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Abstract
Introduction: The present clinical trial aimed to eval-
uate and compare the effect of a single pretreatment
dose of ketorolac (20 mg), prednisolone (30 mg), and
P osttreatment endod-
ontic pain has been
reported in 25%69%
Signicance
Patients often judge the quality of endodontic care
received by the presence and intensity of postop-
placebo on postendodontic pain in patients undergoing of all endodontic pa-
erative pain. This study shows that a preemptive
endodontic therapy for irreversible pulpitis or pulpal ne- tients (13). Among
dose of prednisolone promotes a greater reduction
crosis using a visual analog scale. Methods: Ninety-two various reasons, the
in postoperative pain than ketorolac or placebo.
subjects were included in the present trial; 46 subjects most probable causes for
had a pulpal diagnosis of irreversible pulpitis, and the pain during and after
other 46 had pulpal necrosis. These subjects were endodontic treatment are tissue injury caused by endodontic instrumentation,
randomly allocated into 1 of the 3 pretreatment medica- periapical contamination, caustic irrigants, intracanal medications, and occlusal
tion groups: ketorolac (20 mg), prednisolone (30 mg), or discrepancies (4, 5). The tissue injury triggers a barrage of nociceptor activation
a placebo. The drugs were administered 30 minutes and local inflammatory processes that are regulated by chemical mediators
before the procedure followed by a routine single-visit released from damaged tissues and agents of vascular or neural origin, such as
root canal treatment. Preoperative and postoperative prostaglandins, leukotrienes, bradykinin, serotonin, and cytokines. These
pain was evaluated using a visual analog scale at 6 inflammatory mediators may in turn activate and sensitize nociceptors, leading to
time intervals. A comparison between the different peripheral sensitization (6, 7).
groups was performed using one-way analysis of vari- Pretreatment analgesia is providing analgesia to patients before endodontic
ance followed by the Tukey post hoc test. A comparison treatment is started. This technique can decrease the establishment of central and
of pain within each group at various time intervals was peripheral sensitization, which has the potential to reduce postoperative pain and
performed using repeated measures analysis of variance postoperative analgesic intake (8, 9).
followed by the paired t test and Bonferroni correction. In this context, drugs that modulate the inflammatory response such as steroidal
Results: At the end of 6 hours, in irreversible pulpitis (corticosteroids) and nonsteroidal anti-inflammatory drugs (NSAIDs) can be
cases, the ketorolac group showed an effective considered for the prevention and control of peripheral factors in postendodontic
reduction in pain scores compared with the other drugs. pain (10). Ketorolac and prednisolone are potent anti-inflammatory agents belonging
At the end of 12 hours, the prednisolone group to the NSAID and corticosteroid groups, respectively.
significantly reduced the pain scores compared with
the other drugs. Conclusions: From this study, it could
Ketorolac is an NSAID that inhibits prostaglandin synthesis in the periphery,
be concluded that a single pretreatment dose of
which is a key component in sensitizing the nociceptors to other inflammatory
prednisolone has a more sustained effect in reducing
mediators (11, 12). Prednisolone is a synthetic glucocorticoid, a derivative of
postendodontic pain compared with placebo or
cortisol. A steroid-induced protein, lipocortin, has antiphospholipase A2 activity,
ketorolac. (J Endod 2017;43:667673)
preventing the synthesis of arachidonic acid and thereby reducing the biosynthesis of
both cyclooxygenase and lipoxygenase products (13).
Key Words The effectiveness of preemptive analgesics is well established in surgical models;
Corticosteroids, intravenous, nonsteroidal anti- however, the literature is unclear regarding endodontic models. Many trials favor the
inflammatory agents, pretreatment analgesic, random- use of preemptive anti-inflammatory drugs for endodontic pain (1416),
ized controlled trial, root canal therapy, visual analog whereas some have shown no favorable outcomes (9, 17). Studies have evaluated
pain scale the efficacy of 1 or more NSAIDs or a corticosteroid premedication against a
From the Departments of *Conservative Dentistry and Endodontics and Pedodontic and Preventive Dentistry, Indira Gandhi Institute of Dental Sciences, Puducherry,
India; and Department of Conservative Dentistry and Endodontics, Bapuji Dental College and Hospital, Davangere, India.
Address requests for reprints to Dr R. Praveen, Department of Conservative Dentistry and Endodontics, Indira Gandhi Institute of Dental Sciences, Puducherry, India.
