Does Pre-Emptive Administration of

Intravenous Ibuprofen (Caldolor) or

Intravenous Acetaminophen
(Ofirmev) Reduce Postoperative Pain
and Subsequent Narcotic Consumption
After Third Molar Surgery?
Archana Viswanath, BDS, MS,* Daniel Oreadi, DMD,y Matthew Finkelman, PhD,z
Gustavo Klein, DMD, PhD,x and Maria Papageorge, DMD, MSk
Purpose: Pre-emptive analgesia is known to reduce postoperative pain after third molar removal. The
purpose of this study was to compare postoperative pain in patients receiving either preoperative intrave-
nous (IV) ibuprofen or preoperative IV acetaminophen for third molar surgery.
Patients and Methods: This study was a randomized, single-blinded clinical study conducted in pa-
tients undergoing surgical extraction of 2 or more impacted third molars under deep sedation. This study
compared 2 interventions: 800 mg of IV ibuprofen (Caldolor; Cumberland Pharmaceuticals, Nashville, TN)
and 1,000 mg of IV acetaminophen (Ofirmev; Mallinckrodt Pharmaceuticals, Staines-upon-Thames, United
Kingdom). The primary outcome variable was postoperative pain measured on a visual analog scale at
different time points. The secondary outcome variable was the amount of postoperative analgesic
(narcotic and over-the-counter) medication taken in both groups. The Mann-Whitney U test was used
to compare groups in terms of outcomes, the c2 test was used to assess associations between nominal vari-
ables, and Spearman correlations were used to assess associations between continuous
variables. Significance was set at P < .05.
Results: The study sample consisted of 58 patients (39 female and 19 male patients). A total of 41
patients (IV ibuprofen, n = 19; IV acetaminophen, n = 22) completed the study. Equal distributions of
age, gender, and number of impacted teeth were noted between the groups. At 4 hours postoperatively,
the pain level in the ibuprofen group was significantly lower than that in the acetaminophen group
(P = .004). This trend continued at 24 hours (P = .019) and 48 hours (P = .017). The average amount of
narcotic medication taken in the ibuprofen group (2.68  2.26 doses) was lower than that in the acetamin-
ophen group (7.32  6.68 doses), and the result was statistically significant (P = .005).

*Assistant Professor and Director of Clinical Research,
Department of Oral and Maxillofacial Surgery, Tufts University
School of Dental Medicine, Boston, MA.
yAssistant Professor, Department of Oral and Maxillofacial
Surgery, Tufts University School of Dental Medicine, Boston, MA.
zAssociate Professor, Division of Biostatistics and Experimental
Design, Tufts University School of Dental Medicine, Boston, MA.
xPrivate Practice, Bauru, Brazil.
kProfessor and Chair, Department of Oral and Maxillofacial
Surgery, Tufts University School of Dental Medicine, Boston, MA.
Conflict of Interest Disclosures: Dr Viswanath received a research
grant from Cumberland Pharmaceuticals, used only for the funding
of this study. The contributors to this submission acted as
researchers and consultants only and were not compensated
financially for participating or publishing this study.
Address correspondence and reprint requests to Dr Viswanath:
Department of Oral and Maxillofacial Surgery, Tufts University
School of Dental Medicine, One Kneeland Street, Ste 502, Boston,
MA 02111; e-mail: Archana.Viswanath@tufts.edu
Received July 28 2017
Accepted September 10 2018
Ó 2018 American Association of Oral and Maxillofacial Surgeons
0278-2391/18/31080-2
https://doi.org/10.1016/j.joms.2018.09.010

