Vol. 90 No.

5 November 2000

ORAL SURGERY
ORAL MEDICINE
ORAL PATHOLOGY

ENDODONTICS Editor: Larz Spångberg

Effect of systemic penicillin on pain in untreated

irreversible pulpitis
Douglas Nagle, DMD, MS,a Al Reader, DDS, MS,b Mike Beck, DDS, MA,c and Joel Weaver,
DDS, PhD,d Columbus, Ohio
THE OHIO STATE UNIVERSITY

Objective. The purpose of this prospective, randomized, double-blind study was to determine the effect of penicillin on
pain in untreated teeth diagnosed with irreversible pulpitis.
Study design. Forty emergency patients participated, and each had a clinical diagnosis of an irreversible pulpitis. Patients
randomly received a 7-day oral dose (28 capsules, 500 mg each, to be taken every 6 hours) of either penicillin or a placebo
control in a double-blind manner. No endodontic treatment was performed. Each patient also received ibuprofen; acetaminophen
with codeine (30 mg); and a 7-day diary to record pain, percussion pain, and number and type of pain medication taken.
Results. The administration of penicillin did not significantly (P > .05) reduce pain, percussion pain, or the number of anal-
gesic medications taken by patients with untreated irreversible pulpitis. The majority of patients with untreated irreversible
pulpitis had significant pain and required analgesics to manage this pain.
Conclusion. Penicillin should not be prescribed for untreated irreversible pulpitis because penicillin is ineffective for pain relief.
(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90:636-40)

Many studies have characterized the microflora of
carious dentin and the pulpal reaction to dental caries.1-8
Generally, the inflammation of irreversible pulpitis in
vital painful teeth occurs beneath deep caries before the
microorganisms have invaded the pulp.1,2,8
Currently, endodontic debridement (pulpectomy or
pulpotomy) is the most predictable method to relieve the
pain of irreversible pulpitis.9 However, antibiotics are
often prescribed indiscriminately to treat endodontic
emergencies.10 As stated by Fouad et al,10 “The
prescribing of antibiotics routinely to treat endodontic
emergencies has received much attention but little objec-
tive research. Such usage is empirical with very few
Supported by research funding from the Endodontic Graduate Student
Research Fund and the Steve Goldberg Memorial Fund, The Ohio
State University.
aFormer Graduate Student in Endodontics, The Ohio State University.
Currently in practice limited to endodontics, Hermitage, Pa.
bProfessor and Program Director, Graduate Endodontics.
cAssociate Professor, Department of Health Services Research.
dAssociate Professor, Department of Oral and Maxillofacial Surgery,
Pathology, and Anesthesiology.
Received for publication Dec 9, 1999; returned for revision Jan 25,
2000; accepted for publication Jun 19, 2000.
Copyright © 2000 by Mosby, Inc.
1079-2104/2000/$12.00 + 0 7/15/109777
doi:10.1067/moe.2000.109777
636
published reports on their effectiveness. Nevertheless,
such practice seems widespread in attempting to relieve
patients’ pain or to prevent worsening of the condition.”
Although therapeutic concentrations of systemic antibi-
otics might reach the pulp,11,12 the clinical value of these
antibiotics has not been evaluated.
Therefore, the purpose of this prospective, random-
ized, double-blind, placebo-controlled study was to
determine the effect of penicillin on pain in untreated
teeth diagnosed with irreversible pulpitis.
PATIENTS AND METHODS
Forty adult patients presenting for emergency treat-
ment participated in this study. All patients were in
good health as determined by a written health history
and oral questioning. Subjects were not taking antibi-
otics and had not received them within 30 days before
participation in the study. This study was approved by
The Ohio State University Human Subjects Committee,
and written consent was obtained from each patient.
Each patient included in this study had a tooth with a
clinical diagnosis of irreversible pulpitis and had spon-
taneous moderate to severe pain associated with the
tooth. By definition, these teeth were vital and gave a
positive response to an electric pulp tester (EPT;
Analytic Technology, Redmond, Wash) and a prolonged
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Nagle et al 637
Volume 90, Number 5

Table I. Distribution of tooth type for penicillin and placebo groups

Maxillary teeth Mandibular teeth
Tooth type Number Percentage Tooth type Number Percentage
First molar First molar
Penicillin 2 10% 2 10%
Placebo 3 15% 5 25%

Second molar Second molar

Penicillin 4 20% 7 35%
Placebo 1 5% 4 20%

First premolar First premolar

Penicillin 2 10% 0 0%
Placebo 5 25% 0 0%

Second premolar Second premolar

Penicillin 3 15% 0 0%
Placebo 2 10% 0 0%
n = 20 penicillin, 20 placebo.

