CONSORT Randomized Clinical Trial
Comparative Evaluation of Effect of Preoperative
Oral Medication of Ibuprofen and Ketorolac on
Anesthetic Efficacy of Inferior Alveolar Nerve Block
with Lidocaine in Patients with Irreversible Pulpitis: A
Prospective, Double-blind, Randomized Clinical Trial
Vivek Aggarwal, MDS,* Mamta Singla, MDS,† and Debipada Kabi, MDS*
Abstract
Introduction: Anesthetic efficacy of inferior alveolar
nerve block decreases in patients with irreversible pulpi-
tis. It was hypothesized that premedication with nonste-
roidal anti-inflammatory drugs might improve the
success rates in patients with inflamed pulps. Methods:
Sixty-nine adult volunteers who were actively experi-
encing pain participated in this prospective, random-
ized, double-blind study. The patients were divided into
3 groups on a random basis and were randomly given 1
of the 3 drugs including ibuprofen, ketorolac, and
placebo 1 hour before anesthesia. All patients received
standard inferior alveolar nerve block of 2% lidocaine
with 1:200,000 epinephrine. Endodontic access
preparation was initiated after 15 minutes of initial
inferior alveolar nerve block. Pain during treat-ment was
recorded by using a Heft Parker visual analog scale.
Success was recorded as none or mild pain. Results:
Statistical analysis with nonparametric c2 tests showed
that placebo gave 29% success rate. Premedi-cation
with ibuprofen gave 27%, and premedication with
ketorolac gave 39% success rate. There was no
significant difference between the 3 groups. Conclu-
sions: Preoperative administration of ibuprofen or ke-
torolac has no significant effect on success rate of
inferior alveolar nerve block in patients with irreversible
pulpitis. (J Endod 2010;36:375–378)
Key Words
Ibuprofen, inferior alveolar nerve block,
irreversible pul-pitis, ketorolac, NSAIDs
From the *Department of Dental Surgery,
Safdarjung Hospital, New Delhi; and †Department of
Conservative Dentistry and Endodontics, Institute of
Dental Sciences and Technology, Modinagar, India.
Address requests for reprints to Dr Vivek Aggarwal,
Depart-ment of Dental Surgery, Safdarjung Hospital, New
Delhi, India. E-mail address: drvivekaggarwal@gmail.com.
0099-2399/$0 - see front matter
Copyright ª 2010 American Association of
Endodontists. doi:10.1016/j.joen.2009.11.010
JOE — Volume 36, Number 3, March 2010
L ocal anesthesia is an integral part of management of painful endodontic emergencies
by inhibiting the nociceptive signals (1–4). The inferior alveolar nerve block (IANB) is the
standard and most commonly used technique for achieving pulpal anesthesia for
mandibular endodontic procedures. IANB has a high failure rate, ranging from 7%– 77%
(2, 3, 5–10). The success rates get even worse in patients with inflamed pulpal tissues
(2, 3, 10, 11). Various mechanisms have been hypothesized to explain the failure of
local anesthetics including anatomic variations like cross innervations and accessory
innervations (11–14), decreased local pH (2, 14), tachyphylaxis of anes-thetic solutions
(14), and activation of nociceptors including tetrodotoxin (TTX) and capsaicin-sensitive
transient receptor potential vanilloid type 1 (TRPV1) (14–16). The most plausible
explanation for decrease in success rate in inflamed pulp can be the activation of
nociceptors by inflammation (15–17). Inflammatory mediators reduce the threshold for
activation of nociceptor neurons to a point that a minor stimulus now might fire these
neurons (17, 18). This inflammatory process is mediated via prosta-glandins (PGs),
which are end products of arachidonic acid (AA) metabolism, produced via
cyclooxygenase (COX) pathway (19, 20). PGs act by sensitizing nerve endings to
bradykinins and histamines and hence enhance the pain and tenderness of
inflammation (15–20).
