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Ketoprofen 75 mg qid versus Acetaminophen 1000 mg qid for 3 Days on Swelling, Pain, and Other
Postoperative Events after Third-Molar Surgery
G. A. Bjørnsson, H. R. Haanæs and L. A. Skoglund
J. Clin. Pharmacol. 2003; 43; 305
DOI: 10.1177/0091270002250603

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BJØRNSSON
ARTICLE
EFFECT
ANALGESIA
OF KETOPROFEN
ET AL AND ACETAMINOPHEN ON SWELLING, PAIN
Ketoprofen 75 mg qid versus
Acetaminophen 1000 mg qid for 3 Days on
Swelling, Pain, and Other Postoperative
Events after Third-Molar Surgery
G. A. Bjørnsson, DDS, H. R. Haanæs, DDS, MD, PhD, and L. A. Skoglund, DDS, DSci
A randomized, double-blind, within-patient, crossover study
was carried out after bilateral “identical” surgical procedures
using local anesthesia only. A 3-day tablet regime of racemic
ketoprofen 75 mg or acetaminophen 1000 mg qid (× 4) was
given starting 3 hours after surgery. Ketoprofen reduced ob-
jectively measured swelling 27.8% (p < 0.04) better than
acetaminophen 3 days after surgery and 70.8% (p < 0.02)
better than acetaminophen 6 days after surgery. The pain in-
tensity (PI) was lower after ketoprofen than after
acetaminophen from 2 to 6 hours after the first drug intake
(all p-values ≤ 0.03). Sum PI during the first (SUMPI3.5-6, p =
0.003) and second dose intervals (SUMPI6.5-9, p = 0.007) was
N onsteroidal anti-inflammatory drugs (NSAIDs)
are the drugs of choice for treating inflammatory
pain following limited surgery or trauma. Ketoprofen
(2-(3-benzoylphenyl)-propionic acid) is a NSAID of the
propionic acid class that is used to treat acute and
chronic inflammatory conditions ranging from postop-
erative pain to rheumatoid arthritis. It is also available in
over-the-counter (OTC) strength for various minor pain
conditions. Acetaminophen (4’-hydroxyacetanilide) is
a popular OTC drug that has a long history of use as an
analgesic for various mild to moderate intermittent
From the Section of Dental Pharmacology and Pharmacotherapy (Dr.
Bjørnsson, Dr. Skoglund) and the Department of Oral Medicine and Oral
Surgery (Dr. Bjørnsson, Dr. Haanæs), University of Oslo, Oslo, Norway.
Submitted for publication August 1, 2002; revised version accepted De-
cember 11, 2002. Address for reprints: L. A. Skoglund, Section of Dental
Pharmacology and Pharmacotherapy, P.O. Box 1057 Blindern, University
of Oslo, N-0316 Oslo, Norway.
DOI: 10.1177/0091270002250603
J Clin Pharmacol 2003;43:305-314
lower for ketoprofen than for acetaminophen but not differ-
ent for the third dose interval (SUMPI9.5-11, p = 0.53).
Ketoprofen was a more effective analgesic than
acetaminophen on the day of surgery (SUMPI3.5-11, p = 0.005).
There was no difference (p > 0.05) between the treatments
with respect to mouth opening, drug preference, global evalu-
ation, or adverse reports. Adverse reports included stomach
pain and diarrhea in both treatment groups. Ketoprofen 75
mg × 4 for 3 days reduces subjectively assessed pain and ob-
jectively measured swelling (i.e., anti-inflammatory effect)
following third-molar surgery.
Journal of Clinical Pharmacology, 2003;43:305-314
©2003 the American College of Clinical Pharmacology
pain conditions but also more severe pain conditions
such as postoperative pain.
Both ketoprofen1-3 and acetaminophen2,4,5 in differ-
ent doses are effective in alleviating postoperative
pain compared to placebo medication following oral
surgical procedures such as third-molar surgery.
Acetaminophen regimes, somewhat surprisingly, also
improved symptoms (i.e., postoperative swelling) of an
acute postoperative course compared to placebo after
third-molar surgery.6,7 There seems to be very little, if
any, published information available on ketoprofen’s
effect on an acute inflammatory postoperative course
in humans other than that on pain.
The aim of the present study was to compare the ef-
fect of a 3-day regime of ketoprofen 75 mg × 4 daily with
that of acetaminophen 1000 mg × 4 daily on the acute
postoperative course after third-molar surgery. The pri-
mary variable under investigation was the effect of the
ketoprofen and acetaminophen regimes on acute post-
operative swelling. Secondary variables included pain
and other inflammatory postoperative events.
305
 BJØRNSSON ET AL
METHODS
This was a randomized, double-blind, within-patient
crossover study in which the patients acted as their
own controls. The trial was approved by the Ethical
Committee for Medical Research, Health Region II (S-
93003) and Norwegian Medicines Agency (SLK No. 93-
01089). The trial adhered to the good clinical practice
criteria, including the Declaration of Helsinki.8