262
VISWANATH ET AL
Conclusions: Pre-emptive analgesia with IV ibuprofen is more effective than IV acetaminophen in
reducing postoperative pain and opioid use for third molar surgery.
Ó 2018 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 77:262-270, 2019
Third molar extraction is one of the most common
surgical procedures, and an estimated 10 million
third molars are extracted in the United States
annually.1 Pain is a common sequela of surgical extrac-
tion of impacted third molars. Although most patients
have pain for a short, predictable period after surgery,2
effective postoperative pain management is a chal-
lenge for oral surgeons. Postoperative pain manage-
ment must be performed effectively to reduce the
likelihood of development of a chronic pain state or
addiction to opioids.3,4 In addition to over-the-
counter (OTC) oral analgesics, opioids continue to
be the cornerstone of postoperative pain management
among oral-maxillofacial surgeons (OMSs).5 Unfortu-
nately, opioid use, even when prescribed for short
periods, comes with certain risks. Opioid side effects
include sleepiness, constipation, drug interactions,
and inadequate dosing with pharmacokinetic vari-
ability, and more important, there is a risk of develop-
ment of physical dependence on and addiction to
these drugs.6,7
Several clinical trials have examined different ap-
proaches to minimize pain after third molar extrac-
tion and to curtail the need for additional analgesics
to reduce the incidence of adverse effects. One of
the approaches that has been studied extensively is
pre-emptive analgesia.8 The goal of pre-emptive anal-
gesia is to prevent peripheral and central sensitiza-
tion and attenuation of the postoperative
amplification of the pain sensation.9 Effective anal-
gesia must provide the patient with analgesia during
the surgical procedure and at the beginning of the
postoperative period.
Caldolor (Cumberland Pharmaceuticals, Nashville,
TN) is an intravenous (IV) formulation of ibuprofen
approved by the US Food and Drug Administration in
June 2009. Caldolor is the first injectable product avail-
able in the United States for the treatment of pain and
fever. Ofirmev (Mallinckrodt Pharmaceuticals, Staines-
upon-Thames, United Kingdom) is IV acetaminophen
and was approved by the US Food and Drug Adminis-
tration in 2010 for the management of mild to moder-
ate pain, moderate to severe pain with adjunctive
opioid analgesics, and reduction of fever.10 Several
studies have been performed to look at the clinical
efficacy and safety profile of both medications for peri-
operative pain management, but no studies specif-
ically looking at the pre-emptive analgesic effect of
these medications have been performed.11,12
263
The purpose of this study was to assess the efficacy
of a single dose of 800 mg of ibuprofen (Caldolor) as
an IV formulation compared with a single dose of
1,000 mg of IV acetaminophen (Ofirmev) in reducing
pain when administered 30 minutes before surgical
extraction of impacted third molars. We hypothesized
that pre-emptive administration of a nonsteroidal anti-
inflammatory drug (NSAID) would be more effective
than a non-NSAID in reducing postoperative pain.
The specific aims of this study were 1) to show the
efficacy of Caldolor compared with Ofirmev in pro-
ducing effective pre-emptive analgesia and 2) to deter-
mine any difference in the amount of pain medication
consumed postoperatively in both groups.
Patients and Methods
STUDY DESIGN
We implemented a prospective, randomized, single-
blinded clinical trial. The treatment group (IV
ibuprofen vs IV acetaminophen) was the primary pre-
dictor variable. This study was performed according to
the guidelines of good clinical practice and in accor-
dance with the Declaration of Helsinki. The study
was reviewed and approved by the local institutional
review board (Tufts Medical Center Institutional
Review Board). The clinical trial was registered on
ClinicalTrials.gov on September 17, 2013 (study iden-
tifier NCT02133326).
PATIENTS
The study population included adult patients in
whom the decision to surgically extract impacted third
molars under deep sedation had already been made. To
be included in the study, patients were required to be
aged 18 years or older, to have 2 or more third molars
in the maxilla and/or mandible classified as having
full or partial bony impaction, to have an American
Society of Anesthesiologists physical classification
status of I or II, and to undergo surgery performed un-
der deep sedation. The exclusion criteria were as fol-
lows: pregnant patients; patients with a known
allergy or contraindication to ibuprofen or acetamin-
ophen or any excipient in the IV formulation; patients
with severe hepatic impairment or severe active
liver disease; patients who had had asthma; patients
with urticarial or allergic-type reactions after taking
aspirin or other NSAIDs; patients who were taking
264
angiotensin-converting enzyme inhibitors; patients