COX is available in body in 2 isoforms, COX-1 and COX-2 (21, 22). COX-1
regulates normal cell activities in the stomach, kidneys, and platelets by synthesizing
prostanoids that have cytoprotective functions (21, 22). The COX-2 is normally not
present in tissue (except kidneys) and is present only in areas of tissue injury and
inflammation (22, 23). Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) act by
nonselective inhibi-tion of COX activity, resulting in some gastrointestinal side effects
(23). Specific COX-2 inhibitors were developed to deliver equivalent pain relief to that of
the nonselective NSAIDs, but without the accompanying risk of gastrointestinal
complications. Recently a number of large clinical trials have revealed that the COX-2–
specific inhibitors are associated with an increased risk of cardiovascular toxicity, which
led to withdrawal of Rofecoxib from the market in 2004 (24–27). Among the
nonselective NSAIDs, ibuprofen and ketorolac have been shown to provide significantly
improved pain control over placebo (28–30). Ibuprofen is a propionic acid derivative and
an effective analgesic and anti-inflammatory agent. Ketorolac, a pyrrolo-pyrrole
derivative, is as effective as morphine or meperidine for pain relief (28–31).
Many researchers have identified inflammation as an important component of the
pathogenesis of hyperalgesia and failure of local anesthesia (15–20). Because NSAIDs
reduce nociceptor activation by decreasing the levels of inflammatory mediators, it is
hypothesized that premedication with NSAIDs will affect the success rate of local anes-
thesia in patients with irreversible pulpitis. In 2007 Modaresi et al (32) studied the role of
premedication with ibuprofen and acetaminophen-codeine for achieving deep anes-
thesia in patients with irreversible pulpitis. Efficacy in achieving deep anesthesia was
evaluated with the help of electric pulp tester. The authors did not evaluate the success
or failure rate on basis of pain during root canal treatment. Therefore the present study
Effect of NSAIDs on Anesthetic Efficacy of IANB
375
CONSORT Randomized Clinical Trial
TABLE 1. Comparison of Age, Gender, Initial and Postinjection Pain
Control PLAC IBUP KETA
Age (y) 26 9; range, 21–35 30 8; range, 23–38 29 8; range, 24–37
Gender 14 males, 10 females 10 males, 12 females 12 males, 11 females
Initial pain (Heft Parker VAS) 97 44 106 38 101 45
Postinjection pain (after 15 min) 65 10 4 93
PLAC, placebo; IBUP, ibuprofen; KETA, ketorolac.
There was no significant difference (P > .05) between the groups.

was planned to evaluate the effect of premedication with various 170-mm line marked with various terms describing the levels of pain
NSAIDs on anesthetic success rate in terms of pain during endodontic was used for this purpose (33). The millimeter marks were removed
proce-dure. The purpose of this prospective, randomized, double-blind from the scale, and the scale was divided into 4 categories: no pain cor-
study was to compare the effect of oral premedication of ibuprofen, responded to 0 mm; faint, weak, or mild pain corresponded to 0–54 mm;
ketorolac, and a placebo medication on anesthetic efficacy of IANB with moderate pain corresponded to 55–114 mm; and strong, intense, and
lidocaine with 1:200,000 epinephrine in patients with irreversible pulpitis. maximum possible pain corresponded to more than 114 mm (3).
A trained dental hygienist divided 144 empty capsules of same
color and size into 3 bottles: ibuprofen (IBUP), ketorolac (KETA), and
Materials and Methods placebo (PLAC) group. IBUP capsules were filled with 300 mg of
Seventy-two adult volunteer subjects, who reported in the dental
ibuprofen, KETA capsules were filled with 10 mg of ketorolac, and
emergency department, participated in this 3-month-long prospective,
PLAC capsules were filled with starch. The bottles were masked with an
randomized, double-blind study. The sample size calculation consisted
opaque label and were randomly assigned a 3-digit alphanumeric value.
of a level type I error of 0.05 and b level type II error of 0.20. A power
Another trained dental hygienist randomly divided all the patients into 3
calculation dictated that a sample size of 63 subjects would give 80%
groups of 24 patients each and gave 2 capsules 1 hour before the
power to detect a 20% difference in the success rate of 2 test groups.
procedure. Only the alphanumeric values were recorded on the data
We assumed a dropout rate of approximately 10% and enrolled at least
sheets to blind the experiment.