Subjects
Females and males who were waiting for outpatient
surgical removal of bilateral “identically” impacted
third molars, as evaluated by orthopantomograms,
were identified from the waiting list at the clinic. Pa-
tients were asked to volunteer after receiving written
information about the trial and being explained the na-
ture and intentions of the trial. The signature of each
patient verified informed consent.
Inclusion criteria were females and males between
18 and 40 years of age and weighing between 40 and
100 kg in compliance with the ASA class I physical sta-
tus classification.9 Exclusion criteria were any known
acute or chronic disease. A negative self-report was re-
quired with regard to overt renal or hepatic disease,
asthma bronchiole, ulcus ventriculi or duodeni,
choledoctal spasm, inflammatory gastrointestinal dis-
ease, unspecified symptoms from teeth not related to
surgical intervention, known intolerance to the trial
drugs, suspected or verified pregnancy, breastfeeding
females, or medication within the past 14 days except
peroral contraception. In addition, surgery lasting
more than 60 minutes, concomitant nontrial drugs dur-
ing the observation period, and surgical complications
making the two surgical procedures noncomparable
were also valid causes for exclusion.
Thirty patients entered the trial as intention-to-treat
patients, but 2 patients were excluded from the trial.
One was a 24-year-old female patient who was sub-
jected to wrongly executed swelling measurements
(faulty bite-fork position) on the 3rd postoperative day
during the first treatment (acetaminophen). The other
was a 23-year-old male patient who experienced
perioperative perforation to the antral sinus during the
second treatment (ketoprofen) and subsequent
adjuvant antibiotic therapy. Twenty-eight patients (16
females/12 males, 42.9% females/57.1% males) with a
mean age of 23 (range: 18-32) years, a mean (95% confi-
dence interval [CI]) height of 173.9 (170.8, 176.9) cm,
and a mean (95% CI) weight of 68.3 (63.8, 72.8) kg were
used for statistical analyses as per-protocol patients.
306 • J Clin Pharmacol 2003;43:305-314
Medications
The double-dummy technique was chosen to make the
two trial regimes identical with respect to tablet shape,
size, and number of tablets. The trial drugs consisted of
white ketoprofen tablets (25 mg each) and matching
placebo tablets or white acetaminophen tablets (each
500 mg) and matching placebo tablets. Each trial
drug dose consisted of three ketoprofen tablets and
two placebo (acetaminophen-like) tablets or two
acetaminophen tablets and three placebo (ketoprofen-
like) tablets, depending on the active drug regime.
Packing and labeling of the trial drug were made in-
dependently by the Ullevål Hospital Pharmacy (Oslo,
Norway), according to a randomized list made after
block randomization. Each set of trial drugs was given a
number, which corresponded to the inclusion number.
According to randomization, the first trial drug regime
within each trial drug set was one of two possible trial
drug regimes. One regime consisted of racemic
ketoprofen 75 mg (Orudis™, Rhône-Poulenc Rorer,
Oslo, Norway) taken four times a day (qid) starting 3
hours after completion of surgery and lasting for a total
of 3 days. On 2 subsequent postoperative days,
ketoprofen 75 mg was taken at 08:00, 12:00, 16:00, and
20:00 hours. The other regime was acetaminophen
1000 mg (Pinex™, Alpharma AS, Oslo, Norway) taken
four times a day starting 3 hours after completion of
surgery and lasting for a total of 3 days. On the subse-
quent 2 days, acetaminophen 1000 mg was taken at
08:00, 12:00, 16:00, and 20:00 hours.
Surgery
Each patient had two similar surgical procedures using
Xylocain-Adrenalin™ (lidocaine-hydrochloride 2% +
epinephrine 12.5 µg/mL, Astra, Södertälje, Sweden) as
local anesthetic. No concomitant medication was used
during surgery other than the local anesthetic. Surgery
was carried out to remove a mandibular third molar ac-
cording to a standardized technique, including
mucosal flap elevation, bone removal, and suturing, as
described previously.10 If it was considered necessary
to remove an ipsilateral maxillary third molar during
surgery, this was also done. This was only done on
those patients with bilateral “identically” positioned
maxillary third molars to avoid a dissimilar operative
procedure on the next surgical occasion. Sixteen of the
28 patients also had a bilateral “identically” positioned
maxillary third molar, which was removed during the
same surgical occasion as the ipsilateral mandibular
third molar.
 EFFECT OF KETOPROFEN AND ACETAMINOPHEN ON SWELLING, PAIN

