CONSORT Randomized Clinical Trial
A Randomized Clinical Trial Comparing 2
Ibuprofen Formulations in Patients with Acute
Odontogenic Pain
Tanjit Taggar, DMD, MS,* Di Wu, PhD, and Asma A. Khan, BDS, PhD
Abstract
Introduction: Ibuprofen sodium dihydrate, a new
formulation of ibuprofen, was introduced with the claim
of faster onset of analgesia. Most of the data on this
new ibuprofen formulation are drawn from studies using
the oral surgery model. Because this model differs signif-
icantly from the endodontic pain model, we conducted a
study comparing ibuprofen sodium dihydrate with con-
ventional ibuprofen acid in endodontic pain patients.
Methods: This randomized, double-masked study re-
cruited subjects experiencing moderate to severe pain
from a tooth diagnosed with symptomatic irreversible
pulpitis and symptomatic apical periodontitis (n = 41).
Subjects were randomized to receive 400 mg ibuprofen
acid (Advil; Pfizer, Madison, NJ) or an equivalent dose of
512 mg ibuprofen sodium dihydrate (Advil Sodium,
Pfizer). The outcome measures were time to onset of
50% pain relief recorded using a stopwatch, reduction
in spontaneous pain experienced on a 100-mm visual
analog scale, and change in mechanical allodynia
measured using a bite force transducer. The last 2 mea-
sures were obtained before and 60 minutes after admin-
istration of the drug. Results: The median time to onset
of 50% pain relief after administration of ibuprofen so-
dium dihydrate was significantly faster compared with
ibuprofen acid (26.5 vs 44 minutes, P = .08). Ibuprofen
sodium dihydrate provided a greater reduction in spon-
taneous pain (50.8% vs 33.3%, P < .05) and mechanical
allodynia (15% vs 9%, P > .05). Conclusions: In end-
odontic pain patients, a single dose of ibuprofen sodium
dihydrate provides faster onset of pain relief and a
greater reduction in spontaneous and evoked pain
compared with ibuprofen acid. (J Endod 2017;43:674
678)
Key Words
Ibuprofen, nonsteroidal anti-inflammatory drugs, me-
chanical allodynia, pain, pulpitis
From the *Private Practice, Rochester, NY; and Departments of Periodontology and Endodontics, University of North Carolina at Chapel Hill, Chapel Hill, North
Carolina.
Address requests for reprints to Dr Asma A. Khan, 1170 First Dental Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. E-mail address:
Asma_Khan@unc.edu
0099-2399/$ - see front matter
Copyright 2016 American Association of Endodontists.
http://dx.doi.org/10.1016/j.joen.2016.12.017
674 Taggar et al.
O dontogenic pain asso-
ciated with irreversible
pulpitis usually has an acute
Signicance
The results of this randomized, double-masked,
controlled study showed that a single dose of
onset and is often moderate
ibuprofen sodium dihydrate provides faster and
to severe in intensity (1, 2).
greater pain relief than a comparable dose of con-
A study on the management
ventional ibuprofen acid in endodontic pain pa-
of odontogenic pain reported
tients.
that only half of the pain
patients initially attempt to
contact a dental professional and use over-the-counter (OTC) analgesics instead
(3). Another study reported that between 81% and 83% of odontogenic pain patients
used OTC analgesics for pain relief (4). These analgesics include aspirin, acetamino-
phen, and nonsteroidal anti-inflammatory drugs (NSAIDs).
The speed of onset of an analgesic is critical in acute pain conditions, not only
because of the relief experienced but also because rapid onset of pain relief reduces
the risk of excessive dosing. Patients are likely to use more than the recommended
dose of an analgesic or to supplement it with a different type of analgesic when rapid
pain relief is not achieved. This can be detrimental because many adverse effects are
dose dependent.
Ibuprofen acid has been used for decades to alleviate odontogenic pain and is
considered the gold standard NSAID in clinical trials on acute odontogenic pain
(5, 6). A limitation of ibuprofen acid is that it is not readily soluble, which, in turn,
affects its onset of action (7, 8). Enhancements in ibuprofen acids
pharmacokinetics have led to the development of ibuprofen salts with a faster
dissolution rate and onset of action. These ibuprofen salts include ibuprofen lysine,
ibuprofen arginine, and ibuprofen sodium dihydrate; only the latter is currently
approved by the United States Food and Drug Administration in a tablet formulation.
An in vitro study showed a faster dissolution of ibuprofen sodium dihydrate at a pH
of 1.2, 3.5, and 7.2 in comparison with ibuprofen acid (7). This greater solubility allows
greater absorption and subsequently a faster onset of analgesic effect. In vivo pharma-
cokinetic studies using the oral surgery model show that ibuprofen sodium dihydrate
has a higher drug plasma concentration (41.47 mg/mL vs 31.88 mg/mL) and a lower
time to reach the maximum concentration of the drug (75 minutes vs 90 minutes) than
ibuprofen acid, thereby producing faster and more profound analgesia (72) (7, 9, 10).
The previously mentioned data from the oral surgery model, although useful,
cannot always be readily translated to endodontic pain patients. In the oral surgery
model, the study subjects often presented with either no pain or mild pain before
the removal of their third molars. Thus, the acute inflammatory pain evaluated in
JOE Volume 43, Number 5, May 2017
 CONSORT Randomized Clinical Trial
such clinical trials results mostly from the surgical trauma. In contrast, TABLE 1. Age and Sex Distribution of Study Subjects
endodontic patients often present in pain that may be moderate to se-
Group Age Sex
vere in intensity. The objective of this study was to compare the analgesic
effect of a single dose of ibuprofen sodium dihydrate with that of a com- Ibuprofen acid 37.3  9.7 years 13 women and 8 men
Ibuprofen sodium 33.4  11.7 years 10 women and 10 men
parable dose of ibuprofen acid in endodontic pain patients presenting dihydrate
with moderate to severe pain.