Table II. Initial values recorded for penicillin and Laboratories, Philadelphia, Pa) or a placebo control
placebo groups (lactose) in a double-blind manner. Before the experi-
Value Penicillin Placebo
ment, patient groups (penicillin or placebo) were
assigned by using 4-digit numbers from a random
Age* 30 ± 9.8 34 ± 11.6
Sex 7 women, 16 women,
number table. Only the random numbers were recorded
13 men 4 men on the data collection and postoperative diary sheets to
Weight* 186 ± 48.4 153 ± 38.3 blind the experiment. The medications were blinded,
Initial pain† 2.00 ± 0.00 2.00 ± 1.00 randomized, and packaged by a pharmacy. Each 500-
Initial percussion pain† 2.00 ± 0.50 2.00 ± 1.00 mg gelatin capsule of either penicillin or placebo was
*Mean ± standard deviation. identical in form. The 500-mg tablets of penicillin VK
†Median ± interquartile range.
were ground into a powder and placed into the clear,
unlabeled gelatin capsules. The white powder of the
lactose placebo was indistinguishable from the white
painful response to Endo Ice (Hygenic Corporation, powder of the penicillin tablets when viewed through
Akron, Ohio). If the teeth did not respond to the EPT and the capsule. No endodontic treatment was performed.
Endo Ice, they were not included in the study. The teeth Each patient received a labeled bottle of 600-mg
also had percussion sensitivity, a history of spontaneous tablets of ibuprofen (Motrin; HN Norton Co,
pain, and usually had a radiographically widened peri- Shreveport, La) along with verbal and written instruc-
odontal ligament space. Deep carious lesions or poor tions on how to take the medication. They were
restorations with recurrent caries were the etiologic instructed to take 1 tablet every 4 to 6 hours as needed
factors contributing to the irreversible pulpitis. for pain and to take the ibuprofen first if an analgesic
Age, sex, weight, and tooth type (molar, premolar, was required. Each subject also received a labeled bottle
anterior) were recorded for each patient (Tables I and of acetaminophen with 30 mg of codeine (Tylenol No. 3;
II). Patients were asked to rate the pain they were expe- McNeil Consumer Products, Fort Washington, Pa) along
riencing on a scale from 0 to 3. This scale has been used with verbal and written instructions. They were instructed
in previous studies to measure pain responses.13-20 Zero to take the acetaminophen with codeine (2 tablets every
indicated no pain. One indicated mild pain, that is, pain 4 to 6 hours as needed for pain) only if the ibuprofen
that was recognizable but not discomforting. Two indi- tablet did not relieve their discomfort. Patients were
cated moderate pain, or pain that was discomforting instructed to return the unused medications at the
but bearable. Three indicated severe pain, or pain that seventh day appointment to start the endodontic proce-
caused considerable discomfort and was difficult to dure.
bear. The patients were asked to rate the pain to percus- Each patient received a 7-day diary to record postoper-
sion by using the same scale. ative symptoms. The symptoms were recorded when the
Patients randomly received a 7-day oral dose of 500- patient arose, each day for 7 days. The information
mg capsules to be taken every 6 hours (total, 28 recorded detailed pain, percussion pain (the patient was
capsules) of either penicillin (Penicillin VK, Wyeth asked to tap on her/his tooth), and number and type of
638 Nagle et al ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
November 2000