Table I Mean and Mean Differences (95% CI) of Surgical Characteristics between Bilateral
“Identical” Surgical Procedures Made on Two Separate Occasions in 28 Patients
Receiving a Regime of Acetaminophen 1000 mg × 4 or Ketoprofen 75 mg × 4 for 3 Days
Acetaminophen Ketoprofen Mean
Regimen Regimen Difference p-Value

Volume of LA (mL) 4.5 4.5 0.03 (–0.03, 0.1) 0.32a

LA added during surgery (mL) 0.2 0.01 0.12 (–0.06, 0.31) 0.28a
Waiting time of LA (min:sec) 03:19 03:25 –00:06 (–00:27, 00:14) 0.76a
Time of surgery (min:sec) 17:00 17:00 00:00 (–00:00, 00:01) 0.75b
Significant difference if p < 0.05. LA, local anesthesia.
a. Data analyzed with the two-tailed Wilcoxon signed rank test.
b. Data analyzed with the two-tailed paired samples t-test.

Mean (95% CI) time between operations was 32 (22,

41) days. Descriptive characteristics for the two surgi-
cal interventions are listed in Table I. No statistically
significant difference (p > 0.05) was found between the
characteristics of the two surgical interventions.

Objective and Subjective

Measurements

The clinical record form (CRF) was divided in two

parts: a clinical CRF and a patient CRF. The patients re-
ceived their CRF only after being instructed in its use.
On the clinical CRF, the investigator noted the results of
objective clinical assessments of the patients preop-
eratively, on the 3rd and 6th postoperative days. The
method of measuring the primary objective vari-
able, postoperative swelling, has been described
previously11,12 and consisted of an exact measurement
of the distance from a face bow to the facial skin area
adjacent to the operated mandibular third molar (Fig-
ure 1). The present trial uses an objective method for as-
sessing postoperative swelling. The method has been
validated and reproduces “identical” magnitudes of
postoperative swelling when identical regimes of drugs
devoid of anti-inflammatory effect are used13 or when
drug regimes with comparable antiswelling potencies
are used.14
Secondary variables such as objective measurement Figure 1. The measuring device is shown in place measuring the
distance from the face bow to the skin adjacent to the right impacted
of mouth opening with a ruler11 and subjective assess- mandibular third molar prior to surgery.
ment of clinical postoperative complications such as
wound infections, fibrinolysis of blood clot (dry
socket), and presence of hematomas/ecchymoses were pain by slight bone provocation. Hematomas/
noted by the investigator at the control visit on the 3rd ecchymoses were assessed with a ruler along the lon-
and 6th postoperative days on the clinical CRF. The gest possible diameter as none (1), less than 4 cm (2),
presence (yes/no) of wound infection or dry socket was between 4 and 10 cm (3), and more than 10 cm (4). At
assessed by the investigator depending on clinical ap- the end of each observation period (7th postoperative
pearance, presence of pus, absence of normal coagula- day), the patients were asked if they had taken any con-
tion, odor arising from the alveolus, and extraordinary comitant nontrial drugs.

