unit of
0.87 mm (A); in test; observation. Primary outcome was change in
1.01 mm (B) 23 (9.2%) PD at sites initially >=5 mm in depth. No
in control there analyses based on CAL. Many other
group
analyses based on PD reduction.
Page 158
Locally-delivered antimicrobials: minocycline microspheres + SRP - Review authors’ judgment of each risk of bias item as low,
unclear, or high for each included study
Domain:
Selection bias
Random sequence
generation
Citation:
Author, Year
Support for
judgment
Henderson 2002 No details given
Skaleric 2004
"randomized by
envelope"
Van Dyke 2002 No details given
Performance bias
Detection bias
same except for the
intervention?
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review author's
judgment
Support for
judgment
Review
author's
judgment
Review
author's
judgment
Unclear
No details given
Unclear
No
High
No
High
Yes
Unclear
No details given
Unclear
Details not
provided
Unclear
No
Unclear
control subjects
received irrigation
High
low
No
No
High
High
Yes
Yes
Support for
judgment
Review
author's
judgment
Low
Yes
Low
Low
No details
given
unclear
Low
Evaluator
masked
Low
Unclear
Unclear
NDA 50-781:
103A
No details given
Unclear
No details given
Unclear
Single masked but
unknown who was
masked
Unclear
Single
masked but
unknown who
was masked
Unclear
No details given
Unclear
Single
masked but
unknown
who was
masked
NDA 50-781:
103B
No details given
Unclear
No details given
Unclear
Single masked but
unknown who was
masked
Unclear
Single
masked but
unknown who
was masked
Unclear
No details given
Unclear
Single
masked but
unknown
who was
masked
High
Subjects in 2 of the 3
arms were: they had
the powder (active or
vehicel) reapplied at 3
and 6 months. The
SRP only arm,
however, didn't have
something placed in
the pocket at 3 and 6
months; but came in at
the same periodicity for
measurements. Rate
as low because this is
due to the intervention
and overlaps with
masking
Williams as
proxy for NDA
"predetermined
randomization
plan"
July 2015
Unclear
No details given
Unclear
Not described as
masked; NDA
indicates single
masking of
outcomes
assessors; however
had third arm with
placebo gel
Unclear
No
Low
Attrition bias
Incomplete outcome
Masking of outcomes
lost to follow-up)
assessment
≤10% low; 11-20%
unclear; >20% high
Examiners
were blinded
and it was
they who
assessed
the outcome.
Low
Reporting bias
Selective reporting
Support for
judgment
Review
author's
judgment
Review author's
judgment
No loss
Low
No bias detected
Low
Low
No bias detected
Low
Unclear
No bias detected
Low
% lost
ranged from
5-8.9%
Low
Although CAL results were not
published, they also were not
specified as the primary
outcomes measure
Unclear
% lost
ranged from
4.7-8.7%
Low
outcomes measure
Unclear
Low
outcomes measure. In fact
CAL stated as included "as a
safety assessment"; reported
that "all groups experienced a
mean gain in clinical
attachment at 9 months, but
the minocycline microsphere
group showed a greater gain"
when in fact, the difference was
not statistically signficant
Unclear
Assumed no
losses
although not
stated
Up to 20%
lost
8.4% of SRP
and 4.8% of
test group
incomplete
Page 159
Nonsurgical use of lasers: PDT diode laser + SRP - Study characteristics
Citation:
Author, Year
Country
Special population?
data regarding inclusion refractory, mild, moderate)
exclusion criteria for
patients and teeth
Test subject Control subject
age (mean,
age (mean,
median, range median, range
as described) as described)
Control
Control
Test (typically
adjunct)
Dose/ duration/ frequency/ timing including
one appointment with hand
instruments (Gracey curettes)
SRP+laser
wavelength of 670
nm
For the photodynamic therapy
0.005% methylene blue was used as photosensitizer and
activated with a laser / maximum power of 150 mW for 60
seconds
Was standard
Trial design
counseling
mentioned as part of parallel group /
study
control treatment?
cross over)
No; non smokers
Berakdar 2012
Chondros 2009 J
Lasers med Sci
Christodoulides
2008
Dilsiz 2012
Germany
four teeth with probing depth ≥
SRP with curettes; All patients
5 mm and presence of BOP;
Chronic periodontitis having four
mean age: 59.3 ± 11.7 years (range 38received a professional
no systemic disease; not
teeth with at least one site ≥5 mm
74 years)
tooth cleaning three weeks prior
pregnant; no systemic
probing depth and bleeding.
to the treatment
antibiotics within the last 6
months
(a) chronic periodontitis, (b) no
active periodontal treatment
during the past 6 months, (c)
presence of at least one site
per quadrant exhibiting pocket
depth of ≥4 mm with bleeding
on probing, (d) good general Chronic periodontitis in supportive
health without any signs of
therapy with at least one site per
Netherlands
systemic disease, (e) no use quadrant with pocket depth ≥ 4 mm
of antibiotics for the past
with bleeding.
12 months and (f) no
pregnancy; 3/9 smokers in
control and 4/8 in test; Only
sites with deep pockets
(PPD≥4 mm) were treated
subgingivally
Patients referred to periodontal
clinic, no treatment in past 2
years, no systemic diseases,
Netherlands
no pregancy, no antibiotics for
past 12 months. No exclusion
for smokers.
Turkey
No systemic diseases, not
Chronic periodontitis with at least 5
pregnant, not taking any
teeth in every quadrant, presence
medications, non-smokers, no
of ≥4 non-adjacent teeth with PPD
perio treatment in past 6
of ≥ 5 mm with bleeding and
months, no caries or
radiographic bone loss.
restorations on selected teeth
48.3 (±7.9)
43.7 ± 7.3 years
50.6 (±9.2)
47.3 ±8.8 years
40.7 ± 7.3 years
40.7 ± 7.3 years
44.8 ± 5.6 yrs
44.8 ± 5.6 yrs
HIV patients who had
experienced highly active
antiretroviral therapy; 33.3%
were smokers
Filho 2012
Brazil
at least 4 sites presenting
PPD >4 mm with BOP; not
pregnant; no other systemic
disease; no antimicrobials w/in
the last 6 months
Slight to moderate chronic
periodontitis in HIV patients
Smokers up to 10 cig/day
Gianelli 2012
Italy
at least 2 teeth w/ at least 1
site PD 4-10 w/ BOP in max
quad (3-8 or 9-14); min of 5
teeth/quad
Mod to severe chronic periodontitis
46.7 (range 25-65
yrs)
Split mouth
6 months
No undesirable effects were
observed, and both therapies were tolerated well by
the patients
SRP/ mechanical debridement
with a sonic scaler and
supragingival cleaning and
polishing
YES. Subsequently,
supragingival cleaning
sonic scaler (Sonicflex®,
was performed
KaVo Dental GmbH, Biberach,
Additionally a dye/laser system was applied. The
with a rubber cup and a
Germany) with power set to
systemconsisted of a hand-held battery-operated diode laser
SRP+Photodynam
low-abrasive polishing
6000 Hz and water as coolant. The
(HELBO® minilaser 2075 F dent, HELBO Photodynamic
ic therapy at
paste for both groups and
instrumentation was
Systems GmbH & Co KG, Grieskirchen, Austria). The laser
selected site (≥4
repeated at 3- and 6terminated when the operator judged
wavelength was 670 nm, and the power density 75 mW/cm2.
mm PPD)
month intervals. In
the debridement to be
the diode laser unit was used with an 8.5 cm-long flexible tip
addition, self-performed
adequately performed. Performed
curved at an angle of 60°. Working time was 60 s per tooth
plaque control measures
under local anesthesia in 1 session
were reinforced when
indicated
Parallel group
6 months
there were no sites showing clinical signs of
deterioration. Healing was uneventful in all patients.
