Professional Documents
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6 December 2012
Objective. Controversy exists about the efficacy of antibiotic prophylaxis in preventing complications after lower third molar
surgery. For evidence-based recommendation, a review was performed on clinical trials reporting the use of antibiotic
prophylaxis compared with no treatment or placebo with “infection” as outcome.
Study Design. Useful studies were identified using Embase, Cochrane, and Ovid Medline (1966-January 2011) and references
in retrieved reports and review articles. Twenty-three eligible studies were identified and reviewed by independent
investigators using 2 quality assessment scales.
Results. The review procedure revealed 15 “low-quality” and 8 “high-quality” articles, with major differences in treatment
modalities and heterogeneity of design.
Conclusions. There is limited evidence supporting the efficacy of commonly used antibiotics in preventing complications after
lower third molar removal. Well designed and well reported high-quality randomized trials considering known risk factors
and taking clinical outcomes into account are needed to reach final consensus on the efficacy of antibiotic prophylaxis to
allow evidence-based recommendations. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e5-e12)
The removal of impacted lower third molars is a com- Ren et al.14 conducted a thorough meta-analysis of
mon procedure in oral and maxillofacial surgery. In randomized controlled clinical trials (RCTs) of the ef-
the literature, many complications associated with fectiveness of antibiotic prophylaxis in third molar sur-
lower third molar removal are described, e.g., pain, gery.14 They concluded that systemic antibiotic prophy-
swelling, trismus, infection, inflammation, and nerve laxis given before surgery is effective in reducing the
damage. One of the more common complications is frequencies of alveolar osteitis and wound infection.
alveolar osteitis (i.e., alveolitis sicca dolorosa, dry According to Song et al.,21 significant results are
socket, or localized osteitis), with rates ranging from more likely to get published than nonsignificant find-
0 to 68%.1,2 ings, which can distort the findings of meta-analysis.
There is controversy about the use of antibiotics as The need to assess quality stems mainly from a desire
prophylaxis to prevent complications after lower third to estimate the effects of bias on the results of an RCT.
molar removal. Several authors claim that prophylactic Meta-analysts need to take this into account.22 In the
antibiotics are useful in preventing postoperative com- study by Ren et al.,14 no extensive criteria list for
plications and infections after third molar removal.3-14 judging the methodologic quality was used; however, a
Decreased pain, swelling, and trismus also are re- classification was made into 3 quality categories based
ported.5,6,10,12 Quality of life is stated to be higher on the rigor of the study design. Analysis was made
when antibiotics are prescribed.13 On the other hand, showing differences between the various quality cate-
additional studies were not able to demonstrate the gories in effect size and variation of treatment effect.
effectiveness of antibiotic prophylaxis.15,16 Although Ren et al.14 demonstrated the effectiveness
Antibiotic prophylaxis for preventing postoperative of antibiotic prophylaxis, there is still no consensus on
wound infections accounts for ⬎30% of antibiotic pre- the use of antibiotics as prophylaxis in surgical removal
scriptions in general hospitals.17 Excessive and inap- of lower third molars.
propriate use of antibiotics can lead to bacterial resis- The objective of the present study was to provide an
tance and increase the economic burden of health evidence-based recommendation on the efficacy of an-
care.18 Other risks of indiscriminate antibiotic therapy tibiotics in preventing infectious complications after
include the development of secondary infection, aller- third molar surgery by reviewing eligible randomized
gic reactions, and toxicity of the antibiotic.19,20 controlled trials on lower third molar removal.
Department of Oral and Maxillofacial Surgery/Oral Pathology, Vrije Statement of Clinical Relevance
Universiteit Medical Center/Academic Center for Dentistry Amster-
dam, Amsterdam, The Netherlands. Prescription of antibiotics in third molar surgery, a
Received for publication Jun 10, 2011; returned for revision Oct 4,
frequent procedure, is an important topic. In search-
2011; accepted for publication Oct 13, 2011.