E-mail address: prav.rajesh@gmail.com
0099-2399/$ - see front matter
Copyright 2016 American Association of Endodontists.
http://dx.doi.org/10.1016/j.joen.2016.12.012
JOE Volume 43, Number 5, May 2017 Premedication With Ketorolac and Prednisolone 667
CONSORT Randomized Clinical Trial
placebo (9, 1416). However, concrete evidence on which class of The tablets were dispensed by a blinded investigator not involved in
premedication is best suited for postendodontic pain control does the study. The code details were not revealed to the principal operator
not exist. Hence, this study was conducted to compare the severity of until the end of the study. Similarly, the patient was also unaware of
postoperative pain in patients undergoing single-visit endodontic ther- which 1 of the 3 medications he or she was taking.
apy with irreversible pulpitis or necrotic pulp after a single dose of ke-
torolac (20 mg), prednisolone (30 mg), or placebo as a Intervention
premedication. Thirty minutes before the endodontic procedure, ketorolac
(20 mg, Ketorol; Dr. Reddys Labs Limited, Princeton, NJ), predniso-
Material and Methods lone (30 mg, Wysolone; Pfizer Ltd [Wyeth Ltd], New York, NY), or a pla-
Selection of Subjects cebo was administered. Root canal therapy in all cases (vital and
Approval of the study protocol and ethical clearance were obtained nonvital teeth) was completed by the principal investigator in a single
from the Institutional Review Board, Bapuji Dental College and Hospital, visit. After explanation of the treatment procedures (according to indi-
Davangere, India. A patient information form was given to all enrolled vidual needs), the tooth was anesthetized by a nerve block using 1 to 2
participants, and their informed consent was obtained. The study sub- doses (1.8 mL each) of anesthetic solution (2% lidocaine with
jects recruited in this triple-blind, parallel, randomized controlled trial 1:100,000 epinephrine, Lignox; Indoco [Warren, Mumbai, India]).
were from the pool of patients selected in the Department of Conserva- After this, the tooth was isolated with a rubber dam, and access prepa-
tive Dentistry and Endodontics, Bapuji Dental College and Hospital. ration was performed. Apical patency was maintained with a number 10
K-file. Cleaning and shaping were performed with a hybrid technique
using hand K-files (Kendo; VDW, Munchen, Germany) and the ProTaper
Sample Size (Dentsply Maillefer, Ballaigues, Switzerland) rotary system for all teeth.
The sample size was calculated considering the mean expected dif- Sodium hypochlorite (3%) and EDTA (17%) were used during canal
ference and pooled standard deviation from previous literature (16). preparation, whereas saline was used as the final irrigant. Apical prep-
The minimum sample required to detect differences between 6 groups aration was performed with files at least 3 sizes greater than the initial
(with type I error at 5% and power at 80%) was found to be 9 subjects apical file. After drying the canals with sterile paper points, they were
per group. The sample size was increased to 15 participants per group coated with AH Plus (Dentsply Maillefer) sealer using lentulospirals
to account for the potential refusal to participate, procedural errors, or and obturated with gutta-percha using the lateral condensation tech-
loss of patients during the trial. nique. The tooth was then temporized using Cavit (3M ESPE, St Paul,
MN) and reduced from occlusion.
Inclusion and Exclusion Criteria Patients were kept under observation for 3 hours from the time the
Inclusion criteria included cases with a pulpal diagnosis of irre- drug was administered. A rescue medication (ibuprofen) was pre-
versible pulpitis or pulpal necrosis in single-rooted teeth. Exclusion scribed, and the patients were instructed to take it only if they experi-
criteria were cases with acute periapical conditions (acute apical enced severe pain postoperatively. If rescue medication was taken
periodontitis/acute apical abscess) or teeth with a periapical index within the 48 hours after the treatment, then the patient was excluded
score >3. The periapical index is a severity-based ordinal scale scoring from the study.
system used in radiographic evaluations of apical periodontitis (18).
Also, patients with a known allergy, sensitivity, or history of other Assessment of Pain after Root Canal Treatment
adverse reactions to the medications administered and analgesics/ Patients pain intensity experience was measured using the visual
anti-inflammatory drugs taken within the last 6 hours were excluded analog scale (VAS), which consists of a 10-cm line anchored by 2 ex-
from the study. tremes, no pain and pain as bad as it could be. Patients were asked
to make a mark on the line that represents their level of perceived pain.
They were instructed to complete a pain diary at specific intervals (ie,
Subject Allocation and Randomization Method
before the commencement of any treatment [baseline score]; immedi-
An examiner not involved in the trial assessed 121 patients for
ately after treatment completion; and 6, 12, 24, and 48 hours after the
eligibility based on case history and clinical and radiographic examina-
commencement of treatment). All subjects were recalled after 2 days to
tion (Table 1). Patients were diagnosed using a standard protocol and
return the pain diary and for a clinical evaluation.