23 subjects in each group. The subjects were actively experiencing pain
After 1 hour of oral administration of the capsules, all patients
and were in good health, and none were taking any medication that
received standard IANB injections by using 1.8 mL of 2% lidocaine with
would alter pain perception, as determined by oral questioning and
1:200,000 epinephrine (Xylocaine; AstraZeneca Pharmaceutical
written questionnaire. An ethical clearance was sought from the institute
Products, Wilmington, DE). The solution was injected by the same clini-
review committee, and an informed written consent was obtained from
cian (first author) by using self-aspirating syringes (Septodont, Saint-
each subject.
Maur-des-Fosses Cedex, France) and 27-gauge long needles
Preoperative radiographs were obtained. The inclusion criteria for
(Septoject; Septodont). After reaching the target area, aspiration was
the study were active pain in a mandibular molar; prolonged response to
performed, and 1.7 mL of solution was deposited at a rate of 1 mL/min.
cold testing with an ice stick and an electric pulp tester (Kerr, Analytic
After 15 minutes of the initial IANB, each patient was asked if his
Technology Corp, Redmond, WA); absence of any periapical radiolu-
or her lip was numb. If profound lip numbness was not recorded within
cency on radiographs, except for a widened periodontal ligament and a
15 minutes, the block was considered unsuccessful, and the patients
vital coronal pulp on access opening; and ability to understand the use
were excluded from the study. The patients were again asked to rate
of pain scales. Exclusion criteria included known allergy, sensitivity, or
their pain on Heft Parker VAS. The involved teeth were isolated with a
contraindications to any opioid or nonopioid analgesic including aspirin
rubber dam, and a conventional access opening was initiated. Patients
or NSAIDs, history of active peptic ulcer within the preceding 12
were in-structed to raise their hand if any pain was felt during the
months, history of bleeding problems or anticoagulant use within the last
procedure. In case of pain during the treatment, the procedure was
month, patients who were pregnant or breast-feeding, a history of
stopped, and patients were asked to rate the pain on Heft Parker VAS.
known or suspected drug abuse, and patients who had taken NSAIDs
The extent of access preparation and/or instrumentation was recorded
within 12 hours before administration of the study drugs. Patients having
as within dentin, within pulpal space, and instrumentation of canals.
active pain in more than 1 mandibular molar were excluded from the
Success was defined as no pain or weak/mild pain during endodontic
study. The methodology was similar to our previous study (10). First
access preparation and instrumentation (3).
author (V.A.) screened and recruited the patients in the study.
The findings were recorded on a Microsoft Excel sheet (Microsoft
Randomization of patients was done by simple random sampling with a
Office Excel 2003; Microsoft Corp, Redmond, WA) for statistical evalu-
linear congruential generator. Randomized allocation of the patients
ation by using the program BioEstat, version 4.0 (Mamiraua Institute,
was done by a trained dental hygienist who was blinded to the treatment
Belem, Brazil). Age and initial and postinjection pains of the subjects
procedures.
Before initiating the treatment, the patients were asked to rate their
pain on a Heft Parker visual analog scale (VAS). Heft Parker VAS with TABLE 3. Comparison of Percentage of Successful
Anesthesia in Control and Test Groups
TABLE 2. Distribution of Teeth for Control PLAC, IBUP and KETA Groups Control
PLAC IBUP KETA
Tooth Control PLAC IBUP KETA
Successful 7 of 24 6 of 22 9 of 23
First molar 12/24 (50%) 10/22 (45%) 11/23 (48%) anesthesia patients patients (27%) patients
Second molar 12/24 (50%) 12/22 (55%) 12/23 (52%) (29%) (39%)
PLAC, placebo; IBUP, ibuprofen; KETA, ketorolac. PLAC, placebo; IBUP, ibuprofen; KETA, ketorolac.