with underlying heart disease or kidney disease;
patients with a history of alcohol or drug abuse;
patients currently receiving any anti-inflammatory or
pain medication or having a chronic pain condition;
patients with actively infected third molars with
swelling, trismus, or purulent discharge; and patients
with a contraindication to lidocaine with epinephrine.
Patients were recruited for this study through local
university advertisements on the university website
and flyers, as well as a posting on clinicaltrials.gov.
Each patient agreed to participate and provided writ-
ten informed consent. A complete medical history
and oral examination were performed and radiographs
were obtained to confirm the need for third molar
extraction consistent with the treating clinician’s
findings. On the day of surgery, patients underwent a
second oral examination and pregnancy testing was
performed in all female patients. Patients were ran-
domized in a 1:1 ratio to 1 of the 2 treatment groups
on the morning of their surgical appointment using a
randomization scheme created by a computer (www.
random.org).
STUDY VARIABLES
The primary predictor variable was administration
of pre-emptive IV ibuprofen versus IV acetaminophen.
The primary outcome variable was self-reported post-
operative pain recorded at several time points (4, 24,
48, and 72 hours). Postoperative pain was primarily
measured using a nongraduated 100-mm visual analog
scale (VAS), with anchors of ‘‘no pain’’ and ‘‘worst pain
imaginable.’’ The secondary outcome was the total
amount of postoperative medication (narcotics and
OTC medications) taken during the 7-day postopera-
tive period. The incidence of adverse events was
assessed for safety outcomes. Age, gender, race, and
number of impacted teeth also were assessed as cova-
riates for the study.
DATA ANALYSIS
A sample size of 23 surgical procedures per treat-
ment group was required to detect a difference in
the postoperative assessment of 45 mm in the Caldolor
group and 55 mm in the Ofirmev group, as assessed
by the VAS and assuming a common standard
deviation of 10 mm if we set a equal to .05 (nQuery
Advisor, version 7.0; Statistical Solutions, Cork,
Ireland). Descriptive statistics (counts with percent-
ages and medians with interquartile ranges) were
calculated. The Mann-Whitney U test was used to
compare dichotomously defined groups in terms of
discrete and continuous outcomes (all of which
were non-normally distributed). The c2 test was used
to assess associations between nominal variables,
PRE-EMPTIVE IBUPROFEN OR ACETAMINOPHEN
and Spearman correlations were used to assess associ-
ations between discrete and/or continuous variables.
We used multivariable linear regression models to
predict postoperative pain at different time points
based on the study group (Caldolor vs Ofirmev),
adjusting for gender, race, age, and number of
impacted teeth. Moreover, we used multivariable
negative binomial regression models to predict the
number of narcotic medications and number of
OTC medications based on the study group, adjusting
for gender, race, age, and number of impacted teeth.
Statistical analyses were performed using SPSS soft-
ware (version 24; IBM, Armonk, NY) and the R pack-
age (version 3.3.1; R Foundation for Statistical
Computing, Vienna, Austria). P < .05 was deemed
statistically significant.
MEDICATION AND RANDOMIZATION PROCEDURE
Patients were randomly assigned to 1 of the 2 treat-
ment groups using a computerized random number
generator provided by the statistician. The randomiza-
tion sheet was kept exclusively by the chief residents,
the study nurse, and the Investigational Drug Service
at Tufts Medical Center. On the day of surgery, the
chief residents performed randomization of the pa-
tient and called in the prescription. The Investiga-
tional Drug Service delivered the medication in a
blinded brown bag with the randomization number.
Thus, the patients were unaware of the study drug
assignment. Observers present in the operating room
did not serve as postoperative observers to minimize
any bias during pain reporting. Observers in the post-
operative period were blinded to the treatment group
of the patient.
Patients in the study group received an infusion of
800 mg of IV ibuprofen (Caldolor) over a 30-minute
period, 30 minutes before extraction. Patients in the
comparator group received an infusion of 1,000 mg
of IV acetaminophen (Ofirmev) over a period of 15 mi-
nutes per the manufacturer’s guidelines, 30 minutes
before third molar extraction.
PREOPERATIVE, INTRAOPERATIVE, AND
POSTOPERATIVE PROCEDURES
Preoperative Examination
A baseline pain rating was obtained using the VAS in
the preoperative area before infusion of the
study drug.
Intraoperative Procedures
After the preoperative preparation procedures,
patients received 200 to 500 mL of IV normal saline
solution. The chief resident then infused the
study medications per the manufacturers’ guidelines.
Surgery was performed under ambulatory general
VISWANATH ET AL 265

