JOURNAL OF ENDODONTICS
Copyright 2001 by The American Association of Endodontists
Effect of Prophylactic Amoxicillin on Endodontic
Flare-Up in Asymptomatic, Necrotic Teeth
Leigh Pickenpaugh, DDS, MS, Al Reader, DDS, MS, Mike Beck, DDS, MA, William J. Meyers, DMD, MEd,
and Larry J. Peterson, DDS, MS
The purpose of this prospective, randomized, dou-
ble-blind, placebo-controlled study was to deter-
mine the effect of prophylactic amoxicillin on the
occurrence of endodontic flare-up in asymptom-
atic, necrotic teeth. Seventy patients participated
and had a clinical diagnosis of an asymptomatic,
necrotic tooth with associated periapical radiolu-
cency. One hour before endodontic treatment, pa-
tients randomly received either 3 g of amoxicillin or
3 g of a placebo control in a double-blind manner.
After endodontic treatment, each patient received:
ibuprofen; acetaminophen with codeine (30 mg);
and a 512-day diary to record pain, swelling, per-
cussion pain, and number and type of pain medi-
cation taken. The results demonstrated 10% of the
70 patients had a flare-up characterized by mod-
erate-to-severe postoperative pain or swelling that
began 30 h after endodontic treatment and per-
sisted for an average of 74 h. Of the seven patients
who had flare-ups, 4 were in the amoxicillin group
and 3 were not. Prophylactic amoxicillin did not
significantly (p 0.80) influence the endodontic
flare-up. We concluded that a prophylactic dose of
amoxicillin before endodontic treatment of asymp-
tomatic, necrotic teeth had no effect on the end-
odontic flare-up.
Endodontic treatment of an asymptomatic, necrotic tooth is a
frequent type of therapy in endodontic practice. Postoperatively
there may be some discomfort associated with this treatment (1, 2).
However there may be an acute exacerbation of symptoms, com-
monly known as a flare-up, that occurs in some patients resulting
in moderate-to-severe postoperative pain and/or swelling. The in-
cidence of an endodontic flare-up has been reported to be 1 to 24%
of the time (314).
The use of prophylactic antibiotics to prevent a flare-up in
asymptomatic, necrotic teeth has been investigated. Morse and
co-workers (4 6) concluded that prophylactic antibiotics signifi-
cantly decreased the incidence of flare-up. Torabinejad et al. (7)
53
Printed in U.S.A.
VOL. 27, NO. 1, JANUARY 2001
found antibiotics were less effective than analgesics in reducing
interappointment emergencies. Walton and Chiappinelli (12) con-
cluded that posttreatment symptoms were not affected by prophy-
lactic administration of penicillin.
Various studies (1517) have provided evidence that prophy-
lactic doses of antibiotics may be used to prevent infections. If
bacteria are responsible for endodontic flare-up, perhaps prophy-
lactic antibiotics could prevent their occurrence.
The purpose of this prospective, randomized, double-blind, pla-
cebo-controlled study was to determine the effect of prophylactic
amoxicillin on the occurrence of flare-up in asymptomatic, ne-
crotic teeth.
MATERIALS AND METHODS
Seventy adult patients participated in this study. All patients
were in good health as determined by a written health history and
oral questioning. Subjects were not taking antibiotics nor had they
received them within 30 days before participation in the study. The
study was approved by The Ohio State University Human Subjects
Review Committee, and written consent was obtained from each
patient.
Each patient had an asymptomatic, necrotic tooth needing end-
odontic therapy. Information on each subject was recorded and
included a patient history and biographical information. Addition-
ally information regarding patient allergies, presence of a sinus
tract, and previous endodontic therapy were also recorded. Each
tooth had to test negative to an electric pulp test (Analytic Tech-
nology Corp., Redmond, WA) and to ice, and had to have a
periapical radiolucency of at least 3 3 mm.
One hour before endodontic treatment, each patient randomly
received an oral dose of either 3 g (six capsules) of amoxicillin
(Parke-Davis, Inc., Morris Plains, NJ) or 3 g (six capsules) of a
placebo control in a double-blind manner. The medications were
blinded, randomized, and packaged by The Ohio State University
Hospital Pharmacy. Each 500 mg gelatin capsule of either amoxi-
cillin or placebo were identical in form (i.e. pink and red color with
P.D. 731 imprinted on each capsule).
