Int. J. Oral Maxillofac. Surg.

2009; 38: 350–355

doi:10.1016/j.ijom.2008.12.013, available online at http://www.sciencedirect.com

Clinical Paper
Oral Medicine

A randomized, double-blind, D. Chopra1, H. S. Rehan1,

P. Mehra2, A. K. Kakkar1
1
Department of Pharmacology, Lady

placebo-controlled study Hardinge Medical College, New Delhi, India;

2
Department of Dental and Oral Surgery,
Lady Hardinge Medical College, New Delhi,
India

comparing the efficacy and

safety of paracetamol,
serratiopeptidase, ibuprofen
and betamethasone using the
dental impaction pain model
D. Chopra, H. S. Rehan, P. Mehra, A. K. Kakkar: A randomized, double-blind,
placebo-controlled study comparing the efficacy and safety of paracetamol,
serratiopeptidase, ibuprofen and betamethasone using the dental impaction pain
model. Int. J. Oral Maxillofac. Surg. 2009; 38: 350–355. # 2008 International
Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights
reserved.

Abstract. Assessment of postoperative sequelae following the removal of an impacted

third molar has been used in clinical pharmacology to evaluate the relative efficacy
of various analgesic, anti-inflammatory drugs. This study included 150 patients with
impacted lower third molars. They were randomly sorted to receive ibuprofen,
paracetamol, betamethasone, serratiopeptidase or placebo. Evaluation of efficacy
was made using tape measurement (for swelling), visual analogue scale (for pain
evaluation), mouth opening ability and oral temperature. The effect of treatment on
hematological parameters, bleeding, wound healing and requirement for rescue
medication was also studied. Peak pain scores were observed approximately 5–
6 hours after the operation. Betamethasone showed significant analgesic activity
from day 1. Ibuprofen and betamethasone were significantly more effective than
Keywords: analgesic; pain; swelling; impacted
placebo in reducing swelling. Trismus was least with betamethasone. A significant third molar; postoperative sequelae.
rise in temperature on the operated side occurred only on day 1 in all the groups.
Serratiopeptidase did not showed significant analgesic and anti-inflammatory Accepted for publication 16 December 2008
action. Mild-to-moderate adverse effects were reported. Available online 24 January 2009