Neither pain nor any other discomfort was reported
by any of the patients following both treatments
SRP
OHI individualized for
every subject given at the
Photosensitizer liquid applied with blunt needle starting from
first appt; at 3 months
SRP using hand instruments and SRP+Photodynam apical end of pocket and moving coronally; 3 minutes later all
after clinical
sonic instrumentation until operator
ic therapy with
pockets thoroughly rinsed with sterile saline to remove
measurements, one
believed root surfaces were
diode laser
excess photosensitizer; immediately after, diode laser with
session of prophy
adequately debrided and planed
following SRP
670 nm wavelength and 75 mW power output equipped with
including reinforcement of
under local anesthesia in 1 session
within 24 hours
probe tip placed at depth of pocket and moved around tooth
OH, supragingival
for 1 minute
debridement and tooth
polishing
Parallel group
6 months
Healing was uneventful in all cases. No adverse
effects, such as burning sensation or pain, related
to the laser irradiation have been reported by any of
the subjects
2 sessions with intervals of 7 days
between sessions; tip of laser placed
in perio pockets but laser beam not
activated; full mouth supra and
subgingival SRP with an ultrasonic
instrument with A tip and medium
intensity until clinician considered
Note: although it states BEFORE SRP, does not seem likely
tooth surfaces appropriately debrided
SRP with recall professional
/ preliminary oral rinse for 30 s / pockets filled with 1%
and planed; following SRP, all
SRP+PDT GaAlAs
prophy at 1 and 3 months after
methylene blue solution / after 3 min photosensitizer rinsed
supragingival teeth surfaces polished
(diode) laser
tx / no subgingival tx at recall
out with saline / 100mW, 60s, 6J, 808 nm, 300 micron
with rubber cup and point in
fiberoptic tip
combination with a dental paste; at
2nd session, SRP carried out using
curettes and continued until
researcher felt root surfaces were
hard and smooth; then rinsed with
sterilized phsiological saline (NaCl 9
w/v) solution
SRP using ultrasonic device with
recall weekly for first month and
monthly until the 6th month;
during recall supragingival
prophy performed and OHI
reinforced
SRP with an ultrasonic
SRP with
ultrasonic scaler
followed by the
PDD with diode
laser using
methylene blue
Smokers excluded
43.12 ± 8.2 years
Brazil
[2 treatments:
TBO AND
TBO+laser;
exclude
SRP+TBO arm]
July 2015
3 nonadjacent sites with BOP
and PD of 5-9 mm and at least
20 teeth excluding 3rd molars,
age 35-55
periodontitis
wavelength of 660 nm, 0.03 W power, methylene blue
0.01% lasting 133 seconds; spot size 0.07 cm2; fluence rate
of 0.428 W/cm2, energy fluence of 57.14 J/cm2; pockets
rinsed with saline after tx
OHI at baseline;
Split mouth
OHI pre-tx and
supragingival prophy
monthly post-tx
Split mouth
photoablation: (1 W output power, continuous wave, 66.7
J/cm2), equipped with a 0.6 mm optical fibre touching the
gingiva and removing junctionaln, sulcular and outer gingival
Diode 810 nm
epithelium.Tip moved at constant speed of 2.5 mm/s; with
continuous wave, 1
threshold set at 80°C on the target (Bornstein 2004), to avoid
W, 0.6 mm fiber
SRP + sham laser (including
undesired
for photoablative
All subjects received OHI
methylene blue wash) +fullSham laser then SRP w/ Gracey
heat-induced tissue damage.
Split mouth, max
46.7 (range 25-65
and full-mouth prophy w/
mouth supragingival prophylaxis curettes; methylene blue rinsing then
arch only, teeth 3yrs)
Diode 635 nm
ultrasound and/or hand
by ultrasound and/or hand
laser movements with laser off
PDT: once weekly / (100 mW output power, continuous
8 and 9-14
continuous wave
instruments
instrumentation.
wave), equipped with a 0.6 mm optic fibre / rinsed with the
100 mW, 0.6 mm
photosensitizer agent methylene blue (0.3% w/v in water). /
fiber for
2.5 mm/s speed (average time per tooth: 1 min. inside and 1
photodynamic
min. outside the pocket / treatment was continued until
normalization of the cytodiagnostic parameters, especially
PMN (range: 4 –10 applications
Theodoro 2011
Data for
SRP+TBO+laser
vs SRP
Yes, patient compliance
was required and
monitored by routine
plaque and gingival
measurements
43.12 ± 8.2 years
Inclusion range 35- Inclusion range 3555
55
SRP + toluidine blue O
phenothiazine dye (TBO)
TBO is 100 micrograms/mL /
irrigation with insulin needle
SRP+laser: 660
nm+ TBO
All the patients
participated in a program
of oral hygiene
instruction, professional
power 30 mW, spot size 0.07 cm2, energy 4.5 J / After 1 min
prophylaxis and
of TBO irrigation, the laser optical fiber tip was positioned
motivation weekly
parallel to and in contact with the selected site. The laser was
until day 30 after baseline
delivered for 150 s at a power intensity of 0.4 W/cm2 and
(at the beginning of the
energy density of 64.28 J/cm2.
treatments), then
bimonthly until day 90,
and monthly until
day 180.
Split mouth
No adverse effects of laser therapy were observed
6 months
or reported by the patients; none of the pts revealed
after
any major periodontal inflammatory symptoms after
conclusion of
instrumentation during the entire study; no
tx
complications such as infections, suppuration, or
abscesses were observed
6 months
No complications reported
1 year
Stated that no adverse events occurred
6 months
No postoperative complications,
abscesses or infections were observed during the
whole study period.
Page 160
Nonsurgical use of lasers: PDT diode laser + SRP - Updated literature
Citation:
Author, Year
Alweili, 2013
Betsy, 2014
Country
Special population?
patients and teeth
Jordan
The exclusion criteria were
systemic diseases that could
influence the outcome of
periodontal therapy, including
antiphlogistics, bleeding stimulating pharmaceuticals, or
intake of systemic antibiotics
within the last 6 months. The
inclusion criteria were as
follows: previously untreated
chronic periodontitis, at least
one premolar and one molar in
every quadrant with a minimum
of four teeth each, and at least
one tooth with attachment loss
of ≥4 mm in every quadrant.
India
The inclusion criteria followed
for patient selection comprised
of (a) probing pocket depths
(PPD) between 4 and 6 mm at
least in two different quadrants
of the mouth, (b) a minimum of
20 teeth, (c) age between 18
and 65 years (both males
and females), (d) single rooted
teeth, good general health
without any signs of systemic
disease, (e) no use of
antibiotics for the past 6
months, (f) female patients
were not pregnant or lactating,
(g) non-smoking and (h) nonallergic to methylene/toludine
blue.
at least one tooth with attachment
loss of ≥4 mm
Not stated
Test subject
age (mean,
median, range
as described)
39.9 (13.5)
40.8 (8.3)
Control subject
age (mean,
median, range
as described)
39.4 (13.7)
38.4 (9.6)
Control
SRP
SRP
Control
SRP of all periodontally involved teeth
using both hand instruments (Gracey
Curettes; Hu-Friedy,
Leimen, Germany) and a
piezoelectric ultrasonic handpiece
(Sirosonic L; Sirona, Bensheim,
Germany) with a slim-line
styled scaler tip (Perio Pro Line;
Sirona) by the same clinician.
hand scalers and universal curettes
(Hu-Friedy) and ultrasonic scaler
(Woodpecker ). Full-mouth
supragingival and subgingival scaling
was performed at all sites within
24 h including the evaluated sites
until the operator felt that tooth
and root surfaces were adequately
debrided and planed.
Test (typically
adjunct)
SRP+PDT
including simultaneous/ before/
after
Initially, the subjects
received full mouth SRP
diode laser (wavelength, 660 nm; output
and oral hygiene
power, 100 mW; Helbo Photodynamic
instructions. Briefly,
Systems, Grieskirchen,
subjects were trained in
Austria) in combination with a dedicated the Bass technique. A soft
photosensitizer dye (phenothiazine
bristle toothbrush and a
chloride; Helbo Photodynamic Systems).
fluoride
The photosensitizer dye allowed reacting toothpaste were provided
for at least 1 to 3 min according to the
along to them. The
depth of the pocket. Laser application
patients were
was performed circumferentially at six
called for to check their
sites per tooth, 1 min per tooth in six
adherence to the clinical
areas each one at 10 s..
instructions,
as well as to supragingival
control every 2 weeks.
The photosensitizer
used consisted of freshly prepared
3,7-bis (dimethyl- amino)
phenazathionium
chloride trihydrate [methylene
blue (MB) M9140; Sigma-Aldrich, St.
Louis, MO, USA] suspended in double
distilled water at a concentration
of 10 mg/ml.
SRP+PDT
Was standard
Trial design
counseling
mentioned as part of parallel group
study
control treatment?
/ cross over)
diode laser operating at 655 nm with a
CW output power of 1 W (CSP).
Two millilitre of MB was applied
topically to sites with 4–6 mm
pocket depth for 60 s using a syringe /
The aPDT treatment was performed at a
continuous laser power density of
60 mW/cm2, with top-hat energy
distribution for 60 s, at each mesiobuccal,
distobuccal, mesiolingual or distolingual
site with 4–6 mm pockets
on selected teeth
all subjects were initially
enrolled in an oral
hygiene program and
were given oral hygiene
instructions
that included twice daily
brushing before they
returned for treatment
after 1 week.
split-mouth; 2
quadrants
control and 2
quadrants test
1 year
No adverse effects of aPDT were observed or
reported by the patients.None of the patients
revealed any major periodontal inflammatory
symptoms after instrumentation during the entire
study. Postoperative
complications, such as infections, suppuration, or
abscesses, were not observed.
Parallel
6 months
Healing
was uneventful in all cases and no
adverse effects, such as discomfort,
burning sensation, or pain related to
the laser irradiation, were reported by
any of the subjects.
Parallel
6 months
The subjects did not report
adverse effects after therapies.