One hour after taking the medications, standard endodontic
treatment was performed by graduate endodontic students or end-
odontic faculty. After local anesthetic administration, standard
access openings were performed. The working length was deter-
mined to be 1 mm from the radiographic apex. The canals were
54 Pickenpaugh et al. Journal of Endodontics

TABLE 1. Distribution of patients by groups and by teeth

Maxillary Mandibular
Group No. (%)
Anterior Premolar Molar Anterior Premolar Molar
Nonflare-up group
Group I 15 (21%)
Amoxicillin 7 (10%) 2 2 0 2 0 1
Placebo 8 (11%) 2 0 2 2 0 2
Group II 35 (50%)
Amoxicillin 18 (26%) 5 2 3 3 3 2
Placebo 17 (24%) 3 2 5 3 1 3
Group III 13 (19%)
Amoxicillin 5 (7%) 0 0 2 1 1 1
Placebo 8 (11%) 4 0 2 0 0 2
Total 63 (90%) 16 6 14 11 5 11

Flare-up group
Amoxicillin 4 (6%) 1 1 1 1 0 0
Placebo 3 (4%) 0 2 0 0 1 0
Total 7 (10%) 1 3 1 1 1 0
n 70.

prepared using a step-back preparation and K-type files (L. D.
Caulk, Inc., Milford, DE). The canals were irrigated with 2.62%
sodium hypochlorite initially and after every other file placed to
working length. Complete biomechanical preparation of all canals
was accomplished. The canals were dried, and a sterile cotton
pellet was placed over the canal orifices and the access opening
was sealed with Cavit. The occlusion was not adjusted.
Each patient received a labeled bottle of 200 mg tablets of
ibuprofen (Advil, Whitehall Laboratories, New York, NY), along
with verbal and written instructions on how to take the medication.
They were instructed to take two tablets every 4 to 6 h as needed
for pain and to take the ibuprofen first if an analgesic was required.
Each subject also received a labeled bottle of acetaminophen with
30 mg of codeine (Tylenol #3, MacNeil Consumer Products, Fort
Washington, PA), along with verbal and written instructions. They
were instructed to take the acetaminophen with codeine (one or
two tablets every 4 h as needed for pain), only if two ibuprofen
tablets did not relieve their discomfort. They were instructed to
take only these two medications and to return the unused medica-
tions at the obturation appointment.
Each patient received a 512-day diary to record postoperative
symptoms. The symptoms were recorded before going to bed on
the day of the treatment, then on arising, and before bedtime each
day for 5 days. The information recorded was: pain, percussion
pain (the patient was asked to tap on her/his tooth), swelling, and
number and type of pain medication taken. Pain and percussion
rating scales were: 0 no discomfort, 1 mild (recognizable, not
discomforting), 2 moderate (discomforting, but bearable), and
3 severe (considerable discomfort, difficult to bear). Each pa-
tient rated their swelling on a scale from 0 to 3: 0 no swelling,
1 mild swelling (mild puffiness of the face that was not both-
ersome), 2 moderate swelling (swelling that caused facial dis-
tortion and was bothersome), and 3 severe swelling (swelling
that caused serious facial distortion and was very bothersome).
Patients also recorded if they took pain medications, the amount,
and the type (ibuprofen or acetaminophen with codeine). A section
was also included for subjects comments. At the scheduled obtu-
ration appointment the patient returned the diary and all unused
pain medication to verify the amount of medication taken. A
flare-up was defined as moderate-to-severe postoperative pain or
moderate to severe swelling that began 12 to 48 h after treatment
and lasted at least 48 h.
Data were collected and statistically analyzed. Bivariate analy-
ses for differences between the flare-up and nonflare-up groups
were completed as follows. Age was analyzed using the indepen-
dent t test, whereas gender, prophylactic amoxicillin status, allergy,
sinus tract, and previous endodontic therapy were assessed using
Fishers exact test. An estimate of the radiographic lesion area was
calculated by averaging the smallest and largest measurements and
dividing this number by 2. This number served as a proxy for the
lesions radius had it been round. Lesion area was then estimated
by the following formula: area radius2. Estimated lesion
area was assessed using the Mann-Whitney-Wilcoxon test. Multi-
variate analysis was accomplished using a logistic regression
model with flare-up occurrence as the dependent variable and age,
gender, sinus tract, prophylactic amoxicillin status, allergy, previ-
ous endodontic therapy, and estimated lesion area as the predictor
variables. Differences were considered significant at p 0.05.