effects. The onset of 50% pain relief was analyzed using the Kaplan-
Materials and Methods Meier estimator as in survival analysis.
This randomized, double-masked, controlled, parallel-group trial
Comparisons were made of control and affected teeth between
was approved by the Office of Human Research Ethics at our institution.
preadministration and postadministration of the drug within the 60-
Healthy men and women (aged 1860 years old) experiencing moder- minute study period. The effects caused by the usage of the different
ate to severe pain (defined as >30 mm on a 100-mm visual analog scale
drugs are inferred based on these comparisons. Because of the usage
[VAS]) and diagnosed with symptomatic irreversible pulpitis (defined
of the mixed-effect model, all analysis considered the data as paired
as spontaneous pain and lingering response to thermal stimuli) and data by the subject identification numbers. After checking the box
symptomatic apical periodontitis (defined as sensitivity to percussion) plot, histogram, and QQ plots of the mechanical pain thresholds, the
were recruited to the study. Subjects who had recently used any type of
scores were log2 transformed for a more symmetric distribution so
analgesics were questioned about the dose and type of analgesic used. If
that the assumptions of the models were valid. The restricted maximum
it was determined that the potential study subjects could be experi- likelihood was used for analysis of change in mechanical pain thresh-
encing the therapeutic effect of the drug at the time of the study, they
olds.
were excluded. Subjects with a known hypersensitivity to NSAIDs, a his-
Possible confounders include age and sex. We checked the asso-
tory of gastric or duodenal ulcers, or gastrointestinal bleeding were not ciation between age and each of the 2 outcomes as well as the associ-
recruited to the study. We also excluded pregnant and lactating women
ation between sex and each of the 2 outcomes. Significance was set at
and subjects classified as American Society of Anesthesiologists class III
P < .05. Marginal significance was set at P = .05.1.
through V. Written informed consent was obtained from all subjects.
This study lasted 60 minutes and had 3 outcome measures: onset
of 50% pain relief, reduction in spontaneous pain, and attenuation of Results
mechanical allodynia after administration of the 2 ibuprofen formula- Forty-one subjects were enrolled and completed the study between
tions. Subjects were first asked to report the intensity of the pain they March 2015 and March 2016. The age and sex distributions are listed in
were experiencing on a 100-mm VAS with anchors of 0 mm represent- Table 1. When comparing subjects in the ibuprofen sodium dihydrate
ing no pain and 100 mm representing the worst pain imaginable (11). group with those in the ibuprofen acid, there were no differences in
We then measured mechanical pain thresholds on the painful and age and sex.
contralateral asymptomatic (control) teeth using a digital bite force The median time to onset of 50% pain relief in the ibuprofen so-
transducer as described in previous studies (1214). Mechanical dium dihydrate group was 26.5 minutes compared with 44.0 minutes in
allodynia was calculated as the difference in mechanical pain the ibuprofen acid group (P = .08) (Figure 1). Twelve patients did not
thresholds between the controls and the affected teeth (13).
Subjects were randomly assigned to receive a single dose of
400 mg ibuprofen acid (Advil; Pfizer, Madison, NJ) or an equivalent
dose of 512 mg (2 tablets  256 mg) ibuprofen sodium dihydrate (Ad-
vil). We used a block randomization plan. The senior author (A.K.) as-
signed participants, whereas the first author (T.T.) enrolled all
participants. After administration of the drug, they were given a stop-
watch and instructed to stop it when they felt a 50% decrease in pain
intensity. At 60 minutes after administration of the drug, subjects
were asked to rate their pain on the VAS, and the mechanical pain
thresholds of the painful and control teeth were determined. All the
diagnostic tests and data collection were performed by a single exam-
iner (T.T.) who remained masked about the type of ibuprofen formu-
lation given to the subjects.