NON SMOKERS
Luchesi, 2013
Brazil
July 2015
Exclusion criteria were
pregnancy, lactation, current
smoking and smoking within
the past 10 years, antibiotic
therapies in the previous 6
months, use of long-term
treatment of class II furcation sites
administration of antiin chronic periodontitis subjects. /
inflammatory and
and chronic perio one buccal or
immunosuppressive
lingual class II furcation with
medications, use of mouth
probing pocket depth (PPD) ≥ 5
rinses containing
mm and bleeding on probing (BoP).
antimicrobials
in the preceding 2 months,
systemic conditions reported
during anamneses that could
affect the progression
of periodontitis (e.g. diabetes
mellitus) and SRP in the
preceding 6 months.
50.75 ( 8.18)
50.24 (10.89)
SRP + non-activated
laser/only
photosensitizer (control
group
Scaling and root planing was
performed
using periodontal curettes
(Gracey, Hu-Friedy, Chicago, IL,
USA) and an ultrasonic device
SRP +activated
laser with
photosensitizer
The laser system included a handheld
battery-operated diode laser
(Thera Lase – DMC, S~ao Paulo, Brazil)
with a wavelength of 660 nm, a
power output of 60 mW and energy
dose of 129 J/cm2, together with
methylene blue as a photosensitizer
(10 mg/ml)
patients were submitted to
dental calculus removal,
exodontia, provisional
restorations, and SRP in
all non-experimental sites
At
the end of each
appointment,
supragingival
prophylaxis was
performed.
Page 161
Nonsurgical use of lasers: PDT diode laser + SRP - Outcomes data
Citation:
Author, Year
Berakdar 2012
Outcome measure
CAL, mm
Time period Other time
No. Sites treated
for data
periods for
per mouth / No.
presented in which data
sites averaged
this
are
per tooth
abstraction
available
6 months
Data recorded at 6
sites per tooth with at
least one tooth used
baseline, 1, 3
as test or control. No
months
mention of total
number of teeth
involved in study.
Test sample
size
Baseline
Test mean
Baseline
22 people
8.1
Test
Test SD or
Mean gain
Control
Test SD or SE sample Test mean at SE (list
Mean SD
TEST
sample
(list value) size at end end of test value) at SD or SE?
(or SE)
(Baselinesize
Baseline
of test
period
end of test
gain, TEST
final)
Baseline
period
period
1.3
22 people
not recorded,
only plot graph
shown. No
actual numbers
given for
results.
NA
NA
Range read
Plot graph
off figure: 1.5indicates 2.5
4.0. No SD
mm gain in
or SE
CAL
available
22 people
Control
mean
Baseline
7.2
Control
Control
Control SD or SE
sample
mean at end
(list value)
size at end
of test
Baseline
on test
period
period
1.2
22 people
not recorded,
only plotted
Control SD
Mean gain
or SE (list
Mean SD (or
CONTROL
SE) gain,
value) at SD or SE?
(baselineCONTROL
end of test
final)
period
NA
NA
Caries
data
range read off
Plot graph
figure: 0.5indicates 2.0 3.5. No SD Not reported
mm gain
or SE
available
Christodoulides
2008
CAL
6 months
6 months
10 sites per mouth for
baseline and
each group, no
12 patients with
3 months
mention of #sites per 10.7 ± 3.2 sites
tooth.
6.8
56 test sites (12
patients) and 57
baseline and
control sites (12
3 months
patients). No mention
of # of sites per
mouth.
4.1
56 sites in 12
patients
The nonparametric Wilcoxon test for
paired samples was used for
comparison of the effect of the two
treatments (p ≤ 0.05).
Power calculation; Student’s t-test
was employed for continuous
variables (clinical measurements)
after the
normality of the data distribution had
been confirmed. Likewise, the
significance of the difference within
each group before and after treatment
was evaluated with the pairedsamples t-test
CAL
- distance in millimetres
from a fixed reference
Chondros 2009 J point (cemento-enamel
Lasers med Sci junction or the border of
a restoration) to the
bottom of the probeable
pocket, at the
experimental sites)
0.9
0.5
12
56 sites in 12
patients
6.1
3.4
0.9
0.6
SD
SD
0.7
0.7
0.7
0.3
12
57 sites in 12
patients
7.1
4.5
0.9
1
12
57 sites in 12
patients
6.6
4
0.9
1
SD
SD
0.5
0.5
0.6
0.5
Not reported
The calculation of the sample size
determined that ten subjects per
treatment group would provide 80%
power to
detect a true difference of 1.0 mm
between test and control, using
probing depth (PD) reduction in
pockets as the primary outcome
variable, assuming that the common
standard deviation would be 0.8 mm.
Power calculation; Student’s t-test
was employed for continuous
variables (clinical measurements)
after the normality of the data
distribution had been confirmed.
Likewise, the significance of the
Not reported difference within each group before
and after treatment was evaluated
with the paired samples ttest
Power calculation to detect true
difference of 1 mm with SD of 0.8 for
PD
Dilsiz 2012
Filho 2012
Gianelli 2012
CAL (mm)
CAL
6 months
6 months
CAL, 6 sites per tooth;
minimum 5 teeth per
quadrant
1 year
CAL, mm
6 months
baseline
45 days, 3
and 6 months
3 sites per person;
144 teeth; 1 site per
person per regimen (3
regimens)
24 people
All teeth with at least 12 pts, all teeth
1 site with PD ≥ 4
with ≥ 4 mm PD,
mm; 6 sites/tooth
6 sites/tooth
0,15,30,45,60 5-6 test teeth and 5-6
,90 and 365
control teeth per
for
patient; 6 sites per
cytodiagnosti tooth and values were
c data
averaged
7.67
4
0.56
1.1
24 people
6.13
12 pts, all
teeth with ≥ 4
mm PD, 6
sites/tooth
2.6
0.99
1
SD
SD
1.54
1.1
24 people
7.5
12 pts, all
teeth with ≥ 4
mm PD, 6
sites/tooth
3.7
0.72
0.9
24 people
6.04
12 pts, all
teeth with ≥ 4
mm PD, 6
sites/tooth
3.6
1
0.8
SD
SD
1.5
0.88
Not reported
Not reported Not reported Not reported
Kruskal-Wallis test chosen for
multiple comparisons of the groups in
mean CAL / Wilcoxian signed rank
test for differences in mean clinical
parameters for baseline and 6
months; Mann Whitney U used to
compare the groups
The
ANOVA/Tukey was used for
statistical analysis; power
calculation; per protocol analysis;
patients statistical units; student's t
test for clinical parameters
This analysis indicated that with 12
subjects the study would have an
80% power to detect a 1 mm
difference
in the CAL in the two groups
26 people; 150
teeth
5.6
0.2
26 people;
150 teeth
3.1
0.2
SE
26 people;
150 teeth
5.6
0.2
26 people;
150 teeth
4.8
0.2
SE
The subject’s quadrant was assumed
as a test unit for statistical
comparison.The clinical parameters
were compared by Student’s
t-test for paired values
33
6.52
2.11
33
4.96
2.07
SD
33
6.23
1.25
33
4.25
1.73
SD
Examiner calibration procedure /
power and sample size calculated at
81% / data tested for normality
Theodoro 2011
Data for
SRP+TBO+laser
vs SRP
[2 treatments:
TBO AND
TBO+laser;
exclude
SRP+TBO arm]
July 2015
2, 3 and 6
months
3 sites/mouth, 1
site/tooth
N/A
Page 162
Citation:
Author, Year
Outcome measure
Alweili, 2013
CAL, mm
Time period for
No. Sites treated
data presented in
per mouth / No.
sites averaged per
close to 9 months
tooth
as possible)
1 year
Not described; at least
one tooth with
attachment loss of ≥4
mm per quadrant
Test sample
size
Baseline
Test mean
Baseline
21
9.22
Test
Test SD or
Mean
Mean SD
Test SD or SE
sample
Test mean at
SE (list
difference
(or SE)
(list value)
value) at SD or SE?