anesthesia following standard practice at the Tufts
University Oral and Maxillofacial Surgery Clinic.
Deep sedation medications and a local anesthetic
were administered before the surgical procedure
began. On average, 6 to 8 cartridges of 2% Xylocaine
with 1:100,000 epinephrine were used for nerve
blocks, as well as local infiltration. No long-acting
anesthetic medications were used in this study. The
necessary surgical procedure was performed to re-
move the impacted third molar. This could have
included using elevators and forceps, reflecting a sur-
gical flap, removing bone, or sectioning the tooth ac-
cording to the condition of the third molar. Copious
irrigation was performed in all patients during the
surgical procedure, all granulation tissue was
removed, and the surgical site was closed using No.
3-0 chromic gut sutures. Hemostasis was observed.
The infusion time of the study medications and anes-
thetic medications and the operating time in minutes
were recorded by the study nurse.
Postoperative Procedures and Measurements
Pain ratings using the VAS were collected before sur-
gery as a baseline pain measurement. Patients were
monitored for excessive bleeding, hypertension, or
any adverse events. They were discharged from the
hospital with thirty 5-mg tablets of oxycodone for
the 10-day postoperative period, amounting to three
5-mg tablets per day (15 mg of oxycodone per day).
Because patients were blinded to the study drug
they received, all patients were instructed not to
exceed 2,000 to 2,500 mg of OTC acetaminophen so
that those who did receive IV acetaminophen did not
exceed the maximum daily dose of 4,000 mg. After
discharge, patients completed a self-assessment of
pain using the VAS at 24 hours, 48 hours, and 72 hours
after surgery and on day 7 after the surgical procedure.
They were asked to complete the pain diary before tak-
ing any medications. Follow-up phone calls were made
to assess recovery and remind patients to fill in the
pain and medication diaries.
Results
A total of 58 patients (39 female and 19 male pa-
tients) were randomized and enrolled to participate
in the study. We excluded 5 patients from the study
because there was a change in the method of anes-
thesia. The extraction was performed with patients
under local anesthesia because of the lack of an
attending OMS or the patients did not follow the
nothing-by-mouth status. There was no IV line estab-
lished to administer the study drug. Of the patients,
25 received pre-emptive IV ibuprofen (Caldolor) and
28 received pre-emptive IV acetaminophen (Ofirmev).
We excluded 12 additional patients from the analysis
because they did not return the pain diary and were
considered lost to follow-up. Thus, a total of 41
patients completed the study and were included in
the data analysis (Fig 1).