ANALGESIA 307

On the 6th postoperative day control, after complet-
ing the last trial drug regime, the drug regimen prefer-
ence score on the clinical CRF was shown to the patient
by the investigator. Drug regimen preference score was
made on a vertical 100-mm visual analogue scale (VAS)
running from second postoperative course best (0 mm)
to first postoperative course best (100 mm) via no dif-
ference marked on the VAS halfway (50 mm) between
the two opposing scores.
Other secondary subjective variables such as pain,
global drug regime efficacy score, postoperative bleed-
ing, and occurrence of adverse effects, including de-
scription and duration of adverse drug effects, were
also noted by the patients on their CRFs. Pain intensity
(PI) was rated on a vertical15 VAS running from no pain
(0 mm) to pain cannot be worse (100 mm). On the day
of surgery, the PI was recorded every hour for 11 hours
with extra recordings at 3.5, 6.5, and 9.5 hours, starting
immediately after completing the operation. On the 1st
and 2nd postoperative days, PI was scored at 08:00,
12:00, 16:00, and 20:00 hours. The sum pain intensity
(SUMPI) was calculated by adding all PIs from 0.5
hours after drug intake up to 11 hours after surgery. All
half-hour scores were multiplied by 0.5 before the ad-
dition. Sum PI was also calculated for each of the three
time intervals after the first drug dose (SUMPI3.5-6,
SUMPI6.5-9, and SUMPI9.5-11) on the day of surgery and
for the whole day of surgery (SUMPI).
On the 3rd postoperative day after each operation,
the patients made a global (overall) efficacy assessment
of the particular drug regimen on a 100-mm VAS run-
ning from bad (0 mm) to good (100 mm). Postoperative
bleeding was recorded by the patients on a 4-point ver-
bal rating scale 4 hours postoperatively, at bedtime on
the day of surgery, and at bedtime each day for the next
5 postoperative days. Postoperative bleeding was
scored according to the alternatives no bleeding (1),
taste of blood (2), can spit a little blood (3), or can spit a
lot of blood (4) according to Hepsø et al.16 Every evening
starting from the day of surgery and lasting until the
end of the 5th postoperative day, the patients answered
yes or no to the question, “Have you experienced any
Table II Mean and Mean Difference (95% CI) of Objectively Measured Postoperative Swelling in 28
Patients Being Treated with Acetaminophen 1000 mg × 4 or Ketoprofen 75 mg × 4 for 3 Days following
Surgical Removal of Bilateral, Impacted Third Molars in a Double-Blind, Randomized Crossover Trial
Acetaminophen
3rd p.o. day 29.1 (20.5, 37.8)
6th p.o. day 7.3 (2.4, 12.2)
Postoperative swelling (mm) measured on the 3rd and 6th p.o. days. Data analyzed with the two-tailed paired samples t-test.
308 • J Clin Pharmacol 2003;43:305-314
BJØRNSSON ET AL
other effect than pain relief from the trial drugs?” If yes,
the nature of the adverse effect and a time estimate of
the duration of the effect were specified. The patient
CRFs were collected by the investigator on the 7th post-
operative day control after completing each trial drug
regime.
Statistical Analyses
After descriptive analyses, all pertinent data were sub-
sequently analyzed with the one-sample Kolmogorov-
Smirnov test with respect to normality. According to
normality, continuous data were analyzed with the
two-tailed Wilcoxon signed rank test or the two-tailed
paired samples t-test. Nominal data (binary response)
were analyzed with the two-tailed McNemar Exact
Test. Ordinal data (graded response) were analyzed
with the Marginal Homogeneity Test with the Exact
Test. All data were analyzed using the SPSS for Win-
dows (version 8.0) statistical package.17 The signifi-
cance level was 5%.
RESULTS
Postoperative Swelling
The ketoprofen 75 mg × 4 regime reduced postopera-
tive swelling 27.8% (p < 0.04, two-tailed paired sam-
ples t-test) on the 3rd postoperative day following
third-molar surgery compared to that after the
acetaminophen 1000 mg × 4 regimen. On the 6th post-
operative day, the swelling after ketoprofen was 70.8%
(p < 0.02, two-tailed paired samples t-test) less than
that after acetaminophen. Details of swelling measure-
ments are shown in Table II.
Pain and Other Effects
Excluding Adverse Effects
Figure 2 shows the time course of the PI following the
two treatments on the day of surgery. The difference
(95% CI) between treatments is shown in Table III.
Ketoprofen Mean Difference p-Value Number
21.0 (15.5, 26.6) 8.1 (0.7, 15.5) < 0.04 28
2.1 (–0.4, 4.6) 5.2 (0.9, 9.5) < 0.02 28
 EFFECT OF KETOPROFEN AND ACETAMINOPHEN ON SWELLING, PAIN

Table III Mean and Mean Difference (95% CI) Pain Intensity (PI) Reported by Patients
Being Treated with Acetaminophen 1000 mg × 4 or Ketoprofen 75 mg × 4 on the
Day of Bilateral Third-Molar Surgery in a Double-Blind, Randomized Crossover Trial
Time after Surgery (h) Acetaminophen Ketoprofen Mean Difference p-Value Number