Baseline
of test
period
end of test
baseline)
TEST
period
period
2.16
16 people, 73
sites
7.74
2.02
SD
1.48
1.89
Control
sample
size
Baseline
Control
mean
Baseline
Control SD or SE
(list value)
Baseline
21
9
2
Control
Control SD
Control
sample
or SE (list
mean at end
size at end
value) at SD or SE?
of test
on test
end of test
period
period
period
16 people, 63
sites
8.87
2.13
SD
Mean
difference
CONTROL
(finalbaseline)
0.13
Mean SD (or
SE)
Caries data
difference,
CONTROL
1.7
No caries
data
Used Mann-Whitney for statistical
significance between treatments
Power calculation performed,
minimum effect size (before-after) set
at 0.5 mm with SD = 0.6mm
Subject-level analyses
Betsy, 2014
median CAL, mm
6 months
PDT applied to sites
with PD 4-6 mm
44
6.5
Min-max, IQR:
5.0-8.0; 1.7
44 (ITT)
4
Min-max,
IQR:
(2.6–7.0; 2.0)
IQR
Not reported
Not reported
44
6
Min-max, IQR:
(4.2–8.0; 1.7)
44 (ITT)
4.5
Min-max,
IQR:
(2.0–7.0; 2.0)
IQR
Not reported
Not reported
Not reported
Intention to treat analysis; LOCF
method
the data distribution of clinical
parameters in this study did not
obey the Gaussian law by KolmogorovSmirnov test (p < 0.05),
nonparametric
methods were used for
analysing the data
The minimum
clinically significant value (d)
considered was 1 mm
Luchesi, 2013
relative CAL (RCAL) –
the distance
from the stent to the
bottom of the
periodontal pocket
6 months
Not stated
21 people
10.56
1.79
16 people
9.78
2.33
SD
0.78
1.54
21 people
10.43
2.66
21 people
9.5
2.14
SD
1
1.69
Not reported
Once
normal distribution were obtained,
repeated measures analysis of
variance (ANOVA) and Tukey’s test
were used to detect intra-group and
inter-group differences in clinical
parameters (PGM, PPD and RCAL)
Appears that data analyzed per
tooth/site and not per person
July 2015
Page 163
Nonsurgical use of lasers: PDT diode laser + SRP - Review authors’ judgment of each risk of bias item as low, unclear, or high for each included study
Domain:
Selection bias
Random sequence
Citation:
Author, Year
Support for
judgment
Berakdar 2012 randomization list
Chondros 2009 J
Coin toss
Lasers med Sci
Christodoulides
Coin toss
2008
Dilsiz 2012
computer
generated table
Teeth randomlly
Filho (Noro Filho) allocated using a
2012
computer
generated list
Performance bias
Review
Support for
author's
judgment
judgment
Low
No details given
Review
author's
judgment
Unclear
Were the groups
Attrition bias
Reporting bias
Selective reporting
No - single blinded
Review
author's
judgment
High
No-single blinded
Review
author's
judgment
High
Low
No details given
Unclear
Not described
Unclear
Not described
Unclear
Yes
Low
No details given
Unclear
Not described
Unclear
examiner blind.
Clinician not.
High
Yes
Low
No
High
Yes
Low
"double
blind"
Low
No loss; outcomes
complete
Low
No bias detected
Low
Support for
judgment
Support for
judgment
Support
for
judgment
Yes
Detection bias
Masking of outcomes
Review
Support for
author's
judgment
judgment
examiner
Low
not involved
Examiner
Low
masked
Examiner
Low
masked
Review
author's
judgment
Low
Low
Low
Support for
judgment
No losses
No losses to follow
up
No loss; outcomes
complete
Review
author's
judgment
Low
Support for
judgment
Review author's
judgment
No bias detected
Low
Low
No bias detected
Low
Low
No bias detected
Low
Low
No details given
Unclear
Laser placed in
pocket but not
activated
Low
Code not
broken until
end of study
Low
"Double blinded" but
method not
described
Unclear
"Double blinded"
but method not
described
Low
Yes
Low
"Double
blinded" but
method not
described
Low
All patients finished
and were reported
Low
All data reported
Low
Gianelli 2012
randomization
claimed, but
method not
described
Unclear
Sequentially
numbered
opaque sealed
envelopes
Low
Sham laser
Low
Not masked
High
Yes
Low
Blinding
described;
unaware of
tx
Low
No losses to follow
up
Low
All data reported
Low
Theodoro 2012
Computer
generated table, tx
sequence also
randomized
Low
No details given
Unclear
No detail provided
Unclear
Examiner blinded
Low
Yes
Low
Examiner
blinded as to
treatment
Low
4 patients exited
prior to data
collection
Low
All data reported
Low
July 2015
Page 164
Selection bias
Domain:
Random sequence
generation
Citation:
Author, Year
Support for
judgment
Alweili, 2013
quadrants
were assigned
to different
groups
according to a
computergenerated
random
number table
Betsy, 2014
Tippet’s 2-digit
random
number
table
Luchesi, 2013
July 2015
by a computergenerated list,
Review
author's
judgment
Performance bias
Allocation concealment Masking of participants Masking of personnel
Support for
judgment
Low
The sequence
was
concealed until
the
interventions
were assigned
Low
opaque sealed
envelopes,
which were
sequentially
numbered.
Low
The
randomization
code was not
broken until all
data had been
collected
Review
author's
judgment
Low
Low
Low
Support for
judgment
Not
described
Not
described
Sham laser
Review
author's
judgment
Unclear
Unclear
Low
Support for
judgment
Not
described
Not
described
Not possible
/ described
Were the groups
treated the same
except for the
intervention?
Detection bias
Attrition bias
Reporting bias
Masking of outcomes
assessment
Incomplete outcome
lost to follow-up)
≤10% low; 11-20%
unclear; >20% high
Selective reporting
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Unclear
Reinforcement
regarding oral
hygiene was
provided on an
individual basis
by dental
hygienist not
involved in the
clinical
examination
Unclear
blinded
examiner
Low
6/21 lost
(24%)
High
None noted
Low
Low
All clinical
data
collected by
periodontist
blinded to
study
procedure
Low
8/88 lost; ITT
analysis
Low
None noted
Low
High
clinical
attachment
level (CAL)
change
defined as the
primary
outcome
variable
Low
Unclear
Unclear
No differences
noted
No differences
noted
Low
Examiner
blinded to
therapies
Low
24% for
treatment
group
Page 165
Nonsurgical use of lasers: non-PDT laser + SRP - Study characteristics
Citation:
Author, Year
Country
Special population?
patients and teeth
Alves 2012
Caruso 2008
Brazil
Italy
Systemically healthy subjects
only, no medications or
antibiotic use in past month,
no perio therapy in past 3
months, at least 10 teeth per
arch. No mention of smoking
status.
Control
Control
SRP
supra- and subgingival ultrasonic
scaling of all teeth except for the
experimental teeth;
One day after SRP and polish, laser
46.8±8.11 years (range 37–64 years)
experimental/control teeth
procedure used on the control tooth
received subgingival SRP under
without activation of the laser in a
anesthesia followed by tooth
sham procedure. Laser sham was
polishing
repeated one week after SRP
No; non-smokers only
single-rooted teeth with pocket
depth >5 mm; no perio tx or
antibiotics for the previous 6
months; no systemic
pathogies; no pregnant women
age (mean,
age (mean,
Severe chronic periodontitis
Chronic periodontitis having at
least two sites in contralateral
sextants with probing depths ≥ 5
mm interproximally of the same
arch and within 2 mm difference.
Not stated
Not stated
Hand scaling and RP with a
curette by same person.
Test (typically
adjunct)
"high intensity"
808±5 nm diode
laser
Was standard
Trial design
counseling
study
control treatment?
cross over)
20 s, in two isolated appointments, 1 day after SRP and
again 1 week later. The laser was used in the continuous
all subjects received oral
mode, with 1.5 W and power density of 1,193.7 W/cm2. 400hygiene instruction (OHI)
μm diameter fiber optic device. The mean energy loss in this
study was around 20%. Power meter used.
Split mouth
contralateral
teeth, 1 test & 1
control
6 months
Not reported
Split mouth
6 months
Not reported
mechanical debridement by the
same expert periodontist, using
(Valure S9- Lasering Medical LaserGracey curettes until the operator
Modena; Italy) 980 nm at a power output of 2.5 W in pulsed
All patients were
achieved a hard, smooth and
mode (30 Hz, pulse duration 10 ms) after SRP / The optic
instructed with oral
calculus-free root surface. One
SRP+Diode laser; fiber of 400 μm was moved from the coronal to the apical side
hygiene
treatment appointment for all
of the pocket in parallel paths with an inclination of
instructions after consent
subjects with follow-up for plaque
approximately 20°. Each pocket of the test group was lased
to participate
control at 4,8,12 weeks and final eval
for 30 s twice, with a 60 s interval
at 6 months
Nonsurgical use of lasers: non-PDT laser + SRP - Updated literature
Citation:
Author, Year
Saglam, 2014
Ustun, 2014
July 2015
Country
Special population?
(e.g. smokers) and other data regarding inclusion exclusion criteria for patients and teeth
Turkey
Exclusion criteria were periodontal treatment
received for the last 1 year; systemic diseases that could
influence the outcome of the therapy, pregnancy, smoking,
immunosuppressive chemotherapy; and use of antibiotics and antiinflammatory drugs for the last 6 months. Patients were included if
they had at least 14 teeth with at least two teeth with ≥5 mm
probing depth at each quadrant.
Turkey
at least two teeth with ≥5 mm
probing depth at each quadrant
Inclusion criteria were the presence of at least two incisors or
canines at two quadrants (mandible or maxilla) with periodontal
Not stated, but the selection criteria
pocket depths between 4 and 7 mm.
(4-7 mm pockets) and the
Exclusion criteria were a history of any systemic diseases that
attachment level at the start (about
could affect the periodontal therapy outcome (e.g., diabetes
4.7 mm) would indicate moderate
mellitus, cancer, metabolic or endocrine diseases), smoking,
chronic periodontitis as the most
dental treatment in the past 6 months, antibiotic medication during
likely diagnosis
the 6 months preceding the study, and related teeth with
restoration.