Enrolled to parcipate in
the study (n=58)
ENROLLMENT

Excluded (n=5)
Surgery cancelled (n=3)
Randomized (n=53) Change of anesthesia plans (n=2)
ALLOCATION

Caldolor (n=25) Ofirmev (n=28)

FOLLOW-UP

Lost to follow up (n=6) Lost to follow up (n=6)

Did not return the pain Did not return the pain
diary diary

Completed the study Completed the study

ANALYSIS

(n=19) (n=22)

FIGURE 1. CONSORT (Consolidated Standards of Reporting Trials) flow diagram of patient allocation.
Viswanath et al. Pre-Emptive Ibuprofen or Acetaminophen. J Oral Maxillofac Surg 2019.
266 PRE-EMPTIVE IBUPROFEN OR ACETAMINOPHEN

BASELINE DATA ibuprofen (Caldolor) group were significantly lower

The 2 groups were similar regarding age, gender,
and ethnicity. They were also similar in terms of base-
line pain levels before surgery, number and degree of
impaction of third molars, and total number of maxil-
lary and mandibular third molars extracted. Baseline
characteristics of study participants are summarized
in Table 1.
OUTCOME AND ESTIMATION
Neither group reported any pain during the initial
postoperative period at 30, 60, and 90 minutes after
surgery. At 4 hours after surgery, the mean VAS pain
score was 18.0  19.22 in the IV ibuprofen group
and 41.40  27.46 in the acetaminophen group. This
trend continued at 24 hours postoperatively, with
18.84  14.32 in the IV ibuprofen group and
36.5  25.05 in the IV acetaminophen group. Even
at 48 hours postoperatively, the Caldolor group re-
ported less pain than the Ofirmev group, with mean
scores of 13.16  11.8 versus 33.14  27.34. At 4 hours
and 24 hours after surgery, 84% of the patients in the
IV ibuprofen group (n = 16) reported pain levels lower
than 20 mm on the VAS. Figure 2 shows postoperative
pain scores at each time point.
No correlation was found between gender, race,
age, number of impacted teeth, and development of
postoperative pain (Table 2). Moreover, no correlation
was found between gender, race, age, number of
impacted teeth, and number of postoperative medica-
tions taken.
A separate analysis of each time point (Table 3)
showed that postoperative pain scores in the IV
than those in the IV acetaminophen (Ofirmev) group
at 4 hours (P = .004), 24 hours (P = .019), and 48 hours
(P = .017). After 72 hours, at the end of the acute
inflammatory phase, we observed a trend in reduced
reported pain scores in the IV ibuprofen group
compared with the IV acetaminophen group, although
the difference was no longer significant.
Patients receiving IV ibuprofen before surgery took
fewer rescue analgesics. Although the observed reduc-
tion in OTC medications in the IV ibuprofen group was
not statistically significant compared with the IV acet-
aminophen group, the difference in doses taken was
striking (Table 4). The IV ibuprofen group reported a
maximum of 22 OTC medication doses over a 7-day
period, whereas the IV acetaminophen group reported
a maximum of 51 doses of these medications. Most
important, pre-emptive IV ibuprofen administration
resulted in a significant reduction in prescription
medication consumption (Fig 3). Patients in this group
took a mean of 2.68  2.26 prescription doses versus
7.32  6.68 prescription doses taken in the IV acet-
aminophen patients (P = .005) over a 7-day period.
The maximum number of prescription doses reported
was 7 doses in the IV ibuprofen group versus a
maximum of 27 prescription doses taken by a patient
in the IV acetaminophen group. In the IV ibuprofen
group, 21% of the patients did not take any postoper-
ative narcotics; most of the patients (53%) took 3 or
fewer narcotic medications.
After we adjusted for potential confounders such as
sex, age, and gender, the VAS pain scores at 4 hours
(P = .004), 24 hours (P = .014), and 48 hours
(P = .008) continued to be statistically significant

