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*P 0.03.
P 0.039, Mann-Whitney test with Bonferroni correction placebo compared to celecoxib.
Fig 2. Box plots (showing 10th, 25th, 50th, 75th, and 90th
centiles and outliers) of supplementary analgesic doses
during the rst 24 hours according study group. (*P
0.021, placebo compared to ketoprofen, Mann-Whitney
test with Bonferroni correction.)
Otolaryngology
Head and Neck Surgery
290 NIKANNE et al February 2005
without pain. However, the cessation of signicant pain
during eating occurred a median of 2 days earlier in the
celecoxib-treated patients than in the ketoprofen-
treated patients (P 0.008) (Tables 2 and 3).
At 3 weeks, none of the patients reported signicant
pain, and only 3 reported mild pain at rest and 12
during swallowing. At 3 weeks, 14 patients (9 cele-
coxib-treated and 5 ketoprofen-treated) reported that
pain had still interference on daily activities.
The satisfaction with the analgesic treatment was
closely similar in both groups, the median (range) score
on a scale 0completely satised to 10completely
unsatised was 1 (0-9) among the celecoxib-treated
patients and 2 (0-9) among the ketoprofen-treated pa-
tients. The analgesic efcacy of celecoxib and ketopro-
fen combined with paracetamol-codeine was also as-
sessed as being closely similar, where median score
was 2 (0-9) in both groups.
One primary hemorrhage occurred in the ketoprofen
group and the patient required electrocautery under
local anesthesia to stop bleeding. A major secondary
hemorrhage occurred in 1 celecoxib-treated patient and
in 5 ketoprofen-treated patients (P 0.026). All 6
patients required electrocautery under local anesthesia
to stop the bleeding but no blood transfusions were
needed (Table 4).
A total of 271 adverse events were reported by 104
patients. Thirty-four (30%) vomited, 28 (24%) devel-
oped nausea, and 31 (27%) constipation. Two of the 68
celecoxib-treated patients developed allergic reaction, 4
developed rashes and 1 patient developed a face edema
compared to none of the ketoprofen-treated patients
(Table 4).
DISCUSSION
The primary outcome parameter was the consump-
tion of rescue analgesic during the rst 24 hours after
surgery. Ketoprofen 100 mg by mouth 1 hour before
and 12 hours after surgery seemed to performed better
than 2 doses of celecoxib 200 mg, because only the
ketoprofen-treated patients needed less rescue analgesia
during the rst 24 hours after tonsillectomy compared
to the patients in the placebo group. However, in a post
hoc analysis, it was revealed that the celecoxib-treated
patients needed several doses of rescue analgesic only
during the rst 4 postoperative hours. During the next
20 hours, analgesic consumption was similar in the 2
active treatment groups, and, in both groups, it was less
than in the placebo group. Moreover, after discharge,
celecoxib 200 mg bid seemed to provide a better anal-
gesia than ketoprofen 100 mg administered correspond-
ingly because the celecoxib-treated patients were able
to return to their normal daily activities earlier than the
ketoprofen-treated patients.
The slow onset of an analgesic effect of celecoxib
compared to ketoprofen may be explained by pharma-
cokinetic and pharmacodynamic differences between
these 2 compounds. First, ketoprofen is absorbed
readily after oral administration with the time to peak
plasma concentration occurring after 1 hour,
11
whereas
the absorption of celecoxib is moderate, the peak con-
centration occurs after 2 to 4 hours.
12
Second, the 11
hours half life of celecoxib
13
is signicantly longer than
that of ketoprofen, which is 2 hours.
11
This is a signif-
icant difference because it takes 5 half-lives before the
steady state plasma concentration of a drug is reached.
Fig 3. Box plots (showing 10th, 25th, 50th, 75th, and 90th)
of time to supplementary analgesia in minutes accord-
ing study group. (*P 0.039 celecoxib compared to
ketoprofen, Mann-Whitney test with Bonferroni correc-
tion.)
Fig 4. Pain on swallowing. (*P 0.05, placebo compared
to ketoprofen, Mann-Whitney test with Bonferroni correc-
tion.)
Otolaryngology
Head and Neck Surgery
Volume 132 Number 2 NIKANNE et al 291
With ketoprofen, the steady state concentration should
have been reached within the rst 24 hours; with cele-
coxib, it may have occurred only on day 2 or day 3.
Third, the volume of distribution of celecoxib is signif-
icantly larger, 455 L, compared to ketoprofen, 8 to 14
L. These differences may explain why celecoxib per-
formed less efciently during the rst hours after sur-
gery although it was superior compared to ketoprofen
later. Whether a higher initial dose of celecoxib (400
mg) or earlier administration of the rst dose would
have performed better is open for discussion. However,
the fact that the patients who had received celecoxib
recovered earlier than the patients who had received
ketoprofen is considered important. Recovery of nor-
mal daily activities, such as eating, drinking, and sleep-
ing, is important not only for the patient, but also for the
community because it is just after these activities have
been normalized that the patient is able to return back
to work.
Other studies with tonsillectomy have also found a
better immediate analgesic efcacy with conventional
NSAIDs, but, in the continuation of pain management,
new generation COX-2 selective inhibitors have per-
formed better.
14
The perception of acute pain is more
likely to be modulated by cyclo-oxygenase-1 as time
for induction must elapse for COX-2.
15
It seems that
the COX-1 inhibition is needed to provide appropriate
analgesic efcacy in cases where severe acute pain is
caused by for example surgical trauma. Later, when
COX-2 expression may play a more important role in
the continuation of hyperalgesia, COX-2 inhibitors
seem to perform efciently.