RESULTS
The results were divided into nonflare-up and flare-up groups
according to the onset, severity, and duration of postoperative
symptoms. Table 1 shows the distribution of patients by group and
a summary of the tooth distribution.
The nonflare-up group was subdivided into three subgroups
(Table 1). Subgroup I of the nonflare-up group comprised 21% of
the amoxicillin and placebo patients. They had no pain, no swell-
ing, no percussion sensitivity, and did not take any pain medica-
tions.
Subgroup II included 50% of the amoxicillin and placebo pa-
tients. They had mild-to-moderate pain, mild swelling, mild-to-
moderate percussion pain, or took ibuprofen pain medication (two
patients took acetaminophen with codeine on day of treatment).
However all symptoms resolved within 48 h. Generally the symp-
toms started the day of treatment and decreased steadily over the
next 2 days.
Subgroup III included the other 19% of the amoxicillin and
placebo patients. They had mild-to-moderate pain, mild swelling,
Vol. 27, No. 1, January 2001 Effect of Amoxicillin on Flare-up 55

TABLE 2. Bivariate analysis for flare-up For example, moderate-to-severe pain began 30 h after treatment
and lasted through the fourth day in 60% of the patients in the
Flare-up Nonflare-up
Variable p flare-up group. The patients in the nonflare-up group had only a
(n 7) (n 63)
3% incidence of moderate pain, with the remaining 97% recording
Age* 51 14 41 17 0.1150
none-to-mild pain for the entire 5 days. Moderate-to-severe swell-
Lesion size (mm2)* 14 6 25 23 0.2043
Sinus tract 1.00 ing occurred in three patients in the flare-up groupstarting 15 to
Yes 1 (14%) 8 (13%) 48 h after treatment. Two of the patients continued to report
No 6 (86%) 55 (87%) swelling through the fifth day. The three patients who reported
Gender 0.699 swelling also reported moderate pain and percussion pain.
Female 4 (57%) 29 (46%) Prophylactic amoxicillin did not significantly influence the oc-
Male 3 (43%) 34 (54%) currence of the endodontic flare-up in asymptomatic, necrotic teeth
Drug 0.706
when considered alone or when controlled for age, estimated lesion
Amoxicillin 4 (57%) 30 (48%)
Placebo 3 (43%) 33 (52%)
area, sinus tract, gender, allergy, or previous endodontic therapy.
Allergy 1.00 Our results agree with the findings of Walton and Chiappinelli
Yes 1 (14%) 13 (21%) (12), but disagree with the work of Morse and co-authors (4 6).
No 6 (86%) 50 (79%) However, even if this study showed that prophylactic antibiotics
Previous endodontic therapy 1.00 prevented a flare-up, then 100 patients would have to be prophy-
Yes 1 (14%) 13 (21%) laxed to prevent 10 patients from having moderate-to-severe post-
No 6 (86%) 50 (79%) operative symptoms. We do not believe this is a sufficient inci-
* Mean standard deviation. dence to warrant the use of prophylactic antibiotics for all patients,
Independent t test (two-tailed).
Mann-Whitney-Wilcoxon test (two-tailed). considering the adverse reactions involved with indiscriminate use
Fishers exact test (two-tailed). of antibiotics (12).
The use of prophylactic antibiotics to prevent an infection is
based on the work of Burke and Miles (15, 18, 19). They demon-
mild-to-moderate percussion pain, or took ibuprofen pain medica- strated that, for antibiotics to be effective, they must be in the
tion (one patient took acetaminophen with codeine for 1 day). The system when the wound is seeded with bacteria. Delays of 3 to 4 h
symptoms started the day of the appointment, but persisted past in antibiotic administration resulted in lesions that were identical to
48 h. None of the ratings were severe. those in the animals receiving no prophylaxis. Clinically then the
In the flare-up group, 10% of the amoxicillin and placebo
antibiotic must be effective against the organisms encountered, it
patients had moderate-to-severe pain or moderate-to-severe swell-
must be present in the tissues when contamination begins (initial
ing, moderate-to-severe percussion pain, or took acetaminophen
instrumentation), continued during the period of operation (de-
with codeine medications for at least 3 days. The moderate-to-
bridement of the root canal), and discontinued after the operation
severe symptoms began 30 h (range 15 to 48 h) after treatment
is complete. The dose of amoxicillin used in this study would fulfill
and persisted for at least another 48 h. The average duration of the
this requirement (i.e. it is effective against the bacteria present in
flare-up was 74 h (range 48 to 120 h).