© 2012 Elsevier Inc. All rights reserved. ing the evidence, it can be questioned if this com-
2212-4403/$ - see front matter mon practice should still be recommended.
doi:10.1016/j.oooo.2011.10.023
e5
ORAL AND MAXILLOFACIAL SURGERY OOOO
e6 Oomens and Forouzanfar December 2012
MATERIALS AND METHODS erarchic list in which higher scores indicate studies with
Literature search a higher methodologic quality.
A computer-assisted search of the Embase, Cochrane,
and Ovid Medline databases from 1966 through Janu- Statistics
ary 2011 was conducted using the key words “wisdom Agreement regarding the required minimum score for
tooth,” “third molar,” “alveolitis,” “dry socket,” and methodological quality was reached in a consensus
“alveolar osteitis” in combination with “anti* agents.” meeting.
A search with the combination of the Medical Subject A score of 3 for the Jadad Scale and a score of 5 for
Headings Terms (MeSH) “Molar, Third” and “Antibac- the Delphi List was chosen as a cutoff point for meth-
terial Agents” or “Antibiotic Prophylaxis” was also odologic quality. These scores were combined, which
conducted. All reference lists in the obtained literature means that only studies with a Jadad score of 4-5 and a
were checked for additional relevant articles. The Co- Delphi score of 6-9 were assessed to be of “high qual-
chrane highly sensitive search strategy for identifying ity.” Studies with a Jadad score of 0-3 or a Delphi score
randomized trials was applied to restrict studies to 0-5 were considered to be of “low quality.” Only stud-
clinical trials in Medline, and a language restriction for ies considered to be high quality were described exten-
“English” was imposed. sively. However, in the synthesis of results, all studies,
including those of “low quality,” were reflected on.
Type of study and participants
RCTs were included that compared antibiotic prophy- RESULTS
laxis with placebo treatment or no treatment in prevent-
ing infection or inflammation in patients undergoing Literature searches
surgical removal of the lower third molar. Only studies As shown in Figure 1, the search resulted in 117 titles
written in English were included. as potentially relevant studies. After reviewing the ab-
stracts, 32 articles involving orally or intravenous ad-
Type of interventions ministered antibiotics were identified. Four more po-
Studies making a comparison between antibiotic pro- tentially relevant studies were identified from the
phylaxis and a placebo or no treatment were included. references. By evaluating full article content, with in-
Antibiotics were considered if used as prophylaxis, formation provided by correspondence with authors
independently from concentration, frequency of use, when needed, these remaining 36 citations were limited
duration, and technique of administration. to 23 (see Table II for reasons for exclusion of stud-
ies13,26-37). Methodologic assessment of the 23 eligible
Type of outcome publications revealed 8 methodologically “high-qual-
Trials describing infections, wound infections, inflam- ity” articles, and 15 “low-quality” studies. A list of the
mations, dry sockets, alveolitis, or alveolar osteitis quality scores is presented in Table III. Eleven clinical
were considered as eligible studies. RCTs scored ⬎3 on the Jadad Scale and 10 trials scored
⬎5 on the Delphi List. A total of 8 studies scored above
the cutoff points both for the Jadad Scale and the
Quality assessment of studies
Delphi List and were therefore considered to be “high-
An RCT is mostly assessed on internal validity, exter-
quality” studies. The mean Jadad quality score was 3.00
nal validity, and statistical analysis.23 In the literature,
points (range 1-5 points), and mean Delphi score was
there are several criteria lists measuring the methodo-
4.78 points (range 0-9 points). The investigators man-
logic quality of randomized controlled trials. Olivo et
aged to resolve disagreements by consensus and a third
al.24 showed in their systematic review that the Delphi
investigator was never involved.