Table III. Pain and percussion pain ratings for baseline and 7 days for penicillin and placebo groups
Pain ratings Percussion pain ratings
Day None Mild Moderate Severe None Mild Moderate Severe
Baseline
Penicillin 0 (0%) 0 (0%) 13 (65%) 7 (35%) 0 (0%) 4 (20%) 10 (50%) 6 (30%)
Placebo 0 (0%) 0 (0%) 16 (80%) 4 (20%) 0 (0%) 5 (25%) 13 (65%) 2 (10%)
Day 1
Penicillin 2 (10%) 6 (30%) 8 (40%) 4 (20%) 3 (15%) 5 (25%) 8 (40%) 4 (20%)
Placebo 4 (20%) 6 (30%) 9 (45%) 1 (5%) 3 (15%) 9 (45%) 6 (30%) 2 (10%)
Day 2
Penicillin 2 (10%) 7 (35%) 9 (45%) 2 (10%) 2 (10%) 7 (35%) 8 (40%) 3 (15%)
Placebo 4 (20%) 7 (35%) 7 (35%) 2 (10%) 4 (20%) 8 (40%) 5 (25%) 3 (15%)
Day 3
Penicillin 3 (15%) 9 (45%) 6 (30%) 2 (10%) 2 (10%) 7 (35%) 7 (35%) 4 (20%)
Placebo 2 (10%) 10 (50%) 7 (35%) 1 (5%) 2 (10%) 11 (55%) 3 (15%) 4 (20%)
Day 4
Penicillin 3 (15%) 6 (30%) 9 (45%) 2 (10%) 3 (15%) 7 (35%) 8 (40%) 2 (10%)
Placebo 8 (40%) 3 (15%) 7 (35%) 2 (10%) 3 (15%) 10 (50%) 2 (10%) 5 (25%)
Day 5
Penicillin 5 (25%) 7 (35%) 5 (25%) 3 (15%) 5 (25%) 6 (30%) 6 (30%) 3 (15%)
Placebo 5 (25%) 5 (25%) 6 (30%) 4 (20%) 3 (15%) 7 (35%) 6 (30%) 4 (20%)
Day 6
Penicillin 5 (25%) 9 (45%) 4 (20%) 2 (10%) 2 (10%) 11 (55%) 5 (25%) 2 (10%)
Placebo 3 (15%) 6 (30%) 7 (35%) 4 (20%) 2 (10%) 6 (30%) 7 (35%) 5 (25%)
Day 7
Penicillin 6 (30%) 6 (30%) 6 (30%) 2 (10%) 3 (15%) 9 (45%) 6 (30%) 2 (10%)
Placebo 4 (20%) 7 (35%) 7 (35%) 2 (10%) 2 (10%) 8 (40%) 4 (20%) 6 (30%)
n = 20 penicillin, 20 placebo.

pain medication taken (ibuprofen or acetaminophen with
codeine). Pain and percussion pain rating scales were the
same as outlined previously. At the scheduled endodontic
appointment, the patient returned the questionnaire and
all unused pain medication to verify the number of pills
taken. At this appointment the teeth were pulp tested, and
the presence or absence of vital tissue was confirmed on
endodontic access and instrumentation.
Data were collected and statistically analyzed. Between-
group differences in sum pain intensity differences (SPID),
sum pain percussion intensity differences (SPPID), and
quantity of pain medications taken were assessed by
using the Mann-Whitney-Wilcoxon test. Differences
were considered significant at P < .05.
RESULTS
Each group consisted of 20 patients. The distribu-
tion of tooth type is found in Table I.
Table II shows the initial values of age, sex, weight,
initial pain, and initial percussion pain for the 2 groups.
The pain ratings are summarized in Table III. The
SPID between the penicillin and placebo groups was
not statistically significant (Table IV, P = .776). As
shown in Table III, 100% (40 of 40) of the subjects
presented with moderate to severe pain ratings at the
baseline. For both groups, the mean pain ratings
decreased on day 1 and then remained relatively stable
over the 7-day observation period (Table III).
The percussion pain ratings are summarized in Table
III. The SPPID was not statistically significant (Table
IV, P = .290). For both groups, the mean percussion pain
ratings decreased on day 1 and then remained relatively
stable over the 7-day observation period (Table III).
Table V illustrates the number, percentage, and average
use and nonuse of ibuprofen and acetaminophen with
codeine during the 7 days. There was no significant differ-
ence in the mean total number of ibuprofen tablets (P =
.839) and acetaminophen with codeine tablets (P = .325)
taken over the 7-day observation period between the peni-
cillin and placebo groups (Table IV). Only 5% of the
patients reported not taking ibuprofen or acetaminophen
with codeine on day 1. On day 2, 5% of the patients did
not take analgesic medications; on day 3, the percentage
was 15% to 20%; day 4, 10% to 30%; and 15% to 35%
did not take medications on days 5 through 7.
At the 7-day appointment to start endodontic treat-
ment, 75% (15 of 20) of the teeth in the penicillin
group were vital on access, whereas 80% (16 of 20)
were vital in the placebo group. None of the teeth were
cariously exposed clinically. That is, all teeth required
removal of coronal dentin with a high-speed bur to
reach the pulp chamber.
DISCUSSION
The administration of penicillin did not significantly (P
> .05) reduce pain, percussion pain, or the number of
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Nagle et al 639
Volume 90, Number 5

Table IV. Values recorded for penicillin and placebo groups

Variable Penicillin Placebo P value
Sum pain intensity difference* 6.0 ± 10.5 6.0 ± 9.5 .776
Sum percussion pain intensity difference* 3.5 ± 7.5 2.0 ± 7.0 .290
Total number ibuprofen† 9.2 ± 6.02 9.6 ± 6.34 .839
Total number acetaminophen with codeine† 6.9 ± 6.87 4.45 ± 4.82 .325
*Median ± interquartile range.
†Mean ± standard deviation.