assigned to the pulpal necrosis or irreversible pulpitis groups (as
shown in Table 2). The intraoral periapical radiographs were viewed
on an x-ray viewer, and the areas other than the periapex were covered Statistical Analysis
with 4 pieces of black photographic paper. The periapical region was Normality of the data was tested using the Kolmogorov-Smirnov
then scored between 1 and 5 categories according to the periapical test. Because the data showed normal distribution, parametric tests
index using reference photographs (18). Among them, 13 patients were used for comparing the means.
did not meet the inclusion/exclusion criteria, and 16 patients refused Pain experienced by subjects belonging to different drug groups
to participate in the trial. Provisional diagnoses of irreversible pulpitis was analyzed using one-way analysis of variance (ANOVA) followed
(46 subjects) and pulpal necrosis (46 subjects) were made for the by the Tukey post hoc test. A subgroup analysis between irreversible pul-
included 92 subjects. A computer-generated random sequence of the pitis cases and pulpal necrosis cases was performed using the unpaired
chosen subjects was obtained. Allocation concealment to ensure proper t test. A comparison of pain (mean VAS scores) within each group
randomization was performed using sealed numbered opaque at various time intervals was performed using repeated-measures
envelopes; patients had to randomly pick up their envelope, which ANOVA followed by the paired t test and Bonferroni correction.
contained the group code. The drugs were placed in 3 identical opaque
containers and were coded (code A, ketorolac; code B, prednisolone; Results
or code C, placebo). All medications were orally administered There were 42 women and 44 men included in this clinical trial.
30 minutes before the initiation of conventional root canal therapy. There were no significant differences between the groups with respect to
Excluded (n = 31)
Assessed for eligibility
Not meeting inclusion/exclusion
(n = 121) criteria (n = 13)
Pulpal necrosis
Irreversible Pulpitis
(n = 0) (n = 0) (n = 0) (n = 0) (n = 0) (n = 0)
(n = 1) - (n = 1) (n = 2) (n = 1) (n = 0) (n = 1)
Took Took Took Took Took Took
rescue rescue rescue rescue rescue rescue
medication medication medication medication medication medication
age, sex, and arch (Table 3). A comparison of pain among the ketoro- (P < .05) (Table 4). Tukey post hoc analysis was performed to
lac, prednisolone, and placebo groups measured by the VAS at different determine the differences between the specific groups. At the 6-
time intervals is shown in Table 4. Preceding endodontic therapy, the hour time interval, a significant reduction in pain was observed
baseline pain data showed no significant difference (P > .05) between in the ketorolac group compared with the placebo group. At
the 3 premedication groups in both the irreversible pulpitis and pulpal the 12- and 24-hour time intervals, prednisolone showed a signif-
necrosis cases (Figs. 1 and 2). icant pain reduction compared with the placebo and ketorolac
The one-way ANOVA test was performed on the drug groups groups. At the 48-hour time interval, prednisolone still showed
(ketorolac, prednisolone, and placebo), and significant differ- a significantly lower mean VAS score compared with the placebo
ences in VAS score means were noted at 6, 12, 24, and 48 hours group.
JOE Volume 43, Number 5, May 2017 Premedication With Ketorolac and Prednisolone 669
CONSORT Randomized Clinical Trial
TABLE 2. Diagnostic Procedure for Grouping into Irreversible Pulpitis or Pulpal Necrosis Groups
Stage Procedure Irreversible pulpitis Pulpal necrosis
History Description of presenting complaint/ Severe or lingering or Pain on chewing or intermittent
pain history continuous or spontaneous pain or dull pain
Clinical Extraoral signs/intraoral signs/ Any sign of pulpal involvement Any sign of pulpal involvement
examination individual tooth assessment Restoration or discoloration of tooth or
assessment sinus tract
Percussion and palpation No or mild tenderness Mild tenderness
Pulp sensibility Cold Test (Endo Frost; Roeko, Positive response for both tests Negative response for both tests
test tten, Switzerland) with
Altsta
a cotton pellet
Electric pulp testing
Radiographic Periapical radiograph for assessment No periapical changes No changes or presence of
assessment of periapical and periodontal status periapical rarefaction
Definitive Combination of above findings
diagnosis
The immediate postoperative pain intensity generally decreased already in a state of inflammation. This inflammatory response might
in all groups because of the effect of local anesthesia. Pulpal anes- have been partially or completely mitigated by the active drugs given
thesia usually lasts for 60 to 90 minutes (24). The irreversible pul- in the other 2 groups. These findings are in accordance with a previous
pitis cases recorded greater pain scores compared with pulpal study by Jalalzadeh et al (28). Although care was taken during the
necrosis, which may be explained by difficulty in obtaining anes- cleaning and shaping procedures (use of apex locator and
thesia in teeth with irreversible pulpitis, especially in mandibular crown-down technique) to cause minimal harm to periapical
teeth (25). tissues and minimize extrusion of debris, some amount of extrusion
At the end of 6 hours, the ketorolac group showed a significant is unavoidable (29). This could have been minimized if negative
reduction in pain scores compared with the placebo. This can be pressure irrigation techniques were used (30).