Statistical Analysis
Sample size analysis was based on our prior studies examining me-
chanical allodynia in odontogenic pain patients (13, 14). There were 3
outcome variables for this study. The decrease of pain intensity and
change in mechanical allodynia were analyzed by fitting a linear
mixed-effects model to data via the restricted maximum likelihood. Sta-
tistical analysis was performed in R statistical software (version 3.2.3,
www.cran.r-project.org). The R function lmer in package lme4 was Figure 1. Time to onset of 50% pain relief using the Kaplan-Meier estimator.
used for this mixed-effects model in which the subject identification The administration of ibuprofen sodium dihydrate 512 mg resulted in faster
numbers are considered as the random variable to affect the intercept onset of pain relief than ibuprofen acid 400 mg in odontogenic pain patients
of the regression. The effects of the 3 outcomes are considered as fixed experiencing moderate to severe pain (P = .08).

JOE Volume 43, Number 5, May 2017 Ibuprofen and Acute Odontogenic Pain 675
CONSORT Randomized Clinical Trial

Figure 2. Box plots of pain intensity before and 60 minutes after the administration of ibuprofen acid 400 mg and ibuprofen sodium dihydrate 512 mg in patients
with symptomatic irreversible pulpitis and symptomatic apical periodontitis. Pain intensity was measured on a 100 mm VAS.

experience at least 50% pain relief within the 60-minute study period. a 33.3% decrease in pain intensity (P < .001) (Figure 2). When
These included 8 subjects who received ibuprofen acid and 4 subjects comparing the 2 groups, it was noted that ibuprofen sodium dihydrate
who received ibuprofen sodium dihydrate. resulted in a greater decrease in pain intensity than ibuprofen acid
The administration of both formulations of ibuprofen resulted in a (P < .05).
significant decrease in spontaneous pain. Subjects who received Analysis of mechanical pain thresholds at baseline showed that
ibuprofen sodium dihydrate experienced a 50.8% decrease in pain in- the control teeth in the 2 groups had similar mechanical pain thresh-
tensity (P < .001), and those who received ibuprofen acid experienced olds and that the pain thresholds of symptomatic teeth in both
-1
-2
-3
MECHANICAL
ALLODYNIA
-4
-5
-6

All controls All cases Ibuprofen Ibuprofen Ibuprofen Ibuprofen

Acid Controls Acid Cases Sodium Controls Sodium Cases

BEFORE DRUG ADMINISTRATION 60 MIN AFTER DRUG ADMINISTRATION

Figure 3. Mechanical allodynia before and 60 minutes after the administration of ibuprofen acid 400 mg and ibuprofen sodium dihydrate 512 mg in patients with
symptomatic irreversible pulpitis and symptomatic apical periodontitis. The administration of ibuprofen sodium dihydrate resulted in a significant decrease in
mechanical allodynia (P < .05).