0 0.3 0.0 0.3 (–0.1, 0.6) 0.18 28

1 3.8 7.6 –3.8 (–10.4, 0.9) 0.57 28
2 11.2 17.3 –6.1 (–15.7, 3.4) 0.18 28
3 38.0 38.2 –0.2 (–9.0, 8.5) 0.96 28
3.5 31.6 29.2 2.4 (–3.2, 8.0) 0.46 28
4 26.3 18.4 7.9 (–0.4, 16.2) 0.06 28
5 25.0 14.1 10.9 (3.5, 18.3) 0.003a 28
6 27.8 14.2 13.6 (5.6, 21.6) 0.001a 28
6.5 21.4 10.6 10.8 (4.3, 17.3) 0.001a 28
7 15.9 9.9 6.0 (1.3, 10.7) 0.008a 28
8 13.9 9.7 4.2 (–0.1, 8.4) 0.03a 27
9 15.9 10.7 5.2 (1.0, 9.3) 0.02a 27
9.5 15.5 9.3 6.3 (0.2, 12.4) 0.07 24
10 11.3 8.0 3.4 (–1.9, 8.7) 0.31 21
11 8.0 5.2 2.8 (–1.0, 6.7) 0.14 20
Summed measures of PI
SUMPI3.5-6 94.8 61.3 33.6 (12.7, 54.4) 0.003b 28
SUMPI6.5-9 58.3 34.9 23.4 (7.0, 39.9) 0.007b 28
SUMPI9.5-11 24.3 20.2 4.1 (–9.2, 17.4) 0.53 28
SUMPI3.5-11 174.0 116.9 57.1 (18.6, 95.5) 0.005b 28
Trial medication started 3 hours after end of surgery. Pain scored on 100-mm visual analogue scale (VAS). Significant difference if p < 0.05.
a. Data analyzed with the two-tailed Wilcoxon signed rank test.
b. Data analyzed with the two-tailed paired samples t-test.

There was a statistically significant difference (all p-
values ≤ 0.03) in favor of a lower PI after ketoprofen 75
mg × 4 than after acetaminophen 1000 mg × 4 from 5 to
9 hours after surgery, which corresponds to 2 to 6 hours
after first drug intake. There was a tendency toward a
statistically significant difference between treatments 4
(p = 0.06) and 9 (p = 0.07) hours after surgery. All hourly
analyses were made with the two-tailed Wilcoxon
signed rank test.
The summed PI difference (95% CI) between the
acetaminophen and ketoprofen treatment correspond-
ing to each dose interval and for the whole regime on
the day of surgery is shown in Table III. There was a sta-
tistically significant difference in favor of ketoprofen
for the first dose interval (SUMPI3.5-6, p = 0.003) and the
second dose interval (SUMPI6.5-9, p = 0.007) but not for
the last dose interval (SUMPI9.5-11, p = 0.53). The
ketoprofen regime gave lower PI for the sum of all dose
intervals on the day of surgery (SUMPI3.5-11, p = 0.005).
All statistical analyses were made with the two-tailed
paired samples t-test.
Figure 3 shows the time course of the PI after the
treatments on the 1st to the 4th postoperative days. The
difference (95% CI) between treatments is shown in Ta-
ble IV. There was a statistically significant difference
with lower PI after ketoprofen at 12:00 hours (p = 0.01)
and 16:00 hours (p = 0.03) on the first postoperative day
and at 16:00 hours (p = 0.005) and 20:00 hours (p =
0.04) on the second postoperative day using the two-
tailed Wilcoxon signed rank test.
The patients’ global or overall evaluation of the effi-
cacy of the trial drug regimes showed no statistically
significant difference (p = 0.34, two-tailed paired sam-
ples t-test) between treatments. The difference (95%
CI) between the acetaminophen and the ketoprofen
treatments was –3.6 (–11.1, 3.9) mm.
There was no statistically significant difference
(p = 0.45, two-tailed Wilcoxon signed rank exact test)
between the treatments with respect to drug regime
preference. The difference between the acetaminophen
and the ketoprofen treatments was –2.1 (–11.0,
6.9) mm.
There was no statistically significant difference be-
tween the acetaminophen and the ketoprofen regime
with respect to mouth opening on the 3rd (p = 0.11,
two-tailed paired samples t-test) and the 6th (p = 0.11,

ANALGESIA 309
 BJØRNSSON ET AL

study. The difference between treatments (95% CI)