There was no significant difference (P > .05) between the groups. There was no significant difference (P > .05) between the groups.

376 Aggarwal et al. JOE — Volume 36, Number 3, March 2010

 CONSORT Randomized Clinical Trial

were summarized by using means and standard deviations.
Multiple comparison analysis of variance and post hoc tests
were used to deter-mine significant differences at P <.05.
Anesthetic success of the IBUP, KETA, and PLAC groups was
dichotomous in nature and was analyzed by using c2 tests.
Results
Seventy-two adult volunteer subjects, 38 men and 34 women, with
an average age of 31 years, range 21–38 years, participated in this
prospective, randomized, double-blind study. Of the original 72 patients,
3 patients, 2 from IBUP group and 1 from KETA group, did not have
profound lip numbness at 15 minutes and were excluded from the study.
The age, gender, and initial and 15-minute postinjection pain of all the
patients are presented in Table 1. Distribution of teeth for PLAC
(control), IBUP, and KETA groups is presented in Table 2. There was
no statistical difference between the age (P = .72), gender (P = .94),
initial pain (P > .05), and distribution of teeth. All patients included in the
study had profound lip anesthesia after 15 minutes. All patients reported
a significant decrease in active pain after local anes-thesia (P < .05).
The postinjection pain Heft Parker VAS scores of different groups were
insignificant (P = .94).
The comparison of percentage of patients with successful anes-
thesia (no pain or weak/mild pain during endodontic access prepara-tion
and instrumentation) is presented in Table 3. Control PLAC gave 29%
success rate (7 of 24 patients). Premedication with ibuprofen (IBUP)
Pathogenesis of irreversible pulpitis includes inflammation of pulp,
leading to breakdown of damaged cell membranes and release of AA,
mediated by either secretory (sPLA2) or cytoplasmic (cPLA2)
phospholipases (21, 22, 34). In response to various inflammatory
stimuli, AA is acted on by COX or prostaglandin H synthase (PGHS)
enzymes and gets converted into 20 carbon chain molecules called
eicosanoids, which are further converted by various cell-specific isom-
erases and synthases to produce 5 biologically active primary PGs that
include PGD2, PGE2, PGF2a, prostacyclin (PGI2), and thromboxane A2
(TxA2) (34–37). PGs sensitize nerve endings to bradykinins and hista-
mines and enhance the pain and tenderness of inflammation.
In the early 1990s, an inducible isoform of COX enzyme, now
called COX-2, was discovered (21, 22). It is now well-accepted that
COX enzymes are present in 2 isoforms: COX-1 and COX-2. The COX-
1 isoform is constitutively expressed at high levels in cells and tissues
and is responsible for synthesizing prostanoids that have cytoprotective
functions (22, 35–38). The COX-1 enzymes regulate normal cell activ-
ities in endothelium, monocytes, platelets, renal collecting tubules, and
seminal vesicles. The COX-2 isoform, normally not present in tissue, is
induced by mediators of inflammation such as lipopolysaccharides,
interleukin-1, and tumor necrosis factor-alpha (22, 35–37).
COX enzymes consist of a COX active site and a long hydro-
phobic channel. The entrance of the COX channel is guarded by a
network of hydrogen bonds comprising Arg120, Glu524, Tyr355, and
His90 (38, 39). The carboxyl moiety of NSAIDs generally binds at
Tyr385 and Arg120 and inhibits both isoforms of COX. The COX-2
˚ ˚

gave 27% (6 of 22 patients), and premedication with ketorolac (KETA)

(394 A) active site is 20% larger than COX-1 (316 A)
gave 39% (9 of 23 patients) success rate. There was no signif-icant
(39). Hence, selective COX-2 inhibitors bind to COX-2 as
difference between the 3 groups. None of the techniques gave 100% a result of reduced steric and ionic crowding at the
success rate. The pain and discomfort ratings of the patients with mouth of the channel (binding site) by Arg120 (38–41).