676 Taggar et al. JOE Volume 43, Number 5, May 2017


groups were also comparable. At 60 minutes after the administration
of ibuprofen sodium dihydrate, there was a 15% decrease in me-
chanical allodynia (P < .05) (Figure 3). Ibuprofen acid decreased
the mechanical allodynia by 9%.
Discussion
The results of this study show that in pulpitis patients experiencing
moderate to severe pain, a single dose of ibuprofen sodium dihydrate
provides faster onset of pain relief and a significantly greater reduction
in pain intensity and mechanical allodynia compared with ibuprofen
acid.
The faster onset of action of ibuprofen sodium dihydrate noted in
this study is in agreement with previous studies comparing the 2
ibuprofen formulations (15, 16). The sodium formulation has a
faster dissolution because of sodium hydrogen carbonate, an
excipient of the tablet, which reacts with gastric acid and leads to
breakdown of the tablet. The resultant fine ibuprofen particles are
absorbed at a faster rate than ibuprofen acid (7). Although we could
have obtained valuable information by extending the study period, we
chose instead to limit the study to 60 minutes and to provide definitive
treatment (pulpectomy or extraction) at the end of the study period.
Data from acute pain trials clearly show that a rapid reduction in
pain intensity in the first hour after drug administration is strongly asso-
ciated with better overall pain relief (10). Data also show that a rapid
reduction in pain intensity is associated with longer lasting analgesia
and the reduced need for remedication. This suggests that the use of
ibuprofen sodium dihydrate in pulpitis patients may result in better
overall pain relief and longer lasting analgesia.
In this study, which examined the effect of a single dose of an anal-
gesic over a short period of time, we did not actively collect data on
adverse effects. None of the study subjects reported any adverse effects
experienced. Prior studies on ibuprofen acid and ibuprofen sodium
concluded that the 2 formulations have the same safety profile (7,
16). The common adverse effects after a single dose of the drug are
nausea, vomiting, dizziness, and headache. It is important to note that
a large number of studies now suggest that NSAIDs cause an
increased risk of serious cardiovascular thrombotic events (1720).
This risk is associated with both the dose and duration of intake.
Some study subjects did not achieve 50% pain relief within the 60-
minute trial. The percentage of subjects who did not experience at least
50% pain relief is consistent with a previous study that had a larger sam-
ple size (n = 198/group) (16). It is important to note that although
ibuprofen is an effective analgesic for acute odontogenic pain, not all
patients respond to it. These interindividual variations in the analgesic
response may be genetically mediated. A study on cyclooxygenase
(COX)-1 (PTGS-1) and COX-2 (PTGS-2) and the analgesic response
to COX-inhibiting drugs (including ibuprofen) in oral surgery patients
suggests that the wide variability in gene expression and functional poly-
morphisms in COX-2 may explain the interindividual differences in the
analgesic efficacy of NSAIDs (21).
This study is the first to compare the effect of the 2 ibuprofen for-
mulations on mechanical allodynia. Mechanical allodynia is not often
studied in clinical trials on acute pain even though it is a significant
component of odontogenic pain. Many odontogenic pain patients pre-
sent with the complaint of pain on biting, and in the clinic it is detected
by percussing the tooth with a mirror handle. In the current study, we
used a validated instrument, a digital bite fork force transducer to quan-
titatively measure mechanical allodynia. Our study shows a significant
change after the administration of ibuprofen sodium dihydrate
512 mg but not after the administration of ibuprofen acid 400 mg. Given
that both studies were terminated at 60 minutes, it is possible that both
JOE Volume 43, Number 5, May 2017
CONSORT Randomized Clinical Trial
ibuprofen formulations could potentially attenuate mechanical allody-
nia to a greater extent over time.
This study examines the analgesic effects of the ibuprofen formu-
lations before the initiation of endodontic treatment. Most studies on
analgesics in the endodontic literature focus on their effect on postop-
erative pain or their use as an adjunct to obtaining profound pulpal
anesthesia. Based on these studies, the current recommendation for
pain relief includes the use of 600 mg ibuprofen acid alone or a com-
bination of 650 mg ibuprofen acid with 1000 mg acetaminophen for
pain relief (5, 6). We chose to use 400 mg ibuprofen acid (and an
equivalent dose of 512 mg ibuprofen sodium) because this dose has
produced at least 55% pain relief in patients with acute inflammation.
A higher dose could result in a possible ceiling effect, making it
difficult to detect differences between the 2 formulations. Also, based
on the current reports of adverse cardiovascular events associated
with NSAIDs, we chose the lower dose.
One of the limitations of this study was the use of a single stopwatch
to mark the onset of 50% pain relief. An alternative design for future
studies is a double stopwatch method in which study subjects are in-
structed to stop 1 watch at the first sign of pain relief and to stop the
other stopwatch when meaningful pain relief is achieved. This method
would ensure that the patient is reporting meaningful pain relief and not
merely just the onset. If the patient does not stop the second stopwatch,
then it could be concluded that proper analgesia has not been achieved.
Thus, the double stopwatch method would allow for a decrease in false
positives. Meaningful pain relief is usually when 50% pain relief is
achieved.
In conclusion, the results of this study show that a single dose of
ibuprofen sodium dihydrate provides faster and greater pain relief than
a comparable dose of conventional ibuprofen acid in endodontic pain
patients.
Acknowledgments
Supported by a grant from the American Association of End-
odontists Foundation to Dr Tanjit Taggar.
The authors deny any conflicts of interest related to this study.
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