Figure 2. The mean pain intensity scores assessed on the day of sur-
gery by 28 patients who had “identical” bilaterally impacted third
molars removed on two separate occasions. On one occasion, they re-
ceived acetaminophen 1000 mg × 4 for 3 days. On the other occasion,
they received ketoprofen 75 mg × 4 for the same time period.
two-tailed paired samples t-test) postoperative days.
The difference (95% CI) between the acetaminophen
and the ketoprofen treatments was 2.9 (–0.7, 6.4) mm
on the 3rd postoperative day and 2.3 (–0.6, 5.2) on the
6th postoperative day.
No complications such as wound infection or dry
socket were seen in any of the patients entering this
with respect to assessment of postoperative
hematomas/ecchymoses was –0.1 (–0.5, 0.3) on the 3rd
postoperative day and –0.1 (–0.3, 0.1) on the 6th post-
operative day. There was no statistically significant dif-
ference (all p-values > 0.68) between treatments with
respect to hematomas/ecchymoses using the two-
tailed Marginal Homogeneity Test with the Exact Test
option.
The difference between treatments (95% CI), with
respect to assessment of postoperative bleeding after
ketoprofen 75 mg × 4 or acetaminophen 1000 mg × 4 for
3 days, was –0.3 (–0.8, 0.3) (p = 0.86) 4 hours after sur-
gery, –0.3 (–0.8, 0.3) (p = 1.00) on the bedtime day of
surgery, –0.1 (–0.5, 0.4) (p = 0.17) on the 1st postopera-
tive day, –0.2 (–0.5, 0.2) (p = 0.06) on the 2nd postoper-
ative day, –0.1 (–0.6, 0.3) (p = 0.15) on the 3rd postoper-
ative day, –0.1 (–0.4, 0.1) (p = 1.00) on the 4th
postoperative day, and 0.0 (–0.2, 0.2) (p = 0.75) on the
5th postoperative day. There was no statistically signif-
icant difference between the treatments using the two-
tailed Marginal Homogeneity Test with the Exact Test
option. However, acetaminophen tended to cause less
postoperative bleeding on the 2nd postoperative day.
Adverse Effects
Adverse effects reported after the acetaminophen or
ketoprofen regime associated with gender are shown in
Table V. No serious adverse effects were reported. All

Table IV Mean and Mean Difference (95% CI) Pain Intensity (PI) Reported by Patients Being Treated with
Acetaminophen 1000 mg × 4 or Ketoprofen 75 mg × 4 for 3 Days on the 1st to 4th Postoperative Days
following Bilateral Third-Molar Surgery in a Double-Blind, Randomized Crossover Trial
Time after Surgery Acetaminophen Ketoprofen Mean Difference p-Value Number

1st p.o. day

08:00 hours 13.5 14.0 –0.5 (–7.5, 6.4) 0.76 28
12:00 hours 11.9 9.1 2.8 (–1.6, 7.2) 0.01a 28
16:00 hours 11.2 6.4 4.8 (1.1, 8.5) 0.03a 28
20:00 hours 9.1 7.2 2.0 (–1.7, 5.6) 0.21 28
2nd p.o. day
08:00 hours 12.7 13.2 –0.5 (–7.2, 6.1) 0.78 28
12:00 hours 6.6 4.5 2.2 (–0.9, 5.2) 0.09 28
16:00 hours 8.1 4.5 4.6 (0.9, 8.4) 0.005a 28
20:00 hours 8.6 3.4 5.2 (0.5, 9.9) 0.04a 28
3rd p.o. day
Bedtime 8.8 12.0 –3.2 (–9.7, 3.3) 0.53 28
4th p.o. day
Bedtime 7.3 9.6 –2.3 (–6.3, 1.8) 0.35 28
Pain scored on 100-mm visual analogue scale (VAS). Significant difference if p < 0.05.
a. Data analyzed with the two-tailed Wilcoxon signed rank test.