unsuccessful anesthesia (Heft Parker VAS score >54) with relation to Because of efficacy of NSAIDs to effectively block the COX
extent of access preparation and/or instrumentation are presented in pathway, it was hypothesized that premedication with NSAIDs will help
Table 4. in management of patients with irreversible pulpitis by inhibiting the
formation of PGs and thus minimizing the activation of nocicep-tors. In
Discussion 2007 Modaresi et al (32) advocated premedication with ibuprofen for
achieving deep anesthesia in patients with irreversible pulpitis. They
IANB is an effective tool in management of mandibular endodontic
evaluated the depth of anesthesia with the help of elec-tric pulp tester
procedures by reversibly interrupting the propagation of inferior alve-olar
and did not evaluate the success or failure rate on basis of pain during
nerve impulses. IANB might provide successful anesthesia in 70% of
root canal treatment (32). In the present study, effect of premedication
uninflamed pulp, but the success rate drastically decreases to 30% or
with ibuprofen and ketorolac was studied by using pain response on
even less in patients with irreversible pulpitis (2, 3, 5–10). The litera-ture
modified Heft Parker VAS in a prospective, randomized, double-blind
suggests activation of nociceptors by inflammatory mediators such as
trial. Success was considered as no pain or weak/mild pain during
PGs as a major cause of increased incidence of failure of IANB in
endodontic access preparation and instru-mentation. Premedication
patients with irreversible pulpitis (15–20).
was given 1 hour before the procedure to allow NSAIDs to achieve
satisfactory plasma concentration. In the present study, PLAC group
TABLE 4. Comparison of Number of Unsuccessful gave 29% success rate, which is compa-rable with previous studies (3,
Anesthesia in Control and Test Groups 10, 14). Premedication with ibuprofen (27%) or ketorolac (39%) did not
significantly increase the success rate. The results do not match with
Heft Parker Heft Parker
the findings of Mod-aresi et al, although the method of evaluation is
VAS score VAS score
54–114 >114 different. All the patients in the present study had active pain during the
presentation. It is possible that because of acute inflammatory reaction,
Within Control 5 of 17 3 of 17
the inflam-matory mediators had already activated the nociceptors.
dentin PLAC
IBUP 4 of 16 5 of 16 Medication with NSAIDs only inhibits the formation of PGs but has no
KETA 4 of 14 3 of 14 effect on already activated nociceptors. There was no significant
Within Control 2 of 17 4 of 17 difference between the pain and discomfort ratings of the patients with
pulpal space PLAC unsuc-cessful anesthesia (Heft Parker VAS score >54, moderate or
IBUP 2 of 16 3 of 16
KETA 3 of 14 1 of 14 strong, intense pain) with relation to extent of access preparation and/or
Instrumentation Control 2 of 17 1 of 17 instrumentation. Majority of the unsuccessful patients had pain during
of canals PLAC dentin penetration and did not allow penetration of the pulpal chamber.
IBUP 2 of 16 2 of 16 Intrapulpal anesthesia, which is a last resort in such patients, could be
KETA 2 of 14 1 of 14
given only after small penetration in the pulpal
VAS, visual analog scale.

JOE — Volume 36, Number 3, March 2010 Effect of NSAIDs on Anesthetic Efficacy of IANB
377
CONSORT Randomized Clinical Trial
roof. In the present study, intraosseous injection was used in further
management of patients with unsuccessful anesthesia. It should also be
noted that although all the patients had subjective symptoms of lip
numbness, the anesthesia was not successful in all cases. This
phenomenon is also seen in uninflamed pulps, in which in spite of
successful lip numbness, the clinician failed to get a response to the
maximum stimulus on electric pulp testing (8–11, 14). A further clinical
study on a larger sample size, with the latest NSAIDs, is planned to
strengthen the results.
In conclusion, preoperative administration of ibuprofen or
ketor-olac has no significant effect on success rate of IANB in
patients with irreversible pulpitis. There was no significant
difference between the ibuprofen or ketorolac groups.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.joen.2009.11.010
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JOE — Volume 36, Number 3, March 2010