List and Jadad Scale are the most valid quality assess-
ment scales.23,25 Therefore, in the present study, both
criteria lists were used. Study description
In Table I, both criteria lists are shown. Maximum The 8 high-quality studies were diverse (Table IV) with
scores for the Delphi List and Jadad Scale are 9 and 5, 2 originating from New Zealand38,39 and 1 each from
respectively. Two independent investigators (the au- the USA,40 Poland,41 Spain,10 India,16 Sweden,42 and
thors) scored methodologic quality of the trials. Dis- Denmark.43 All reports were placebo-controlled trials
agreement was resolved by consensus between the 2 and were published from 1987 to 2010. The study
investigators. If no agreement could be reached, a third conducted by Siddiqi et al.38 was the only split-mouth
investigator was consulted. Where needed, authors of trial and the only trial reporting to have been performed
studies were contacted for additional information to without external funding. Halpern et al.40 reported to
resolve ambiguities. Final assessment resulted in a hi- have been externally supported in part. All of the other
OOOO REVIEW ARTICLE
Volume 114, Number 6 Oomens and Forouzanfar e7
high-quality trials did not report any source of fund- was used as intervention in 4 studies.16,39,42,43 Two of
ing.10,16,39,41-43 these studies administered metronidazole in a single
The study conducted by Halpern et al.40 administered dose preoperatively,42,43 1 study administered a preop-
the treatment modalities intravenously, whereas the erative dose and continued postoperatively,39 and 1 trial
other studies used oral administration. Metronidazole compared a single preoperative dose with solely post-
ORAL AND MAXILLOFACIAL SURGERY OOOO
e8 Oomens and Forouzanfar December 2012
Table III. Hierarchic list of the quality score In most studies it was not clear whether the care pro-
Scores of the vider or the observer was blinded, and the blinding was
Jadad Scale Scores of the Delphi List never evaluated. A further methodologic flaw was that
First author A B C Total A B C D E F G H I Total some studies stated to be randomized but cleared no
Maximum 2 2 1 5 1 1 1 1 1 1 1 1 1 9 method of randomization.3-6,8,9,11,12,15,44-46 Almost all
Arteagoitia10 2 2 1 5 1 1 0 1 1 1 1 1 1 8 of these studies show a lack of statistical power, mean-
Halpern28 2 2 1 5 1 1 1 1 1 1 1 1 0 8 ing that the conclusion is not supported by the sample
Barclay27 2 1 1 4 1 1 1 1 1 1 1 1 1 9 size.
Bergdahl30 2 2 1 5 1 1 1 1 0 1 1 1 0 7
Kaczmarzyk29 2 2 0 4 1 1 1 1 1 1 1 1 0 8
In the high-quality trials, randomization was per-
Mitchell7 2 2 1 5 1 1 0 0 0 1 1 1 0 5 formed by a table of random numbers,39,41 sealed en-
Ritzau31 2 2 0 4 1 1 0 0 1 1 1 1 0 6 velopes,16,38,40 or computer-assisted programs.10,43 In
Sekhar16 2 1 1 4 1 1 1 1 1 0 0 1 0 6 all high-quality trials except that of Sekhar et al.,16 the
Siddiqi26 2 2 0 4 1 1 1 0 0 1 1 1 0 6 administered treatment modality and placebo looked
Lacasa11 1 2 1 4 0 0 1 1 0 1 1 1 0 5
Lyall8 1 2 1 4 0 0 1 0 1 1 1 1 0 5
identical for blinding purposes. Two studies did not
Happonen15 1 2 0 3 0 0 1 0 1 1 1 1 1 6 report sufficient information to assess whether the out-
Curran35 2 0 0 2 1 1 1 1 1 0 0 1 0 6 come assessor was blinded.38,42 Some studies reported
Bulut33 1 2 0 3 0 0 1 0 0 1 1 1 0 4 the blinded surgeon to be the outcome assessor as
Poeschl36 2 0 0 2 1 1 1 0 0 1 0 1 0 5 well.39,40 Two of the 8 high-quality studies reported a
Delilbasi9 1 0 0 1 0 0 1 1 0 1 0 1 0 4
Bystedt5 1 1 0 2 0 0 0 0 0 0 1 1 0 2
power analysis.10,43
Bystedt6 1 1 0 2 0 0 0 0 0 0 1 1 0 2
Monaco34 1 0 0 1 0 0 0 1 1 0 0 1 0 3
Synthesis of results
Monaco12 1 0 0 1 0 0 0 0 1 1 0 1 0 3
Krekmanov3 1 0 0 1 0 0 0 0 0 0 0 1 0 1 Low-quality studies. The studies investigating peni-
Krekmanov4 1 0 1 2 0 0 0 0 0 0 0 1 0 1 cillin as antibiotic prophylaxis show contradictory out-
Ataoğlu32 1 0 0 1 0 0 0 0 0 0 0 0 0 0 comes. Two studies classified as low quality15,47 dem-
onstrated no statistically significant differences when
prescribing penicillin compared with no treatment,
operative administration.16 Other investigated antibiot- whereas 3 other low-quality studies3,4,6 reported peni-
ics included: augmentin,10 clindamycin,41 penicillin40 cillin to decrease the incidence of alveolitis more than
and amoxicillin.38 placebo.