Table 1. COMPARISON OF CALDOLOR AND OFIRMEV GROUPS IN TERMS OF DEMOGRAPHIC VARIABLES AND
NUMBER OF IMPACTED TEETH

Caldolor (n = 19) Ofirmev (n = 22) P Value

Gender, n
Male 7 (36.8%) 9 (40.9%) .79
Female 12 (63.2%) 13 (59.1%)
Race, n
White 7 (36.8%) 12 (54.5%) .26
Nonwhite 12 (63.2%) 10 (45.5%)
Age, median (IQR), yr 22 (6) 22 (7) .83
Degree of impaction, n
Simple Maxillary in 11 (39.35%) and Maxillary in 18 (50%) and mandibular
mandibular in 0 in 1 (2.4%)
Partial bony impaction Maxillary in 12 (42.9%) and Maxillary in 15 (41.7%) and .89
mandibular in 25 (71.4%) mandibular in 27 (65.9%)
Full bony impaction Maxillary in 5 (17.9%) and mandibular Maxillary in 3 (8.3%) and mandibular
in 10 (28.6%) in 13 (31.7%)

Abbreviation: IQR, interquartile range.

Viswanath et al. Pre-Emptive Ibuprofen or Acetaminophen. J Oral Maxillofac Surg 2019.
VISWANATH ET AL 267

FIGURE 2. Pain scores at 4, 24, 48, and 72 hours after surgery as measured on visual analog scale (VAS).
Viswanath et al. Pre-Emptive Ibuprofen or Acetaminophen. J Oral Maxillofac Surg 2019.

between the 2 study groups (Table 4). The difference ADVERSE EVENTS
in the number of narcotic medications taken was During the 1-week follow-up period, no adverse
statistically significant (P = .009) after adjustment for effects were reported in both groups and none of
potential confounders. the patients returned for an emergency follow-up visit.

Table 2. VAS PAIN SCORES BY GENDER, RACE, AGE, AND NUMBER OF IMPACTED TEETH

VAS Pain Score at VAS Pain Score at VAS Pain Score at VAS Pain Score at
4 Hours 24 Hours 48 Hours 72 Hours

Median (IQR) P Value Median (IQR) P Value Median (IQR) P Value Median (IQR) P Value

Gender
Male 17 (45) 18 (33) 15.5 (21) 8 (12)
Female 31 (45) .23 26 (29) .45 21 (28) .59 16 (29) .22
Race
White 22 (42) .80 24 (30) .97 16 (27) .78 15 (18) .49
Nonwhite 28.5 (52) 22 (30) 20.5 (26) 11.5 (20)
Spearman correlation
Age 0.03 .82 0.11 .46 0.16 .31 0.02 .89
No. of impacted teeth 0.26 .10 0.21 .18 0.17 .26 0.06 .69

Abbreviations: IQR, interquartile range; VAS, visual analog scale (0- to 100-mm scale).
Viswanath et al. Pre-Emptive Ibuprofen or Acetaminophen. J Oral Maxillofac Surg 2019.
268 PRE-EMPTIVE IBUPROFEN OR ACETAMINOPHEN

Table 3. ASSOCIATION BETWEEN STUDY MEDICATIONS AND PAIN MEASUREMENTS ON VAS

VAS Pain Score at 24 VAS Pain Score at 48 VAS Pain Score at 72

VAS Pain Score at 4 Hours Hours Hours Hours

Median (IQR) P Value Median (IQR) P Value Median (IQR) P Value Median (IQR) P Value

Caldolor 10 (31) 17 (15) 10 (17) 9 (13)

Ofirmev 46 (50.75) .004* 34.5 (44.25) .019* 28 (51.75) .017* 16.5 (23.75) .064
Abbreviations: IQR, interquartile range; VAS, visual analog scale.
* The difference between the groups was statistically significant.
Viswanath et al. Pre-Emptive Ibuprofen or Acetaminophen. J Oral Maxillofac Surg 2019.

No reported cases of excessive bleeding were found
during or after surgery in both groups.
Discussion
The primary purpose of this study was to assess the
efficacy of a single dose of the IV formulation of
800 mg of ibuprofen (Caldolor) compared with a sin-
gle dose of 1,000 mg of IV acetaminophen (Ofirmev)
in reducing pain when administered 30 minutes
before surgical extraction of impacted third molars.
This study confirmed the hypothesis that pre-
emptive IV ibuprofen administration is superior to IV
acetaminophen in reducing postoperative pain.
Pain after surgical extraction of impacted third mo-
lars is primarily mediated by trauma-induced release
of local inflammatory mediators, so a rational
approach to treat it would be peripheral inhibition
of these inflammatory mediators.13 NSAIDs have
been proved to be effective for postoperative dental
pain and have been regarded as the basic treat-
ment.14,15 Most NSAIDs act primarily by inhibiting
the enzyme cyclooxygenase, thereby preventing
local synthesis of prostaglandins from arachidonic
acid in the inflamed tissues.16 In vitro studies also
have shown that NSAIDs are able to modulate the
neurogenic part of the inflammatory mediators by hav-
ing a chemotactic effect of substance P on monocytes
and polymorphonuclear leukocytes.16-18 NSAIDs
should be given before the surgical incision and
should be timed so that the maximum plasma
concentration of the drug is reached at the time of
surgical incision. This will prevent the release of the
inflammatory mediators, giving immediate analgesic
effects. This technique is known as pre-emptive
analgesia.19,20 Several studies have looked at the pre-
emptive analgesic effect of NSAIDs,21,22 but they
have conflicting results. Most of the studies have
used oral ibuprofen.3,23 The use of IV analgesia has
an added benefit over oral administration: Oral
ibuprofen reaches its maximum concentration after
1.5 hours, whereas Caldolor (IV ibuprofen) reaches
its maximum concentration after only 6 to
7 minutes.24 Because third molar extraction is a rela-
tively short surgical procedure, pre-emptive Caldolor
administration is beneficial. Along with a faster mode
of action, IV ibuprofen has a maximum plasma concen-
tration that is twice that of oral ibuprofen, providing a