Table V. Recorded use of pain medications for penicillin and placebo groups
Number who took no
Number who Number who took acetaminophen with
Day took ibuprofen acetaminophen with codeine codeine or ibuprofen
Day 1
Penicillin 17 (85%) 10 (50%) 1 (5%)
No. of tablets 33 21
Placebo 16 (80%) 8 (40%) 1 (5%)
No. of tablets 28 11
Day 2
Penicillin 17 (85%) 10 (50%) 1 (5%)
No. of tablets 30 28
Placebo 16 (80%) 9 (45%) 1 (5%)
No. of tablets 31 18
Day 3
Penicillin 13 (65%) 9 (45%) 4 (20%)
No. of tablets 27 20
Placebo 15 (75%) 8 (40%) 3 (15%)
No. of tablets 28 14
Day 4
Penicillin 12 (60%) 9 (45%) 6 (30%)
No. of tablets 24 23
Placebo 17 (85%) 5 (25%) 2 (10%)
No. of tablets 28 8
Day 5
Penicillin 12 (60%) 8 (40%) 7 (35%)
No. of tablets 21 15
Placebo 16 (80%) 7 (35%) 3 (15%)
No. of tablets 32 11
Day 6
Penicillin 13 (65%) 8 (40%) 5 (25%)
No. of tablets 24 15
Placebo 13 (65%) 6 (30%) 6 (30%)
No. of tablets 24 13
Day 7
Penicillin 14 (70%) 10 (50%) 4 (20%)
No. of tablets 25 16
Placebo 11 (55%) 7 (35%) 7 (35%)
No. of tablets 20 14
n = 20 penicillin, 20 placebo.