310 • J Clin Pharmacol 2003;43:305-314

 EFFECT OF KETOPROFEN AND ACETAMINOPHEN ON SWELLING, PAIN
Figure 3. The mean pain intensity scores assessed on the 1st to the
4th postoperative days by 28 patients who had “identical” bilaterally
impacted third molars removed on two separate occasions. On one
occasion, they received acetaminophen 1000 mg × 4 for 3 days. On
the other occasion, they received ketoprofen 75 mg × 4 for the same
time period.
adverse effects were categorized as mild to moderate.
The was no statistically significant difference (all p-
values > 0.45) between the treatments with regard to
the number of adverse reports each day during the ob-
servation period using the two-tailed McNemar Exact
Test.
DISCUSSION
The analgesic effectiveness of NSAIDs is claimed to be
the main reason for their popularity in inflammatory
conditions.18,19 It has also been proposed that the
antiswelling efficacy of NSAIDs is dissociated from
their analgesic efficacy.20,21 The somewhat diffuse con-
cept of “anti-inflammatory effect,” however, is widely
used to categorize NSAIDs as therapeutic agents, mar-
ket NSAIDs, and justify their use in inflammatory con-
ditions. A clinical demonstration of anti-inflammatory
drug effect on acute and chronic noninfectious inflam-
mation would include drug effects on all of the tradi-
tional cardinal symptoms of inflammation (e.g., ery-
thema, pain, local temperature elevation, swelling, and
reduced function).22
Changes in tissue redness and local temperature ele-
vation do not, for obvious reasons, seem clinically in-
teresting judged against pain, swelling, and reduced
function as test variables for assessing patient improve-
ment. Clinical studies of NSAIDs on acute and chronic
noninfectious inflammation include mostly subjec-
tively assessed pain and various objective measures of
ANALGESIA
reduced function as the primary test variables of inter-
est. Surprisingly few papers address the effects of
NSAIDs on noninfectious inflammation in which
swelling, as a test variable, is measured objectively.
The trial shows that ketoprofen, a traditional
NSAID, actually reduces acute postoperative swelling.
A 3-day regime of ketoprofen 75 mg × 4 reduces acute
inflammatory postoperative swelling by 27.8% com-
pared to a 3-day regime of acetaminophen 1000 mg × 4,
as measured on the 3rd postoperative day. On the 6th
postoperative day, the swelling after treatment with the
ketoprofen regime was reduced by 70.8% compared
with that after the acetaminophen regime.
This effect on acute postoperative swelling follow-
ing treatment with the ketoprofen regime is remark-
able. The pharmacological profiles of several analgesic
and anti-inflammatory drugs have been examined in
our department using the same trial design as the pres-
ent study. The most effective are, not unexpectedly,
glucocorticoid drugs. A single dose of betamethasone
9 mg, given i.m. prior to surgery, reduced acute postop-
erative swelling compared to placebo on the 3rd post-
operative day by 55%.23 Betamethasone 9 mg, injected
i.m. 3 hours after surgery as a single dose, reduced
acute swelling compared to placebo on the 3rd postop-
erative day by 47%.24 Intravenously administered
methylprednisolone (40 mg) as a single dose reduced
swelling compared to placebo by 46% on the 3rd post-
operative day.25
Previous findings that acetaminophen actually re-
duces swelling after the removal of impacted third mo-
lars are more unexpected. The fact that acetaminophen
actually reduces an acute postoperative soft tissue
swelling following surgery involving a limited area of
surgical trauma and limited bleeding remains relatively
unknown to clinicians. Swelling after acetaminophen
1000 mg × 4 given p.o. for 2 days, followed by
acetaminophen 500 mg × 4 for the subsequent 2 days,
was 29% less than that found after placebo on the 3rd
postoperative day.6 Acetaminophen 1000 mg × 4, fol-
lowed by acetaminophen 500 mg × 4 for the next 2
days, reduced swelling on the 3rd postoperative day by
31%.7
The effect of acetaminophen 1000 mg × 4 daily on
swelling has also been compared in the same model
with a tablet regime of methylprednisolone starting
with 24 mg after surgery, declining to an evening
dose of 4 mg on the 3rd postoperative day.
Methylprednisolone reduced acute postoperative
swelling better than acetaminophen by 29% on the 3rd
postoperative day.26 An indirect comparison of the
antiswelling capacity of the methylprednisolone re-
gime versus that of acetaminophen, as well as the re-
311
 BJØRNSSON ET AL

Table V Adverse Effects Reported by 28 Patients Being Treated with Ketoprofen 75 mg × 4 or Acetaminophen
1000 mg × 4 for 3 Days in a Double-Blind, Randomized Crossover Trial after Bilateral Oral Surgery
Time of Occurrence Ketoprofen Acetaminophen

Day of surgery 3 Tired (2 F/1 M) 2 Tired (all M)

1 Tired/stomach pain/diarrhea (M) 1 Nausea (M)
1 Diarrhea (F)
1 Muscular stiffness (M)
22 None (13 F/9 M) 25 None (14 F/11 M)
Postoperative day 1 1 Tired (F) 2 Nausea (all F)
1 Tired/stomach pain/diarrhea (M) 1 Tired (F)
1 Tired/headache (F) 1 Tired/stomach pain/diarrhea (M)
1 Diarrhea (F) 1 Tired/dizzy (M)
1 Muscular stiffness (M)
1 Stomach pain (M)
22 None (13 F/9 M) 23 None (13 F/10 M)
Postoperative day 2 1 Tired/stomach pain/diarrhea (M) 1 Tired (F)
1 Tired/headache (F) 1 Tired/dizzy (M)
1 Muscular stiffness (M) 1 Tired/stomach pain/diarrhea (M)
1 Diarrhea (F)
1 Stomach pain (M)
1 Headache/fever (F)
25 None (15 F/10 M) 22 None (13 F/9 M)
Postoperative day 3 1 Tired/diarrhea (M) 1 Tired/dizzy (M)
1 Tired/headache (F) 1 Diarrhea (F)
26 None (15 F/11 M) 26 None (15 F/11 M)
Postoperative day 4 1 Tired/diarrhea (M) 1 Diarrhea (M)
1 Tired/headache (F)
26 None (15 F/11 M) 27 None (16 F/11 M)
Postoperative day 5 1 Tired/headache (F)
1 Stomach pain (M)
26 None (15 F/11 M) 28 None (16 F, 12 M)
The number of specific reports associated with gender of patient are shown in parentheses (F = female/M = male).