Table 4. ASSOCIATION BETWEEN STUDY MEDICA-

TIONS AND NUMBER OF POSTOPERATIVE PAIN MED-
ICATIONS TAKEN

No. of Narcotic No. of Over-the-

Medications Counter Medications

Median (IQR) P Value Median (IQR) P Value

Caldolor 2 (3) 2 (6)

Ofirmev 6.5 (6.25) .005* 6 (8.25) .120
Abbreviation: IQR, interquartile range.
* The difference between the groups was statistically sig- FIGURE 3. Total number of narcotic medications taken during 7-
nificant. day postoperative period.
Viswanath et al. Pre-Emptive Ibuprofen or Acetaminophen. J Oral Viswanath et al. Pre-Emptive Ibuprofen or Acetaminophen. J Oral
Maxillofac Surg 2019. Maxillofac Surg 2019.
VISWANATH ET AL
stronger pre-emptive analgesic effect.25 The results of
this study provide support for pre-emptive IV
ibuprofen as a compelling component of this manage-
ment. In this study, pre-emptive IV ibuprofen adminis-
tration resulted in not only a reduction in prescription
medications and OTC medications postoperatively but
also, most important, a reduction in pain when
compared with IV acetaminophen. With a reduction
in pain experienced by patients, there is less of a
necessity for clinicians to prescribe more analgesia
or for patients to use excess narcotics.
In 2 previous studies, Caldolor infusions given intra-
operatively and Caldolor infusions given every 6 hours
were effective in managing pain and reducing
morphine intake after elective orthopedic and abdom-
inal surgical procedures compared with placebo.12,25
In another trial, conducted in total abdominal
hysterectomy patients, pre-emptive IV paracetamol
(acetaminophen) provided adequate postoperative
analgesia, with decreased consumption of morphine
and minimal side effects.26 Our study improves on
those findings, indicating that preoperative NSAID
administration is superior to non-NSAID administra-
tion for reducing postoperative pain and the intake
of postoperative pain analgesics.
Pre-emptive Caldolor administration resulted in a
marked reduction in pain. Eighty-four percent of the
patients reported mild pain, with a score lower than
20 mm on the VAS, at 4 hours and 24 hours after sur-
gery, resulting in a marked reduction in narcotic and
OTC medication taken. Patients in the IV ibuprofen
group took an average of 2.5 oxycodone tablets,
whereas the IV acetaminophen group took 7.32 oxy-
codone tablets on average. The IV ibuprofen group
reported a maximum of 22 OTC medication doses
over a 7-day period, whereas the IV acetaminophen
group reported a maximum of 51 doses of these med-
ications. This striking reduction in the need for pain
medication and reduction in postoperative medication
use warrant further examination and practice as novel
means of reducing pain are discovered. With Caldolor,
the IV route of administration grants new flexibility to
an effective NSAID.
Prescription opioid abuse is a significant problem in
the United States. The Centers for Disease Control and
Prevention estimates that nearly 80 persons die each
day from overdosing on opioids, including heroin
and prescription pain pills; half of these deaths are
attributed to prescription pain pills. Furthermore,
merely having a history of a prescription for an opioid
pain medication increases the risk of overdose and
opioid use disorder.27 The more pills that are pre-
scribed, the more pills that are available for potential
misuse or overdose.
OMSs are frequent prescribers of opioid analgesics
for postoperative pain management after third molar
269
extractions and are well positioned to help keep
these drugs from becoming a source of harm. In a
survey-based study of 563 practicing OMSs from a sam-
ple from the American Dental Association, 73.5% of re-
spondents indicated that their preferred postoperative
analgesic was ibuprofen. However, 85% of the respon-
dents prescribed opioids and, on average, prescribed
20 tablets of hydrocodone with acetaminophen to
take as needed for pain. Approximately 5 million young
adults are having their third molars extracted annually
and are being exposed to opioids and would have
excess narcotic prescriptions.1 Many patients are first
exposed to narcotics after third molar extraction.
Because most third molar extractions are performed un-
der deep sedation or conscious sedation, IV analgesic
medications administered in the preoperative period
may provide sufficient analgesia, thereby decreasing
narcotic dosing and resultant side effects. Therefore,
we suggest that OMSs, who generally have short-term
relationships with their patients, should consider alter-
natives to prescription opioids and incorporate pre-
emptive analgesia into routine practice. This practice
will restrict overprescription of narcotics.
Caldolor has a relatively higher cost than other post-
operative analgesics including narcotics. The cost of
Ofirmev is approximately 3 times the cost of Caldolor.
The wholesale acquisition cost of 1 vial of Caldolor is
$14.92, and the wholesale acquisition cost of 1 vial
of Ofirmev is $45.00. The cost of IV ketorolac is $16.
However, there is potential for oral surgeons to
eliminate narcotic prescription in their practice. This
narcotic-free surgical environment is a contemporary
goal for surgical procedures with moderate pre-
dicted pain.
To our knowledge, this is one of the first third molar
studies directly comparing Caldolor and Ofirmev,
which are relatively newer medications on the market.
The main strength of the study was that it used a single-
blinded, randomized study design. An additional
advantage included multiple pain recordings during
the clinically relevant postoperative period.
Some important points should be noted. Pre-
emptive analgesia is known to reduce peripheral and
central sensitization, and several studies have shown
that this is best achieved when a combination of 2
pharmacologic methods of pre-emptive analgesia is
used: 1) local anesthesia injected through local infiltra-
tion and nerve blocks and 2) pre-emptive systemic
administration of NSAIDs or acetaminophen. In this
study, in the immediate postoperative period, both
groups did not report any pain. This might be due to
the ongoing effect of local anesthesia and shows that
IV Caldolor and Ofirmev with a faster onset had
most likely taken effect before the local anesthetic
effect had worn off. However, local anesthesia admin-
istration still nullifies any effect of pre-emptive
270
administration of systemic IV Caldolor and Ofirmev in
the immediate postoperative period. This finding
likely represents the ongoing effect of local anes-
thetics administered.
The major limitation of this study was the small sam-
ple size owing to the substantial number of patients
lost to follow-up. This issue could have been resolved