attributed to its pharmacodynamics; peak analgesia is experienced at At the end of 12 hours, prednisolone significantly reduced the pain
2 to 3 hours and lasts for 6 hours. Similar findings were observed in scores compared with the other 2 drugs. This may be because of its
other studies (21, 26, 27). The placebo and prednisolone groups greater anti-inflammatory potency compared with NSAIDs (13) and
did not significantly reduce the pain scores at this time interval. the longer biologic half-life of 12 to 36 hours (12). At this time interval,
Prednisolone, although it achieves a plasma peak in 2 hours, an increase in pain scores was observed in the ketorolac group, which
requires greater time for its biologic effects to set it because it works can be attributed to its plasma half-life of around 6 hours, after which
through transcription of mRNA and production of new proteins, the inflammation might have spiked. The concept of preemptive
which can take a few hours (27). The placebo group showed a signif- analgesia allows us to expect the analgesic effect of the drug to extend
icant spike in the VAS score at 6 hours in the pulpal necrosis cases, beyond its expected clinical duration of action because of the prevention
probably because of the more intense inflammatory response that could of peripheral sensitization (31), but this was not the case in this study
be set up in periapical tissues because of debris extrusion, which are with respect to ketorolac.
60
VAS Score
60
50
50
40
40
30 30
20 20
10 10
0 0
baseline immediate 6 hours 12 hours 24 hours 48 hours baseline immediate 6 hours 12 hours 24 hours 48 hours
post op post op
Time Interval Time Interval
Figure 1. Graphic representation of VAS scores of the 3 medication groups in Figure 2. Graphic representation of VAS scores of the 3 medication groups in
the irreversible pulpitis cases. pulpal necrosis cases.
JOE Volume 43, Number 5, May 2017 Premedication With Ketorolac and Prednisolone 671
CONSORT Randomized Clinical Trial
TABLE 5. Subgroup Analysis of Irreversible Pulpitis (IP) and Pulpal Necrosis (PN)
Ketorolac Prednisolone Placebo
IP PN IP PN IP PN
Time intervals Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD)
Baseline 57.33 (16.54) 23.87 (20.50) 45.8 (22.7) 17.7 (10.0) 48.2 (23.8) 14.4 (9.66)
IP vs PN t = 4.92, P = .001 (S) t = 4.39, P = .001(S) t = 5.081, P = .001 (S)
Immediate postoperative 29.3 (17.8) 17.4 (12.8) 33.7 (21.1) 18.1 (12.9) 34.0 (19.7) 12.8 (8.06)
IP vs PN t = 2.08, P = .04 (S) t = 2.45, P = .021 (S) t = 3.83, P = .001 (S)
6 hours 22.1 (14.3) 19.0 (10.6) 31.5 (18.4) 21.8 (10.8) 36.7 (17.5) 23.8 (12.0)
IP vs PN t = 0.66, P = .51 (NS) t = 1.75, P = .09 (NS) t = 2.35, P = .03 (S)
12 hours 30.1 (15.9) 30.8 (8.4) 19.2 (11.7) 15.8 (7.65) 41.2 (14.5) 22.8 (11.2)
IP vs PN t = 0.143, P = .88 (NS) t = 0.93, P = .35 (NS) t = 3.86, P = .001 (S)
24 hours 26.6 (10.6) 27.6 (10.7) 15.5 (11.0) 13.6 (9.5) 36.2 (13.3) 16.9 (7.01)
IP vs PN t = 0.257, P = .79 (NS) t = 0.49, P = .62 (NS) t = 4.94, P = .001 (S)
48 hours 20.6 (9.6) 22.1 (11.6) 10.4 (8.09) 8.2 (5.51) 27.1 (15.6) 12.8 (5.85)
IP vs PN t = 0.376, P = .71 (NS) t = 0.89, P = .37 (NS) t = 3.31, P = .003 (S)
NS, not statistically significant; S, statistically significant; SD, standard deviation.
Unpaired t test.
At the 24-hour evaluation, there was a slight reduction in pain Supplementary Material
in all the groups. This was suggestive of a gradual reduction in the Supplementary material associated with this article can be
inflammatory pain postendodontic therapy. This finding is in accor- found in the online version at www.jendodon.com (http://dx.doi.
dance with Harrison et als study (32) in which they found that org/10.1016/j.joen.2016.12.012).
more than 90% of the patients reported no or mild pain 24 hours
after obturation. Similarly, the pain scores further reduced from 24
to 48 hours because of a further reduction in the inflammatory re- References
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JOE Volume 43, Number 5, May 2017 Premedication With Ketorolac and Prednisolone 673