sults from the present ketoprofen regime versus that of
the acetaminophen, adds credibility to the claim of a
major anti-inflammatory effect of ketoprofen.
Ketoprofen provides pain relief in single doses rang-
ing from 12.5 mg and at least up to 100 mg.2-4,27,28
Acetaminophen provides pain relief in single doses
ranging from 500 to 1000 mg.2,5,29,30 The present trial
showed that a single dose of ketoprofen 75 mg was su-
perior to acetaminophen 1000 mg over a 3-hour obser-
vation period. Ketoprofen 75 mg × 4 was also superior
as an analgesic compared to a regime of acetaminophen
1000 mg on the day of surgery when the postoperative
pain was most intense after third-molar surgery.
It is noteworthy that even though the subjective pain
assessments by the patients and the objective swelling
measurements clearly favored the ketoprofen regime
compared to the acetaminophen regime, there was no
statistically significant difference between the treat-
ments with respect to global evaluation and preference
scores. There was no clear statistical difference be-
tween the treatments with respect to mouth opening as
a measure of the clinical cardinal symptom of inflam-
mation “reduced function.” The results found by mea-
suring mouth opening contrasts with the results found
measuring swelling and assessing pain. This finding
suggests that mouth opening may be a less useful vari-
able for the measurement of the anti-inflammatory ef-
fect of drugs.
There was no complication with respect to wound
healing, which could be attributed to any of the trial
drugs during this study. Following both treatments,
there were reports of adverse effects, which could be
ascribed to the drug treatments, although there was no
statistically significant difference between treatments.
This study does not allow for the large numbers of pa-
tients needed to assess the relative relationship of drug-

312 • J Clin Pharmacol 2003;43:305-314

 EFFECT OF KETOPROFEN AND ACETAMINOPHEN ON SWELLING, PAIN
induced side effects between ketoprofen and
acetaminophen. The adverse effects reported in the
present study, which deserve special attention, are
those associated with the gastrointestinal tract (e.g.,
stomach pain and diarrhea). It should be noted that all
adverse effects reported were judged as mild to moder-
ate in severity. Ketoprofen, among other potent
NSAIDs, has been associated with a risk of gastrointes-
tinal irritation,31-33 while acetaminophen is reported to
cause no significant gastrointestinal irritation.34 It
seems reasonable to assume that the relatively short
duration of the ketoprofen drug regime poses a limited
risk for gastrointestinal distress among patients with-
out previous experience of gastrointestinal symptoms
or reactions to other NSAIDs.
There was no statistically significant difference be-
tween treatments with respect to subjective reports of
postoperative bleeding after surgery. But a tendency to-
ward more bleeding, as reported subjectively by the pa-
tients, after the ketoprofen regime was observed, espe-
cially on the 2nd postoperative day when the 3-day
drug regime ended. Acetaminophen 1000 mg has ap-
parently no significant effect on platelet function.35-37
Ketoprofen inhibits platelet aggregation in a dose-
dependent manner37,38 with a possible effect on bleed-
ing. Abiding to the well-known contraindications
against the use of ketoprofen, which include patients
on anticoagulant therapy or coagulation disorders,
should be strictly observed.
Both acetaminophen and racemic ketoprofen, taking
into consideration the two enantiomers, display very
similar terminal half-lives varying between 1 and 4
hours.39,40 The chosen drug regime thus presents a trial
setting that permits a direct comparison of the trial
drugs’ pharmacodynamic efficacy. Ketoprofen 75 mg ×
4 used as a 3-day regime provides significantly better
analgesia and antiswelling efficacy compared to a simi-
lar regime of acetaminophen 1000 mg following third-
molar surgery.
The authors thank Alpharma, Oslo, Norway, and Rhône-Poulenc
Rorer, Oslo, Norway, for their gift of trial drugs, including matching
placebo medication.
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