The efcacy of celecoxib during tonsillectomy has
been evaluated in 2 clinical trials. In the rst trial of
celecoxib 200 mg by mouth 30 minutes before otolar-
yngologic surgery alone was no more effective than
placebo or paracetamol 2000 mg in reducing postoper-
ative pain.
16
In a dose-nding study, celecoxib 400 mg
was more effective than celecoxib 200 mg in reducing
postoperative pain, but the lower dose did not perform
better than placebo in the early postoperative period.
17
Unfortunately, in these 2 studies, the patients were
provided with a single dose of celecoxib only and the
follow-up consisted only the rst 24 hours after the
surgery so the efcacy of celecoxib on cessation of
postoperative pain and on full recovery after surgery is
not known. Because signicant pain after tonsillectomy
may last for 1 to 2 weeks
3
further follow-up studies
with COX-2 selective inhibitors are needed.
Operative site bleeding is a concern during tonsil-
lectomy. In the present trial, no clinically signicant
differences in the intraoperative bleeding was seen be-
tween the patients who had received celecoxib, keto-
profen, or placebo. Patients were operated on with an
Table 2. The secondary outcome endpoints after discharge in the two study groups. Data are median
(minimum - maximum).
Celecoxib-treated
patients (n 66)
Ketoprofen-treated
patients (n 42) P
Number of study drug doses 28 (6-32) 28 (12-30) 0.47
Number of rescue analgesic doses 35 (0-120) 36 (6-112) 0.92
Duration of analgesic treatment (d) 14 (3-21) 14 (8-18) 0.64
Cessation of signicant pain during drinking (d) 7 (0-14) 8 (0-21) 0.055
Cessation of signicant pain during eating (d) 10 (1-17) 12 (1-21) 0.008
Normal night sleep (d) 7 (0-14) 8 (0-14) 0.097
Normal daily activities (d) 14 (3-20) 14 (4-21) 0.92
Table 3. Interfere of pain on daily activities. Data are worst scores expressed during the rst week after
surgery on an 11-point scale, 0 does not interfere, 10 completely interfere. Data are median
(minimum-maximum).
Celecoxib-treated
patients (n 66)
Ketoprofen-treated
patients (n 42) P
General daily activities 6 (1-10) 6 (1-10) 0.47
Drinking 5 (1-9) 4 (2-9) 0.57
Eating 7 (2-10) 7 (2-10) 0.93
Speech 6 (0-9) 6 (1-10) 0.36
Sleep 5 (0-9) 4 (0-9) 0.39
Mood 4 (0-10) 5 (0-10) 0.69
Relations to other people 5 (1-9) 6 (0-9) 0.79
Otolaryngology
Head and Neck Surgery
292 NIKANNE et al February 2005
electrocautery technique and based on our clinical ex-
perience, the amount of bleeding is relatively small
with this technique. However, the celecoxib-treated
patients experienced less secondary hemorrhage than
the patients who had received ketoprofen. All together
6 patients experienced major secondary bleeding; 5 of
them had received ketoprofen and 1 celecoxib. All the
patients were treated with electrocautery with local
anesthesia and recovered without any further compli-
cations. The lower number of bleeding episodes in the
celecoxib group is in agreement with the expectations
because COX-2 selective NSAIDs do not affect platelet
aggregation and should cause less risk for perioperative
bleeding than the conventional NSAIDs.
6
In our study, a high number (90%) of the patients
reported adverse effects. The logical explanation is that
every event the patient reported was noted, but this
approach does not allow causality assessment. The
most frequently reported adverse effects, somnolence,
vomiting, constipation, and nausea are, however, more
likely connected with anesthetic drugs, codeine, or sur-
gery than the NSAIDs. On the contrary, some adverse
effects are likely to be caused by the study drugs.
Conventional NSAIDs can cause a direct local injury to
the gastric mucosa whereas COX-2 selective agents
should exert a decreased risk for gastrointestinal ad-
verse effects.
18
In the present trial, however, the inci-
dence of gastrointestinal adverse effects was similar in
the 2 groups. Nine patients reported symptoms of hy-
persensitivity reactions with celecoxib. As celecoxib
contain sulphonamide, there is a risk for hypersensitiv-
ity reactions, caution should be exercised in prescribing
celecoxib for patients with a history of allergic-type
reactions to NSAIDs or sulphonamides.
In conclusion, in patients with tonsillectomy, keto-
profen provided a better analgesic efcacy during the
rst 24 hours after surgery, but, after discharge, cele-
coxib allowed the patients to return to their normal
daily activities earlier. Secondary hemorrhage occurred
more commonly with ketoprofen, but the incidence of
other adverse effects was closely similar between the 2
drugs.
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Ketoprofen-
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Patients with one or more
adverse events
61 43
Total number of adverse
events
152 119
Adverse event
Vomiting 17 17
Nausea 21 7
Abdominal pain 4 2
Constipation 18 13
Somnolence 26 21
Dizziness 4 6
Confusion 5 6
Allergic reaction 2
Rash 4
Face/mouth edema 3
Tongue edema 4
Glossitis 2 2
Larynx pain 2 3
Taste perversion 1 2
Respiratory insufciency 2
Headache 2 2
Sweating increased 3
Fever 1 2
Major bleeding 1 5 0.026
Minor bleeding 6 1
Insignicant bleeding 20 15
*Adverse events with a single mention.Celecoxib-treated patients: atulence,
emotional lability, paroniria, nervousness, larynx edema, rhinitis, pruritus,
sputum increased, coughing, hypotension.
Ketoprofen-treated patients; eructation, diarrhea, abdominal rumbling, halluci-
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Head and Neck Surgery
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