Test subject
age (mean,
median, range
as described)
42.13±9.05
Control subject
age (mean,
median, range
as described)
40.83±7.64
Control
SRP
Control
Full-mouth subgingival scaling and
root planing under local anesthesia
was performed in a single
appointment for each patient in all
groups using an ultrasonic
scaler and hand instruments.
Test (typically
adjunct)
SRP followed by
diode laser
In order to control for the same
conditions, pockets were also rinsed
with saline after SRP in the control
group.
SRP
one week later, SRP treatment alone.
The entire quadrant was treated
according to the procedure,
but only one incisor or canine was
sampled.
Was standard
Trial design
counseling
study
control treatment?
/ cross over)
Laser treatment was performed by using a
940 nm indium–gallium–
All patients received oral
aluminum–phosphate diode laser (Ezlase,
hygiene instructions and
Biolase, USA). The periodontal pocket
supragingival
was set at 1.5 W with a pulse interval of
scaling in a single
20 ms and pulse length of 20 ms
appointment 1 week apart
delivering 20 s/ cm2 and 15 J/cm2 of
before treatment.
energy. Irradiation was accomplished with
a 300 μm fiber optic delivery system.
Parallel
6 months
No adverse effects, such as discomfort,
burning sensation, dentin hypersensitivity, or pain
related to the laser irradiation were reported by any
of the subjects.
Both patients and the operator wore protective
glasses during laser application.
One week after subgingival scaling; SRP
and laser treatment;
subgingival scaling with a combined
use of hand (Hu-Friedy, Chicago, IL)
and ultrasonic instruments
40.23 +/– 10.18.
after
SRP+diode laser
All patients received initial
periodontal therapy
810 nm diode laser (Fotona XD-2, Fotona
consisting of thorough
d.d., Slovenia). Laser parameters were
oral hygiene instructions
Ppeak = 2.5 W, duty cycle ½, Pavg =
and full-mouth
1.25W, 20Hz and 80 sec/tooth (mesialy,
supragingival
distally, lingually and buccally; 20
scaling
sec/site). Laser was applied before root
planing
Healing was uneventful in all cases. No adverse
effects related to the laser irradiation were reported.
split mouth
6 months
During the laser treatment, protective eyeglasses
were used by patient and operator.
Page 166
Nonsurgical use of lasers: non-PDT laser + SRP - Outcomes data
Citation:
Author, Year
Time
Other time
period for
No. Sites treated
periods for
data
per mouth / No.
Outcome measure
which data
presented
sites averaged
are
in this
per tooth
available
abstraction
6 months
6 weeks
One pair of
contralateral
single-rooted teeth
was chosen from each
subject; 6 sites per
tooth measured and
"deepest site of each
experimental tooth as
defined as the
experimental site"
6 months
CAL only
recorded at
baseline and
6 months
Recorded data with
customized stent at
interproximal sites
only. Had 38 teeth
involved as 19 pairs.
CAL
Alves 2012
Caruso 2008
Not stat sig between
groups; 1.0 mm
difference
CAL (referring to the
enamel-cementum
junction) /
Williams probe
Test
Test SD
Test sample
Test
sample Test mean at
or SE (list
size
mean
value)
Baseline
Baseline
of test
period
Baseline
period
Test
SD or
Mean gain
Control
SE (list
Mean SD
TEST
sample
value) SD or SE?
(or SE)
(Baselinesize
at end
gain, TEST
final)
Baseline
of test
period
37 people
6.91
1.94
36 people
5.33
2.13
SD
13 patients with
19 sites
7.123
0.9
13 patients
5.089
0.8
SD
1.7
1.72
Control
mean
Baseline
Control
Control
Control SD or
Control SD or SE
sample
mean at end SE (list value)
(list value)
size at end
of test
at end of test
Baseline
on test
period
period
period
SD or SE?
37 people
6.5
1.74
36 people
4.61
1.88
SD
13 patients
6.912
1
13 patients
5.123
0.9
SD
Mean gain
Mean SD (or
CONTROL
SE) gain,
(baselineCONTROL
final)
2.1
1.64
Caries
data
N/A
power calculation to determine 1.0
difference in CAL; ANOVA to
determine differences between
averages of groups and time periods;
Newman Keuls test for multiple
comparisons
Wilcoxon signed-rank test for paired
samples. No statistical data given for
P- values, only shown for probing
depth not CAL.
Citation:
Author, Year
Outcome measure
Whole mouth CAL, mm
Time period for
No. Sites treated
data presented in
per mouth / No.
sites averaged per
close to 9 months
tooth
as possible)
6 months
Saglam, 2014
The maxillary anterior
region (maxillary
incisors, canine, and
premolar teeth) was
used as the test site
for the evaluation of
site-specific clinical
parameters
The entire quadrant
was treated according
to the procedure,
but only one incisor or
canine was sampled
Site specific CAL, mm
Ustun, 2014
July 2015
CAL, mm
Clinical
parameters were
performed at six sites
per tooth
(mesiobuccal,
mid-buccal, distobuccal, mesio-palatal,
mid-palatal,
and disto-palatal).
6 months
CAL measurements
were recorded at six
points (mesio-buccal,
mid-buccal,
disto-buccal, mesiolingual, mid-lingual,
and disto-lingual)
around each tooth with
a manual periodontal
probe
Test sample
size
Baseline
Test mean
Baseline
Test
Test SD or
Mean
Mean SD
Test SD or SE
sample
Test mean at
SE (list
difference
(or SE)
(list value)
value) at SD or SE?
Baseline
of test
period
end of test
baseline)
TEST
period
period
Control
sample
size
Baseline
Control
mean
Baseline
Control SD or SE
(list value)
Baseline
Control
Control SD
Control
sample
or SE (list
mean at end
size at end
value) at SD or SE?
of test
on test
end of test
period
period
period
Mean
difference
CONTROL
(finalbaseline)
Mean SD (or
SE)
Caries data
difference,
CONTROL
CAL difference in the
change between methods of 1 mm
15
2.7
±0.4
15
1.7
±0.2
SD
Not reported
Not reported
15
2.8
±0.6
15
1.9
±0.4
SD
Not reported
Normality tests performed and
statistical analyses adjusted based on
the results
Not reported
No caries
data
15
5.3
±0.6
15
1.9
±0.4
SD
Not reported
Not reported
15
5.2
±1.1
15
2.5
±0.9
SD
Not reported
Not reported
21
4.68
0.75
19
3.01
0.67
SD
Not reported
Not reported
21
4.75
0.78
19
3.46
0.71
SD
Not reported
Not reported
No stat sig differences between
groups
Power based on 1 mm difference in
PPD
Not reported
Stat sig difference at end between
groups
Page 167
Nonsurgical use of lasers: non-PDT laser + SRP - Review authors’ judgment of each risk of bias item as low, unclear, or high for each included study
Domain:
Selection bias
Random sequence
generation
Performance bias
Were the groups
treated the same
except for the
intervention?
Citation:
Author, Year
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Alves 2012
Coin toss after
initial tx
Low
2nd examiner
did coin toss
Low
"Double blinded"
with sham
Low
Examiner was not
aware of tx; 2nd
examiner did coin
toss
Low
Caruso 2008
Coin toss
Low
No details given
Unclear
Not described
Unclear
Not described
Unclear
Detection bias
Attrition bias
Reporting bias
Masking of outcomes
assessment
follow-up)
>20% high
Selective reporting
Support
Review
Support for
for
author's
judgment
judgment judgment
Initial tx
same for all
teeth; study
Blinded
Low
SRP same
examiner
for both
teeth
Yes
Low
Not
described
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review author's
judgment
Low
1 subj excluded for
missing appt
Low
All data reported
Low
Unclear
not reported
Unclear
Stat sig not
reported. No p
values reported for
CAL table
Unclear
Selection bias
Domain:
Random sequence
generation
Performance bias
Allocation concealment Masking of participants Masking of personnel
Review
author's
judgment
Support for
judgment
Saglam, 2014
Methods not
described
Unclear
Patients did not
know which
group they
were
assigned to
until
interventions
were
performed
Unclear
Not masked
High
Ustun, 2014
coin toss
Low
Not described
Unclear
Not masked
High
Citation:
Author, Year
July 2015
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Were the groups
treated the same
except for the
intervention?