the root canal system, serum blood levels are high initially and are
Bivariate analysis (Table 2) revealed no significant differences
between the nonflare-up and flare-up patients for age, gender, maintained for 10 to 12 h, thus making it an excellent choice for
prophylactic amoxicillin status, allergy, sinus tract, previous end- a single dose regimen (20)). However the difference between the
odontic therapy, or lesion area. Similarly multivariate analysis experimental lesion of Burke and Miles (15, 19), a freshly seeded
failed to demonstrate a significant effect for any of these variables bacterial wound, and the endodontic lesion is that the lesion of
when considered simultaneously. Prophylactic amoxicillin had no endodontic origin is long-standing in nature. Therefore immuno-
effect on the incidence of flare-up. logical factors of a pre-existing, chronic lesion may also be in-
volved in a flare-up.
What are the predictive factors associated with a flare-up?
DISCUSSION Previous studies have related flare-ups to retreatment cases (8, 13),
maxillary lateral incisors (3), canines (4 6), and mandibular pre-
The nonflare-up and flare-up groups describe the range of molars (7), gender (5), age (3, 7), and patients with allergies (7).
experiences that patients may encounter after endodontic treatment We did not find a statistical relationship between endodontic
of an asymptomatic, necrotic tooth. In the nonflare-up group, flare-up and any of the predictive factors studied. If further re-
subgroup I is representative of the patients who do not experience search could determine which patient and what factors are specif-
any problems following endodontic treatment. Subgroup II repre- ically involved in the flare-up, we may then be able to direct
sents immediate postoperative problems related to endodontic therapy to treat or prevent its occurrence.
treatment. Subgroup III is representative of the variability in pa-
We conclude that a prophylactic dose of amoxicillin before
tients with postoperative symptoms. That is patients may have
endodontic treatment of asymptomatic, necrotic teeth has no effect
problems past 48 h, but none of the problems were severe. Some
on the postoperative flare-up.
patients in this group related that the pain and percussion sensi-
tivity started after they bit down on something hard.
The flare-up group represents patients who have significant This study was supported by research funding from the Graduate End-
postoperative sequelae. Moderate-to-severe symptoms began 30 odontic Student Research Fund and the Goldberg Memorial Fund, Graduate
h (range 15 to 48 h) after treatment and lasted 74 h (range 48 to Endodontics, College of Dentistry, The Ohio State University. A portion of this
article was presented at the 49th Annual Session of the American Association
120 h). Clearly this group of patients reacted very differently to of Endodontists, San Francisco, CA, and was awarded a second place in the
endodontic treatment than the patients in the nonflare-up group. graduate student competition.
56 Pickenpaugh et al.
This article was adapted from a thesis submitted by Dr. Pickenpaugh in
partial fulfillment of the requirements for the MS degree at The Ohio State
University.
Dr. Pickenpaugh is in private practice limited to endodontics, Columbus,
OH. Dr. Reader is professor and director of the Graduate Endodontic Pro-
gram, Dr. Beck is associate professor and acting chairperson in the Depart-
ment of Health Services Research, Dr. Meyers is emeritus professor and
director of Endodontics, Dr. Peterson is professor and former chairperson in
the Department of Oral Maxillofacial Surgery, Pathology, and Anesthesiology,
College of Dentistry, The Ohio State University, Columbus, OH. Address
requests for reprints to Dr. Al Reader, Program Director of Graduate End-
odontics, College of Dentistry, The Ohio State University, 305 W. 12th Avenue,
Columbus, OH 43210.
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The Way It Was
Ever wonder why smallpox was small? It was to contrast it with syphilis, the
great pox, which having just ravaged a previously unexposed 16th century
population caused numerous extensive cutaneous lesions.
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Lewis Pallid