In 7 trials, alveolar osteitis (e.g., “dry socket” or There were 3 low-quality trials investigating the ef-
“alveolitis sicca dolorosa”) was recorded when 2 crite- fectiveness of amoxicillin.12,45,46 Two of these studies
ria were present simultaneously: severe pain radiating demonstrated no significant difference between treat-
from the emptied socket and disintegration of the ment and control groups.45,46 The third study showed a
socket coagulum.10,38-43 Complications were recorded significant reduction in incidence of wound infection
by Arteagoitia et al.10 when presenting dry socket as after 6 months’ follow-up.12
described above accompanied by inflammatory signs, Augmentin administered postoperatively proved to
including intraoral erythema, abscess, and body tem- be effective in reducing the incidence of inflammation
perature ⬎37.8°C (measured orally). Halpern et al.40 and infectious complications in 2 low-quality stud-
distinguished between alveolar osteitis and a “surgical ies.9,11 Two other low-quality trials investigating aug-
site infection” as outcome measure. The criteria for mentin found no significant difference between treat-
“surgical site infection” were visual evidence of frank ment and control groups.44,48
purulence in ⱖ1 of the extraction sites and a positive One low-quality study administered a single dose
Gram stain. Sekhar et al.16 also recorded “dry socket” of metronidazole as intervention and failed to dem-
but theirs was the only article that did not describe the onstrate any preventive effect on the development of
criteria used for diagnosing “dry socket.” Besides dry alveolitis.8 Investigating tinidazole compared with a
socket, they also recorded the state of the wound by placebo treatment demonstrated a statistical signifi-
clinical diagnosis of purulent discharge from the cant decrease in infection.7 A study administering
wound. azidocillin, erythromycin, clindamycin, or doxycy-
cline as intervention compared with placebo treat-
Quality assessment ment stated that all interventions could decrease the
Major methodologic flaws in the reviewed studies clas- rate of infections.5
sified as low quality included poor specification of the High-quality studies. Four high-quality trials16,39,42,43
inclusion criteria, no intention to treat analyses, and investigated the efficacy of metronidazole and did
poor description of number of and reasons for dropouts. not demonstrate a statistically significant reduction
OOOO REVIEW ARTICLE
Volume 114, Number 6 Oomens and Forouzanfar e9
in frequency of alveolitis compared with placebo demonstrated that penicillin decreased the incidence
groups. In the high-quality study by Arteagoitia et of surgical wound infection significantly. Clindamy-
al.,8 augmentin reduced the incidence of inflamma- cin41 and amoxicillin38 were not able to reduce the
tion and infectious complications. Halpern et al.29 frequency of complications.
ORAL AND MAXILLOFACIAL SURGERY OOOO
e10 Oomens and Forouzanfar December 2012
risk factors, as mentioned above, antibiotic prophylaxis third molar surgery, a comparative placebo controlled clinical
should still be prescribed. trial. Br J Oral Maxillofac Surg 1990;28:12-5.
16. Sekhar CH, Narayanan V, Baig MF. Role of antimicrobials in
third molar surgery: prospective, double blind,randomized, pla-
The authors thank the authors of the studies included in cebo-controlled clinical study. Br J Oral Maxillofac Surg
this review, especially those who answered requests for 2001;39:134-7.
additional information. 17. Alerany C, Campany D, Monterde J, Semeraro C. Impact of local
guidelines and an integrated dispensing system on antibiotic prophy-
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