Review
author's
judgment
Support for
judgment
Not masked
Not masked
Support for
judgment
Detection bias
Attrition bias
Reporting bias
Masking of outcomes
assessment
Incomplete outcome
lost to follow-up)
≤10% low; 11-20%
unclear; >20% high
Selective reporting
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
High
No differences
noted
High
No differences
noted
Review
author's
judgment
Support
for
judgment
Review
author's
judgment
Low
Statistician
masked
Low
All subjects
completed the
entire study
Low
CAL
primary
outcome
and results
reported
Low
Low
Masked
Low
2/21 lost; 10%
Low
None noted
Low
Page 168
Nonsurgical use of lasers: Nd:YAG laser + SRP - Study characteristics
Citation:
Author, Year
Country
Eltas 2012
Turkey
Special population?
patients and teeth
No periodontal therapy in past
Moderate chronic periodontitis with
12 months, no systemic
at least two qaudrants of ≥ 3 teeth
diseases, no antiobiotics in
with 4 - 6 mm pocketing and
past 6 months, no pregnancy,
radiographic bone loss.
no restored teeth
age (mean,
age (mean,
Control
Control
Test (typically
adjunct)
median age of 46.1±8.3 years
SRP
full mouth / supra and subgingival
with combined use of hand and
ultrasonic instruments in 1 session
under local anesthesia
SRP+Nd:YAG
laser (NDL)
Subsequent to SRP / 1.0 W NDLlllll (wavelength 1064 nm,
100 mJ, 10 Hz) / optic fiber 200 micron diameter / fiber tip
inserted bottom of perio pocket and slowly moved from apical
to coronal in sweeping motion / 120 s exposition time
Was standard
Trial design
counseling
study
control treatment?
cross over)
OHI
Split mouth
9 months
Not reported
6 months
None reported; minimal post-op pain reported
Split mouth
No
Neill 1997
U.S.
probing depths > 4 mm with
radiographic bone loss
moderate to severe adult
periodontitis (PD 4mm or greater)
average age of 44 years (range 3353)
SRP
Mechanical SRP was used to
remove calculus and other deposits
from the root surfaces to achieve the
SRP+low powered Sulcular debridement using energy/pulse of 80 mJ, repetition
endoint of a smoot, glass-like root
pulsed Nd:YAG
rate of 25 Hz and average power of 2.0 W, average time of 2
surface. Ultrasonic instrumentation
laser
min. Depth of pocket influenced time of laser application.
was included where appropriate, and
the site was irrigated with a sterile
saline solution.
quadrants
Yes; but only mentioned
randomly
for no treatment group assigned to one of
(not SRP group or laser three experimental
group); patient plaque
groups: if 4th
control instructions
quadrant had an
elegible site, it
was assigned to
the laser group
Nonsurgical use of lasers: Nd:YAG laser + SRP - Updated literature
Citation:
Author, Year
Eltas, 2012
Country
Special population?
(e.g. smokers) and other data regarding inclusion exclusion criteria for patients and teeth
Turkey
(1) Patients with generalized
moderate CP with the presence of at least 2 teeth
with PD between 4 and 6mm and radiographic signs of bone
loss per quadrants were included.(2) Smokers were
identified as smoking > 10 cigarettes per day for > 5 years,
whereas nonsmokers were identified as never having
smoked. Standard exclusions (tx in prior 12 months;
systemic diseases; systemic or topical antibiotics or
steroidal/nonsteroidal anti-inflammatories within last 6
months; currently pregnant or breastfeeding; teeth with tx
that could affect perio outcomes
moderate
July 2015
Test subject
age (mean,
median, range
as described)
Control subject
age (mean,
median, range
as described)
mean age of 43.5
years old (range: 32–52 years)
Control
Control
Test (typically
adjunct)
after
SRP+ placebo
subgingival SRP with the
combined use of
hand and ultrasonic instruments
under local anesthesia in
the same session.
SRP + Nd:YAG
laser
1.0 W NDL (wavelength
1,064 nm, 100 mJ, 10 Hz), exposure
time of 120 sec
Was standard
Trial design
counseling
study
control treatment?
/ cross over)
initial periodontal
therapy consisting
of thorough oral
hygiene instructions
and full-mouth
supragingival
split mouth for
effect of laser;
parallel group
for effect in
smoking vs non
smoking
Adverse outcomes were not assessed
6 months
protective eyeglasses were worn by the patient,
the operator, and the assistants
Page 169
Nonsurgical use of lasers: Nd:YAG laser + SRP - Outcomes data
Citation:
Author, Year
Eltas 2012
Neill 1997
Outcome measure
Time period Other time
No. Sites treated
for data
periods for
per mouth / No.
presented in which data
sites averaged
this
are
per tooth
abstraction
available
CAL (cementoenamel
junction and deepest
aspect of pocket,)
This study was
performed on 40 teeth
(probing depth
between 4 and 6 mm)
from 20 patients / 6
surfaces per tooth /
one site per person
per test
CAL gain, mm
9 months
baseline, 3
months
6 months
1 week, 1
month, 3
months
10 pts, 186 total teeth:
91 laser, 49 SRP and
46 NT
744 total sites: 364
laser, 196 SRP and
184 NT
Test sample
size
Baseline
Test mean
Baseline
Test
Test SD or
Mean gain
Control
Test SD or SE sample Test mean at SE (list
Mean SD
TEST
sample
(list value) size at end end of test value) at SD or SE?
(or SE)
(Baselinesize
Baseline
of test
period
end of test
gain, TEST
final)
Baseline
period
period
20 patients
5.24
1.51
20 patients,
20 teeth
10 people; 91
teeth
Not reported
Not reported
10 people; 91
teeth
2.83
Not reported
1.44
SD
Control
Control
Control SD or SE
sample
mean at end
(list value)
size at end
of test
Baseline
on test
period
period
Control
mean
Baseline
20 patients,
20 teeth
5.13
1.21
20 patients,
20 teeth
4.03
Control SD
Mean gain
or SE (list
Mean SD (or
CONTROL
SE) gain,
value) at SD or SE?
(baselineCONTROL
end of test
final)
period
1.27
SD
NOTE:
different from
figure
1.9
10 people; 49
Not reported
teeth
Not reported
10 people; 49
Not reported
teeth
Kruskal–Wallis and
Mann–Whitney U tests were used to
determine the significance of the
differences between groups, while
Friedman and Wilcoxon tests were
used to determine the significance of
the differences within groups
1.0
1.1
Caries
data
Note:
different from
figure
1.7
Not reported
Comparisons by individual tooth
utilized ANOVA, Kruskal-Wallis
nonparametric ANOVA, and chisquare tests; SD or SE not defined;
figure data different from text data
Citation:
Author, Year
Outcome measure
Time period for
No. Sites treated
data presented in
per mouth / No.
sites averaged per
close to 9 months
tooth
as possible)
SMOKERS
CAL, mm
Eltas, 2012
6 months
NONSMOKERS
CAL, mm
July 2015
208 teeth (with PD
between
4 and 6mm) from 52
patients with CP (26
smokers/26
nonsmokers). Two
test teeth and two
control teeth were
randomly selected
from each patient
(one tooth from each
quadrant). CAL at 6
surfaces per tooth.
Test sample
size
Baseline
Test mean
Baseline
52 teeth (26
people)
smokers
6.7
Test
Test SD or
Mean
Mean SD
Test SD or SE
sample
Test mean at
SE (list
difference
(or SE)
(list value)
value) at SD or SE?
Baseline
of test
period
end of test
baseline)
TEST
period
period
1.1
52 teeth (26
people)
smokers
6.4
1.1
SD
Control
sample
size
Baseline
Control
mean
Baseline
Control SD or SE
(list value)
Baseline
52 teeth (26
people)
smokers
6.6
1.2
Control
Control SD
Control
sample
or SE (list
mean at end
size at end
value) at SD or SE?
of test
on test
end of test
period
period
period
52 teeth (26
people)
smokers
6.5
1.1
6.1
1.1
52 teeth (26
people)
nonsmokers
5.6
1
SD
Mean SD (or
SE)
Caries data
difference,
CONTROL
SD
Not reported
52 teeth (26
people)
nonsmokers
Mean
difference
CONTROL
(finalbaseline)
Not reported
52 teeth (26
people)
nonsmokers
6.1
0.9
52 teeth (26
people)
nonsmokers
5.8
1
No caries
data
Only
the changes in CAL for all groups
proved to not be statistically
significant at R1 and at R2 ( p >
0.05); no statistically
significant changes between R1
and R2 were revealed by the
intragroup analysis in all clinical
parameters and GCF volume
for all groups ( p > 0.05).
SD
Page 170
Nonsurgical use of lasers: Nd:YAG laser + SRP - Review authors’ judgment of each risk of bias item as low, unclear, or high for each included study
Domain:
Selection bias
Random sequence
Performance bias
Were the groups
Citation:
Author, Year
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support
for
judgment
Eltas 2012
randomization
claimed, but
method not
described
Unclear
No details given
Unclear
Not masked
High
Not masked
High
Yes
Low
Neill 1997
States random
assignment but
does not specify
how
Unclear
OHI stated
as given to
control but
not
mentioned if
given to
other
groups
Unclear
Unclear
No details given
Unclear
No details given but
"double blind"
Unclear
No details given
but "double blind"
Detection bias
Attrition bias
Reporting bias
Masking of outcomes
Selective reporting
Review
Support for
author's
judgment
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review author's
judgment
Not involved
in tx
Low
No patients lost
Low
No bias detected
Low
No details
given but
"double
blind"
Unclear
No loss to follow
up; data details
sparse
Unclear
All data reported
Low risk
Selection bias
Domain:
Random sequence
generation
Performance bias
Masking of participants Masking of personnel
Citation:
Author, Year
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Eltas, 2012
coin toss
Low
Not described
Unclear
Placebo
laser
July 2015
Review
Review
Support for
author's
author's
judgment
judgment
judgment
Low
Not
described
Unclear
Were the groups
treated the same
except for the
intervention?