by recalling the patients for a 2-day follow-up or
increasing the number of phone call reminders to
the patients. We planned to increase the sample size,
but our institutional review board did not allow us to
recruit more patients because we had already achieved
statistically significant results. The variation in degree
of impaction could have been a potential confounder.
However, to be eligible to participate in the study,
patients had to have at least 2 third molars classified
as having partial or full bony impaction. As with all
self-reported pain diaries, there could have been inac-
curacy in data recording. The ability of patients to take
OTC medications is a confounder that likely would
have influenced the need for opioids. Moreover, the
study could have been more robust if we had more
closely recorded the potential side effects of Caldolor,
such as hypertension and excessive bleeding. Howev-
er, the treating surgeons were aware of the potential
side effects and monitored the patients closely. None
of the patients had any intraoperative or postoperative
complications.
In conclusion, Caldolor has a significant pre-
emptive analgesic effect resulting in decreased use of
postoperative opioids. Further studies are planned
looking at pre-emptive administration of IV ibuprofen
and postoperative long-acting anesthetics, which
might eliminate the need for prescribing narcotics
for postoperative pain management after surgical
removal of impacted third molars.
Acknowledgments
We thank all oral surgery faculty, residents, and auxiliary staff
involved in this research (study nurse, dental assistants, and admin-
istrators) who work in the Department of Oral and Maxillofacial
Surgery at Tufts University School of Dental Medicine.
References
1. Friedman JW: The prophylactic extraction of third molars: A
public health hazard. Am J Public Health 97:1554, 2007
2. Bauer HC, Duarte FL, Horliana ACRT, et al: Assessment of pre-
emptive analgesia with ibuprofen coadministered or not with
dexamethasone in third molar surgery: A randomized double-
blind controlled clinical trial. Oral Maxillofac Surg 17:165, 2013
3. Silva de Oliveira JC, Grossi de Oliveira GA, Bassi APF: Compara-
tive assessment of the effect of ibuprofen and etodolac on
edema, trismus, and pain in lower third molar surgery: A ran-
domized clinical trial. J Oral Maxillofac Surg 74:1524, 2016
4. Best AD, De Silva RK, Thomson WM, et al: Efficacy of codeine
when added to paracetamol (acetaminophen) and ibuprofen
for relief of postoperative pain after surgical removal of
impacted third molars: A double-blinded randomized control
trial. J Oral Maxillofac Surg 75:2063, 2017
PRE-EMPTIVE IBUPROFEN OR ACETAMINOPHEN
5. Baker JA, Avorn J, Levin R, Bateman BT: Opioid prescribing after
surgical extraction of teeth in Medicaid patients, 2000-2010.
JAMA 315:1653, 2016
6. Mark AM: Relieving dental pain. J Am Dent Assoc 147:996, 2016
7. Benyamin R, Trescot A, Datta S, et al: Opioid complications and
side effects. Pain Physician 11:S105, 2008
8. Costa FWG, Esses DFS, de Barros Silva PG, et al: Does the pre-
emptive use of oral nonsteroidal anti-inflammatory drugs reduce
postoperative pain in surgical removal of third molars? A meta-
analysis of randomized clinical trials. Anesth Prog 62:57, 2015
9. Kelly DJ, Ahmad M, Brull SJ: Preemptive analgesia I: Physiolog-
ical pathways and pharmacological modalities. Can J Anesth
48:1000, 2001
10. Pasero C, Stannard D: The role of intravenous acetaminophen in
acute pain management: A case-illustrated review. Pain Manag
Nurs 13:107, 2012
11. Wininger SJ, Miller H, Minkowitz HS, et al: A randomized,
double-blind, placebo-controlled, multicenter, repeat-dose
study of two intravenous acetaminophen dosing regimens for
the treatment of pain after abdominal laparoscopic surgery.
Clin Ther 32:2348, 2010
12. Southworth S, Peters J, Rock A, Pavliv L: A multicenter, random-
ized, double-blind, placebo-controlled trial of intravenous
ibuprofen 400 and 800 mg every 6 hours in the management
of postoperative pain. Clin Ther 31:1922, 2009
13. Gordon SM, Brahim JS, Rowan J, et al: Peripheral prostanoid
levels and nonsteroidal anti-inflammatory drug analgesia: Repli-
cate clinical trials in a tissue injury model. Clin Pharmacol Ther
72:175, 2002
14. Dionne RA, Khan AA, Gordon SM: Analgesia and COX-2 inhibi-
tion. Clin Exp Rheumatol 19, 2001
15. Ferreira S: Peripheral analgesia: Mechanism of the analgesic
action of aspirin-like drugs and opiate-antagonists. Br J Clin
Pharmacol 10:237S, 1980
16. Roszkowski MT, Swift JQ, Hargreaves KM: Effect of NSAID
administration on tissue levels of immunoreactive prostaglandin
E2, leukotriene B4, and (S)-flurbiprofen following extraction of
impacted third molars. Pain 73:339, 1997
17. Hargreaves KM, Costello A: Glucocorticoids suppress levels of
immunoreactive bradykinin in inflamed tissue as evaluated by
microdialysis probes. Clin Pharmacol Ther 48:168, 1990
18. Bjorkman R: Central antinociceptive effects of non-steroidal
anti-inflammatory drugs and paracetamol. Experimental studies
in the rat. Acta Anaesthesiol Scand Suppl 103:1, 1995
19. Gottschalk A, Smith DS: New concepts in acute pain therapy:
Preemptive analgesia. Am Fam Physician 63:1979, 2001
20. Kaufman E, Epstein JB, Gorsky M, et al: Preemptive analgesia
and local anesthesia as a supplement to general anesthesia: A
review. Anesth Prog 52:29, 2005
21. Bjorkman R, Hallman KM, Hedner J, et al: Nonsteroidal antiin-
flammatory drug modulation of behavioral responses to
intrathecal N-methyl-D-aspartate, but not to substance P and
amino-methyl-isoxazole-propionic acid in the rat. J Clin Pharma-
col 36:S20, 1996
22. Moore RA, Derry S, McQuay HJ, Wiffen PJ: Single dose oral anal-
gesics for acute postoperative pain in adults. Cochrane Database
Syst Rev 9:CD008659, 2011
23. Gazal G, Al-Samadani KH: Comparison of paracetamol,
ibuprofen, and diclofenac potassium for pain relief following
dental extractions and deep cavity preparations. Saudi Med J
38:284, 2017
24. Pavliv L, Voss B, Rock A: Pharmacokinetics, safety, and tolera-
bility of a rapid infusion of i.v. ibuprofen in healthy adults. Am
J Health Syst Pharm 68:47, 2011
25. Kroll PB, Meadows L, Rock A, Pavliv L: A multicenter, random-
ized, double-blind, placebo-controlled trial of intravenous
ibuprofen (i.v.-ibuprofen) in the management of postoperative
pain following abdominal hysterectomy. Pain Pract 11:23, 2010
26. Arici S, Gurbet A, T€ urker G, et al: Preemptive analgesic effects of
intravenous paracetamol in total abdominal hysterectomy. Agri
21:54, 2009
27. Bohnert ASB, Valenstein M, Bair MJ, et al: Association between
opioid prescribing patterns and opioid overdose-related deaths.
JAMA 305:1315, 2011