analgesic medications taken by patients with untreated
irreversible pulpitis. Although bacteria are important in
the pathogenesis of irreversible pulpitis caused by caries,
Massler and Pawlack1 and Torneck2 established that
pulps of teeth with irreversible pulpitis and without a
clinical pulpal exposure contained no demonstrable
bacteria. Early stages of irreversible pulpitis represent an
immunologic response of the pulpal tissue to antigenic
substances produced as a result of the carious lesion.4-8
Haldi and John11 and Akimoto et al12 found that peni-
cillin and ampicillin, when administered systemically,
were present in the dental pulp in the same concentra-
tions as in the blood plasma. Therefore, therapeutic
concentrations of systemic antibiotics can reach the pulp.
However, because pulpal pain is mainly associated with
the inflammatory process and because there are rarely
bacteria in the pulp in irreversible pulpitis (vital painful
teeth), antibiotics have no effective usefulness.
640 Nagle et al
For both pain and percussion pain in the penicillin and
placebo groups, there was an initial decrease in pain
ratings at day 1, and over the 7 days, the ratings generally
remained between moderate and mild pain (Table III).
Similar results were reported by Gallatin et al20 for their
control patients (ie, placebo-treated group) with untreated
irreversible pulpitis. Generally, the decrease in pain from
the baseline ratings would likely be attributed to the use of
the pain medications or, in some patients, to a natural
decrease in pulpal inflammation with necrosis. In
summary, patients with untreated irreversible pulpitis
experience significant pain and percussion pain.
The type and number of medications taken daily
were recorded to give a quantifiable number of anal-
gesic tablets taken because these might affect the
overall pain experience by lowering pain ratings.
Generally, the number of analgesic medications taken
by the 2 groups corresponded to the ratings of postop-
erative pain and percussion pain. The number of
patients who took ibuprofen or acetaminophen with
codeine remained fairly constant over the 7 days (Table
V). Therefore, the majority of subjects with untreated
irreversible pulpitis required analgesic medication.
Penicillin did not affect the use of pain medication.
The continued high percentage of patients reporting
pain and percussion pain at the 7-day return appoint-
ment (Table III) demonstrates that many teeth with
untreated irreversible pulpitis remain symptomatic for
at least 1 week. Gallatin et al20 reported similar
results. Seventy-five percent of the teeth in the peni-
cillin group and 80% of the teeth in the placebo group
tested vital and had hemorrhagic vital tissue on access.
Gallatin et al20 recorded that 19% of the untreated
teeth with irreversible pulpitis were necrotic in their
control group (placebo-treated group). Our study and
that of Gallatin et al20 are the only studies we are
aware of that have followed untreated irreversible
pulpitis in humans for a week. These studies confirm
our clinical impression that untreated irreversible
pulpitis could result in pulpal necrosis in human teeth.
It is reasonable to assume that the irreversible condi-
tion will continue to degenerate until the pulp
becomes necrotic if the condition is not endodonti-
cally treated.
In conclusion, the administration of penicillin did not
significantly (P > .05) reduce pain, percussion pain, or
the number of analgesic medications taken for patients
with untreated irreversible pulpitis. Penicillin should
not be prescribed to treat the pain of untreated irre-
versible pulpitis.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
November 2000
REFERENCES
1. Massler M, Pawlak J. The affected and infected pulp. Oral Surg
Oral Med Oral Pathol 1977;43:929-47.
2. Torneck CD. A report of studies into changes in the fine structure
of the dental pulp in human caries pulpitis. J Endod 1981;7:8-16.
3. Hahn CL, Kalkler WA, Minah GE. Microbiological studies of
carious dentine from human teeth with irreversible pulpitis.
Arch Oral Biol 1991;36:147-53.
4. Hahn CL, Falkler WA. Antibodies in normal and diseased pulps
reactive with microorganisms isolated from deep caries. J Endod
1992;18:28-31.
5. Stashenko P, Wang CY, Teles R. Immunopathologic mecha-
nisms of pulpal and periapical destruction and protection.
Dentin/pulp complex. Chicago: Quintessence Publishing; 1996.
p. 72-8.
6. Rauschenberger CR, Bailey JC, Cootauco CJ. Detection of human
IL-2 in normal and inflamed dental pulps. J Endod 1997;23:366-70.
7. Matsushima K, Ohbayashi E, Takeuchi H, Hosoya S, Abiko Y,
Yamazaki M. Stimulation of interleukin-6 production in human
pulp cells by peptidoglycans from Lactobacillus casei. J Endod
1998;24:252-5.
8. Huang GTJ, Potente AP, Kim JW, Chugal N, Zhang X. Increased
interleukin-8 expression in inflamed human dental pulps. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:214-20.
9. Oguntebi BR, DeSchepper EJ, Taylor TS, White CL, Pink FE.
Postoperative pain incidence related to the type of emergency
treatment of symptomatic pulpitis. Oral Surg Oral Med Oral
Pathol 1992;73:479-83.
10. Fouad AF, Rivera EM, Walton RE. Penicillin as a supplement in
resolving the localized acute apical abscess. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 1996;81:590-5.
11. Haldi J, John K. Sulfanilamide and penicillin in the pulp fluid of
the dog following administration of these compounds. J Dent
Res 1965;44:1386-8.
12. Akimoto Y, Nishimura H, Komiya M, Shibata T, Kaneko K,
Fujii A, et al. Ampicillin concentrations in human serum and
dental pulp following a single oral administration. J Nihon Univ
School Dent 1984;26:148-54.
13. Vreeland D, Reader A, Beck M, Meyers W, Weaver J. An eval-
uation of volumes and concentrations of lidocaine in human
inferior alveolar nerve block. J Endod 1989;15:6-12.
14. McLean C, Reader A, Beck M, Meyers WJ. An evaluation of 4%
prilocaine and 3% mepivacaine compared to 2% lidocaine
(1:100,000 epinephrine) for inferior alveolar nerve block. J
Endod 1993;19:146-50.
15. Replogle K, Reader A, Nist R, Beck M, Weaver J. Anesthetic
efficacy of the intraosseous injection of 2% lidocaine (1:100,000
epinephrine) and 3% mepivacaine in mandibular molars. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:30-7.
16. Coggins R, Reader A, Nist R, Beck M, Meyers WJ. Anesthetic
efficacy of the intraosseous injection in maxillary and
mandibular teeth. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 1996;81:634-41.
17. Dunbar D, Reader A, Nist R, Beck M, Meyers W. Anesthetic
efficacy of the intraosseous injection after an inferior alveolar
nerve block. J Endod 1996;22:481-6.
18. Nusstein J, Reader A, Nist R, Beck M, Meyers WJ. Anesthetic
efficacy of the supplemental intraosseous injection of 2% lido-
caine with 1:100,000 epinephrine in irreversible pulpitis. J
Endod 1998;24:487-91.
19. Reisman D, Reader A, Nist R, Beck M, Weaver J. Anesthetic
efficacy of the supplemental intraosseous injection of 3% mepi-
vacaine in irreversible pulpitis. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 1997;84:676-82.
20. Gallatin E, Reader A, Nist R, Beck M. Pain reduction in
untreated irreversible pulpitis using an intraosseous injection of
Depo-Medrol. J Endod. In press.
Reprint requests:
Al Reader, DDS, MS
Graduate Endodontics
College of Dentistry
PO Box 182357
The Ohio State University
305 W 12th Ave
Columbus, OH 43218-2357