Detection bias
Attrition bias
Reporting bias
Masking of outcomes
assessment
Incomplete outcome
lost to follow-up)
?10% low; 11-20%
unclear; >20% high
Selective reporting
Review
Review
Support for
author's
author's
judgment
judgment
judgment
Examiner
No differences
not involved
Low
Low
noted
in providing
tx
Support for
judgment
Support for
judgment
Review
author's
judgment
Support
for
judgment
Review
author's
judgment
No losses
Low
None noted
Low
Page 171
Nonsurgical use of lasers: erbium laser + SRP - Study characteristics
Citation:
Author, Year
Kelbauskiene
2011
Country
Special population?
patients and teeth
Lithuania
Non-smokers only
Early to moderate periodontitis
Teeth exhibiting BOP,
SRP with supragingival tooth
subgingival calculus and PD of Single-rooted teeth (lower or upper
Range 26 to 58 yrs Range 26 to 58 yrs cleaning 2 weeks prior and at 3
3-6mm on at least 1 site/tooth; incisors and canines, upper secon
and 6 months
single rooted teeth only. No premolars, lower first and second
systemic antibiotics fopr prior
premolars)
6 months
age (mean,
age (mean,
Control
Control
Test (typically
adjunct)
Was standard
Trial design
counseling
study
control treatment?
cross over)
ultrasonic scaler and hand
intstrumentation
9 mm Z6 tip 600 μm is set at 1 W, 10% air, 115% water is
Er,Cr:YSGG laser used to remove junctional, sulcular and gingival epi 5mm from
All subjects received OHI
2,790 nm
margin; Laser tip angled 5-15 degrees toward root & moved
and supragingival
up a down until root appears etched. Procedure repeated
cleaning 2 wks prior to tx
plus SRP
1X/wk for each mm of pocket reduction required to achieve 3
mm depth
Gracey curettes with local
anesthesia until clean
Er:YAG laser 2.94 μm, 250-500 μs exposure duration, 10Hz
SRP+erbiumrepetition rate and a 1.1 X 0.5 mm tip: energy 100 mJ/pulse
doped: yttrium,
with transmitted energy of 71 mJ/pulse at the tip; fluency of
aluminum,andgarn
12.9 J/cm2/pulse. Coolant water used and tip moved
et (Er:YAG) laser
apicocoronally at 30 degrees to the root. For the LA group
irradiation
irradiation was 180-240 seconds; for L+SRP 30 seconds/site
after SRP
Split mouth, 4
quads, one side
SRP, other side
SRP + laser
12 months
Not reported
12 months
Not reported
6 months
5 perio abscesses reported, 3 in the prophy group
and 2 in the laser + SRP group; 1 pt reported fever
during the 1st week post-tx
Non smokers
Lopes 2010
Brazil
Rotundo 2010
Italy
sites with bleeding on probing
(BOP) and probing depth (PD)
from 5 to 9 mm were selected;
no perio tx within previous 12
months; no systemic disease;
no antibiotics prior 6 months;
no anitinflammatories prior 3
months; not pregnant
periodontitis
43 yrs (range 3155)
43 yrs (range 3155)
periodontitis
50.5 ± 11.7 years
50.5 ± 11.7 years
SRP
OHI for 15-30 days and
Split mouth, 1 site
professional prophylaxis
per quad
6 months pre-tx
12 of 27 smokers
July 2015
2 teeth per quad with PD 4-9
mm with BOP; presence of at
least one incisor, premolar and
molar per quad
Supragingival prophy
SRP
SRP with racey curettes and
ultrasonic with local anesthesia PRN
Laser + SRP
Er:YAG laser 2.94 µm wavelength, energy level 150 mJ/pulse,
repetition rate 10 Hz, fiber tip 0.5 mm and 10 mm length,
coronal apical application at 20˚ inclination
OHI
Split mouth with
quadrants
randomly
allocated to 2
controls and 2
treatments
Page 172
Nonsurgical use of lasers: erbium laser + SRP - Outcomes data
Citation:
Author, Year
Outcome measure
Kelbauskiene
2011
CAL in the sites with
baseline PD 3–6 mm;
site averages given (n is
listed by site)
Time period
Other time
No. Sites treated
for data
periods for
per mouth / No.
presented in
which data are sites averaged
this
available
per tooth
abstraction
Test sample
size
Baseline
Test mean
Baseline
Test
Test SD or SE
Test SD or SE sample Test mean at
(list value) at
(list value) size at end end of test
end of test
Baseline
of test
period
period
period
SD or SE?
Mean gain
Control
Mean SD
TEST
sample
(or SE)
(Baselinesize
gain, TEST
final)
Baseline
Control
mean
Baseline
Control
Control
Control SD or
Control SD or SE
sample
mean at end SE (list value)
(list value)
size at end
of test
at end of test
Baseline
on test
period
period
period
SD or SE?
Mean gain
Mean SD (or
CONTROL
SE) gain,
(baselineCONTROL
final)
Caries
data
NR
Power analysis performed; Student's ttest, Kolmogorov-Smirnov test, MannWhainey U test; paired t-test for
continuous data and Wilcoxon's test
for ordinal data
30 pts
Lopes 2010
CAL (computerized
probe)
12 months
12 months
2,3,6 and 12
months
1, 3, 6 and 12
months
278 single rooted
teeth; 9.3 teeth/pt;
1668 sites or 55.6
sites/pt
21 patients with four
non-adjacent sites in
different quadrants
with bleeding on
probing (BOP) and
probing depth (PD)
from 5 to 9 mm were
selected
30 pts
135 teeth; 858
sites
21
30 pts
4.47
6.71
1.2
1.4
509 sites > 3
mm analyzed
19 patients;
76 sites in 76
teeth (n =
19 patients),
42 were at
teeth with
one or two
roots and
34 were at
multirooted
teeth
2.8
1.27
SD
1.68
1.36
143 teeth or
8.4 teeth/pt
4.23
0.92
30 patients;
579 sites
1.3
19 patients;
76 sites in 76
teeth (n =
19 patients),
42 were at
teeth with
one or two
roots and
34 were at
multirooted
teeth
3.4
1.19
SD
810 sites or
50.6/pt
5.56
1.4
SD
21
7.2
5.79
1.3
SD
0.84
1.09
Power calculation 95% with 19 pts
based on CAL diff 1 mm; CAL values
were normally distributed and
analyzed using the analysis of
variance for repeated measurements
(ANOVA) test.
The multiple comparison TukeyKramer test was used for comparison
of PD and CAL variables among
groups and periods when ANOVA
test presented a
significant difference (P <0.05)
1-mm clinical significant difference
between groups, and a mean ± SD of
0.6 mm with the values of clinical
attachment level (CAL).
operator training; examiner calibration
for intra examiner reliability Site =
unit of analysis, ReML method for
fitting mixed model, full factorial for
Er:YAG laser and SRP, post-hoc
Tukey-Kramer honestly significant
difference test
Rotundo 2010
July 2015
CAL
6 months
27 pts, all teeth with
1 week, 3 and 6
at least 1 site with PD
months
≥ 4 mm; 6 sites/tooth
27 pts, 1671
sites ≥ 4 mm
26 pts, 1582
sites ≥ 4 mm
L+SRP: 5.7
Laser + SRP
grp 419 sites
L+SRP: 1.5
Laser + SRP
grp 405 sites
L+SRP: 5.2
L+SRP: 1.8
27 pts, 1671
Not reported
sites ≥ 4 mm
(based on
value,
SRP grp 422
assumed SD)
sites
26 pts, 1582
sites ≥ 4 mm
SRP: 6.1
SRP: 1.6
SRP grp 399
sites
SRP: 5.6
SRP: 2.0
The statistical analysis was intention
to treat. In particular, if a patient
showed up at the 3-month recall visit
and not at the 6-month re-evaluation,
Not reported
the clinical data were imputed to the
(based on
6-month analysis
value,
assumed SD)
The sample size was calculated
using
a=0.05 and the power (1- b)=80%.
For the variability (s=SD), the value of
0.6mm (Sculean et al. 2004) was
used
considering clinical attachment level
(CAL) gain as a variable outcome.
The
minimum clinically significant value
(d)
considered was 0.5mm
Page 173
Nonsurgical use of lasers: erbium laser + SRP - Review authors’ judgment of each risk of bias item as low, unclear, or high for each included study
Domain:
Selection bias
Random sequence
Performance bias
Were the groups
Citation:
Author, Year
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support
for
judgment
Kelbauskiene
2011
Cards pulled from
envelope
Low
No details given
Unclear
Not masked
High
Not masked
High
Yes
Lopes 2010
Computer
generated tables
Low
No details given
Unclear
Not masked
High
SRP clinician
masked but laser
person not
High
Rotundo 2011
Random
assignement by
quad, opaque
sealed envelope
sequentially
number, computer
generated random
permuted block
Low
Envelope not
opened utnil
phase II tx
Low
No
Unclear
No details
Unclear
July 2015
Detection bias
Attrition bias
Reporting bias
Masking of outcomes
Selective reporting
Review
Support for
author's
judgment
judgment
Review
author's
judgment
Support for
judgment
Review
author's
judgment
Support for
judgment
Review author's
judgment
Low
No patients lost but
some teeth
surfaces lost that
are unexplained
Unclear
Data from sites > 3
mm reported
Low
Low
Only 1 site per
tooth measured
and reported; this
was the planned
approach
Low
Low
All data reported
Low
Low
Examiner
kept blinded
Yes
Low
Examiner
did not know
where laser
treatment
was used
Low
19/21 finished
although only out to
3 months for PICO
question 1
Yes
Low
Examiner
was always
blinded as to
treatment
Low
24/26 completed to
6 months; 1 lost; 1
ITT only 3 month
data
Page 174
Appendix 4 – Details on data analysis calculations
Combining results stratified by pocket depth
If the data were only presented stratified by pocket depth, the data were combined by averaging
the means, and for the standard deviation as follows:
(∑𝑛 𝑆𝐷𝑖2 )
𝑆𝐷𝑐𝑜𝑚𝑏𝑖𝑛𝑒𝑑 = √ 𝑖=1
𝑛
Data adjustments for meta-analysis calculations
The equations used to compute the standard deviation (SD) and standard error (SE) between
the treatment and control arms of individual trials are described below and differ by trial design
(split-mouth versus parallel-group) and the type of data that were reported (baseline and followup data versus change scores). Correlation coefficients (designated as ) are required for the
computations. These correlation coefficients refer to the correlation of results within the
individual (for split-mouth trials) or over time (for baseline/follow-up trial reporting).
(1) For split-mouth trials where the change score over time is given for both the treatment
and control, the SD of the difference between treatment and control (effect) is calculated
as:
[SD( Difference )]2  sd12  sd22  2 sd1sd2
And then the standard error is calculated as:
SE (mean difference ) 
SD(difference )
n
The initial value of  is set at 0.2560. Then, for sensitivity analysis,  is changed to
either -0.1 or 0.9, SDs and SEs recalculated for each trial, and a new meta-analysis
performed to calculate the resulting overall summary estimate at different values of .
(2) For split-mouth trials where the change score is not provided, the final values are used for
treatment and control, and the protocol per (1) is conducted. There is a reference in the
Cochrane Handbook that states this approach is statistically valid.
July 2015
Page 175
(3) For parallel-group trials where no change score is provided, a process similar to (1) is used;
however, the  in this case represents the correlation with respect to time and sdBL and
sdFINAL represents the baseline and final SDs for treatment and control:
𝑆𝐷𝑡𝑥 = √𝑠𝑑2𝑡𝑥,𝐵𝐿 + 𝑠𝑑2𝑡𝑥,𝐹𝑖𝑛𝑎𝑙 − 2𝜌𝑠𝑑𝑡𝑥,𝐵𝐿 𝑠𝑑𝑡𝑥,𝐹𝑖𝑛𝑎𝑙
𝑆𝐷𝑐 = √𝑠𝑑2𝑐,𝐵𝐿 + 𝑠𝑑2𝑐,𝐹𝑖𝑛𝑎𝑙 − 2𝜌𝑠𝑑𝑐,𝐵𝐿 𝑠𝑑𝑐,𝐹𝑖𝑛𝑎𝑙
Similar to split-mouth trials, the initial  is set at 0.25, and then for the sensitivity analyses it
is varied to -0.1 and 0.9.
The equation for SE of the treatment vs. control difference (treatment effect) in this case is:
2
𝑆𝐸(𝑀𝑒𝑎𝑛 𝐷𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒) = √𝑆𝐷𝑡𝑥
/𝑛𝑡𝑥 + 𝑆𝐷𝑐2 /𝑛𝑐
And the sensitivity analyses are conducted using the previously calculated SDs.
(4) For parallel-group trials where the change score is provided, then no correlation
coefficients are needed (and no adjustments for sensitivity analysis) and only the
SE(Mean Difference) needs to be calculated per (3):
2
𝑆𝐸(𝑀𝑒𝑎𝑛 𝐷𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒) = √𝑆𝐷𝑡𝑥
/𝑛𝑡𝑥 + 𝑆𝐷𝑐2 /𝑛𝑐
The standard generic inverse-variance methods are then used to calculate the pooled effect
estimate.
July 2015
Page 176
Specific methods for standard error imputation when data not provided
SRP section
Kahl study:
Pg. 320 states, ‘Initial shallow pockets (<0.3mm), no changes in PD and AL were found; these
results are therefore not shown.’ From Fig. 1 we have 6% of values are deep pockets, but only
24% are moderate. The remaining 70% are shallow pockets with no difference between groups
are not reported. However, as the intervention essentially has no effect on healthy sites, 6%
deep sites and 24% moderate sites can be assumed to represent all sites. Therefore, there is a
1/4 ratio of deep to moderate sites leading to 25% deep and 75% moderate sites. It is reported
in the paper and from Fig. 5 and 6 that there is a 0.6mm CAL gain in moderate sites and a
0.9mm CAL gain in deep sites.
Therefore, MD of 0.25 (0.9) + 0.75 (0.6) = 0.675 mm.
Note, that if the shallow sites were counted as representing 70% of the sites, the MD would drop
down to 0.20mm.
The following SD and SE calculations were based on a 25/75 split between deep and shallow
pockets as well.
sd(bl) = 0.75 (1.5) + 0.25 (1.4) = 1.475
sd(final) = 0.75 (1.5) + 0.25 (1.2) = 1.425
SD(diff) = sqrt 1.482 + 1.432 - 2 (0.25)(1.48)(1.43)
SD(diff) = 1.78
SE = 1.78 / sqrt(20)
SE = 0.39
if correlation coefficient is ignored, then the SE jumps slightly to 0.46;
if correlation coefficient is -0.1 then SE = 0.48;
if correlation coefficient is 0.9 then SE = 0.15;
2. Lindhe study: using Kahl data:
SE = 1.78 / sqrt(7)
SE = 0.67 for correlation coefficient of 0.25
SE = 0.82 for correlation coefficient of -0.1
3. Berglundh study (note also in systemic antimicrobials section): using Kahl data:
SE = 1.78 / sqrt (8)
July 2015
Page 177
SE = 0.76 for correlation coefficient of -0.1
4.
Ng study (note: in both SRP and systemic antimicrobials section):
SD = 0.83
SE = 0.29 for correlation coefficient 0.25
SE = 0.35 for correlation coefficient -0.1
Lasers – PDT section
Gianelli study: SE= 0.2 for mean difference at one year follow-up with no correlation coefficient
adjustments.
Systemic Antimicrobial section
1. Mombelli study: Used data from Table 2 rather than Figure 2, and went under assumption
that SD, rather than SE were given. This does not coincide perfectly with Table 1 baseline
data, but it’s the best data provided in the study; thus:
SD (tx) = sqrt 2.72 + 2.42 - 2(0.25)(2.7)(2.4)
SD (tx) = sqrt 7.29 + 5.76 - 3.24
SD (tx) = 3.13
SD (c) = sqrt 2.32 + 1.62 - 2(0.25)(2.3)(1.6)
SD (c) = sqrt 5.29 + 2.56 - 1.84
SD (c) = 2.45
therefore
SE (mean difference) = sqrt 3.132 / 7 + 2.452 / 7
SE (mean difference) = sqrt 1.40 + 0.86
SE (mean difference) for correlation coefficient 0.25 = 1.50
SE (mean difference) for correlation coefficient -0.10 = 1.70
SE (mean difference) for correlation coefficient 0.90 = 0.61
July 2015
Page 178
MD = 1.8 from this method.
2.
Ng study:
Impute data as we have no SD change scores.
SD = 0.83
SE = 0.35 for correlation coefficient -0.1
3. Pradeep Study: Use 9-month data even though SRP repeated at 6 months: MD = 1.07.
4. Berglundh study (note also in SRP section): using Kahl data:
SE = 1.78 / sqrt (8)
SE = 0.63 for correlation cofficient of 0.25
SE = 0.76 for correlation cofficient of -0.1
5. Lindhe study (note also in SRP section): using Kahl data:
SE = 1.78 / sqrt(7)
SE = 0.82 for correlation cofficient of -0.1
July 2015
Page 179

Full Report - Evidence-based Dentistry

Transcription

Similar documents

Embossing 173

57403 Sandy Koufax 1st Pitch Framed

Sports Concessions Adult Beverage Products - Whirley

2014 - SRP Federal Credit Union

Welcome to Shiny

INTRODUCING

Treating the Infected Periodontal Foundation

loudmouth cart bags

Sell Sheet - Zeitgeist Films

SRP Recognizes 100,000th Member