0901-5027/040350 + 06 $36.00/0 # 2008 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Impaction of the third molar is a common
disorder, which often necessitates tooth
removal. The common postoperative
sequelae of surgical removal of impacted
teeth are pain, trismus and swelling,
related to the local inflammatory reaction,
with cyclooxygenase (COX) and prosta-
glandins playing a crucial role23. Good
surgical technique and gentle tissue hand-
ling minimize postoperative inflammation
but do not prevent it6.
Before the development of non-steroi-
dal anti-inflammatory drugs (NSAIDs),
opioids were relied on for pain relief.
Opioid drugs are effective analgesics,
but because they do not have anti-inflam-
matory action their efficacy in dental pain
is doubtful.
NSAIDs are effective in the manage-
ment of postoperative dental pain. The
likely mechanism of action is blockade
of prostaglandin synthesis. One of the
commonly used agents for dental pain is
ibuprofen. The efficacy of ibuprofen in the
treatment of postoperative dental pain has
been evaluated in several clinical trials.
Paracetamol is another commonly used
non-narcotic analgesic that has been eval-
uated in postoperative dental pain. The
mechanism of its action is unclear. Current
evidence from animal and human studies
supports the hypothesis that the analgesic
effect of paracetamol is central, as a result
of the activation of descending serotoner-
gic pathways, but its primary site of action
is inhibition of prostaglandin synthesis.
Biochemical studies suggest COX-3 activ-
ity that is selectively susceptible to para-
cetamol as an alternative site of action1,16.
Corticosteroids relieve pain by acting
on the inflammatory reaction20. Their anti-
inflammatory and immunomodulating
effects are thought to be mediated by
the classical genomic mechanism of
action caused by the cytosolic glucocorti-
coid receptor21. Some studies showed cor-
ticosteroids reducing the inflammatory
sequelae after third-molar surgery, but
others did not show convincing results5,14.
In the present study, betamethasone was
included as the prototype corticosteroid.
Proteolytic enzymes have a role in the
reduction of edema and swelling but the
extent of their effectiveness is unknown.
Serratiopeptidase, a metalloprotease, has
anti-inflammatory, antioedemic and fibri-
nolytic activity. Its anti-inflammatory effi-
cacy has been studied, confirming that
serratiopeptidase has greater efficacy than
placebo. It reduces inflammation and
blocks the release of pain-inducing amines
from inflamed tissues12. Serratiopeptidase
is absorbed through the intestine of rats,
but how enzymic preparations adminis-
Drugs and postsurgical oral pain.
tered orally reach the site of inflammation
in humans is unclear11.
This study evaluated and compared the
efficacy and safety of paracetamol, serra-
tiopeptidase, ibuprofen and betametha-
sone in reducing swelling and pain
following the removal of an impacted
lower third molar.
Material and methods
This randomized, double blind, placebo-
controlled study included 150 outpatients,
with a unilateral impacted lower third
molar, aged 18–45 years, of either sex.
The study protocol was approved by the
Institutional Ethical Committee, L.H.M.C,
New Delhi. Reasons for exclusion from
the study were: known allergy to NSAIDs;
hepatic, renal or heart diseases; diabetes
mellitus; hypertension; concurrent treat-
ment with immunosuppressants, corticos-
teroids; history of peptic ulceration;
gastrointestinal hemorrhage; pregnancy;
use of oral contraceptives; history of
NSAIDs use in the past 10 days; and
evidence of infection at the surgical site.
Baseline investigations including an X-
ray of the mandible, 308 lateral oblique to
diagnose tooth impaction, hemogram
(hemoglobin, total lymphocyte count
and differential leukocyte count), blood
sugar, bilirubin, blood urea, ECG and
blood pressure measurement were carried
out for all the patients.
Patients fulfilling the criteria were ran-
domly allocated from a computer-gener-
ated list of random numbers into one of the
five groups to receive treatment three
times a day with ibuprofen 600 mg, beta-
methasone 0.5 mg, paracetamol 1 g, ser-
ratiopeptidase 20 mg or placebo. The
study drugs were dispensed as identical
capsules by an unblinded staff member.
The placebo was a capsule containing
lactose. All the medications were admi-
nistered orally after meals. The first dose
was administered 1 h after surgery. The
procedure was described to the patients
and written informed consent was
obtained.
The same surgeon operated on all the
patients to avoid any variation in the sur-
gical technique. The operation was carried
out under local anesthesia (2% xylocaine
with 1; 200,000 adrenaline). The surgical
procedure consisted of a 3–4 cm long
buccal incision, elevation of the mucoper-
iosteal flap, removal of buccal bone using
bur and chisel, splitting and elevation of
the impacted tooth, followed by debride-
ment, achievement of hemostasis and clo-
sure of wound by interrupted suture using
3/0 braided silk. The duration of operation
351
and the quantity of local anesthetic agent
used was recorded.
Rescue medication in the form of tra-
madol 100 mg was allowed when required
for 7 days postoperatively. The number of
patients requiring tramadol was recorded.
Postoperatively, all patients received
amoxycillin 500 mg 8 hourly and ornida-
zole 500 mg 12 hourly for 5 days to pre-
vent infection of the surgical site. Oral
hygiene was maintained postoperatively
with the use of a baby brush and mouth
wash (chlorhexidine gluconate 0.2%) after
breakfast and dinner. Standard postopera-
tive instructions were given.
Efficacy of the treatments was assessed
by measuring the following parameters.
Swelling was recorded using a modified
tape measure method described by MOS-
15
QAU et al. The distances from: the tragus
to the outer corner of the mouth, tragus to
progonion; lateral corner of eye to angle of
the mandible; and tragus to angle of the
mandible were obtained preoperatively,
on days 1, 3, 5 and 7. Pain was assessed
using a visual analog scale stretching from
‘no pain’ (0 mm) to ‘pain as bad as it could
be’ (100 mm), preoperatively, immedi-
ately postoperatively, at 30 min interval
for the next hour, every 8 h until day 7.
The measurements were made by the
patient at home and by the investigator
at follow up.
Mouth opening ability was assessed by
measuring the distance between the upper
and lower central incisal edges at maximal
mouth opening on days 0 (baseline), 3 and
524. Wound healing was assessed on days
1, 3 and 58. Bleeding from the wound was
recorded as none, slight (taste of blood),
moderate (some blood in the mouth) or
marked (much blood in the mouth)10.
Local temperature was recorded in the
lower buccal cavity on both sides and any
difference was recorded on days 0 (base-
line), 1, 3, 5 and 7. Hemoglobin, total
lymphocyte count and differential leuko-
cyte counts were measured on days 0, 1
and 5.
Patients attended on days 1, 3, 5 and 7
for the data to be recorded. Adverse drug
reactions observed during the study were
also recorded. Patients were asked to state
whether the postoperative events were
expected, less than expected or more than
expected.
Statistical analysis
ANOVA, Bonferroni’s correction was
used to compare the measurements of
swelling, pain, mouth opening ability, oral
temperature in and between groups. A
non-parametric test (X2 test) was used to
352 Chopra et al.

Table 1. Demographic and baseline characteristics of the study patients (n = 150).

Placebo Paracetamol Serratiopeptidase Ibuprofen Betamethasone
Total No. of patients 30 30 30 30 30
Age (years)
Mean 29 27.33 29.53 26.47 27.93
SE 0.91 1.37 1.06 0.9 1.01
Gender
Male 18 18 18 20 18
Female 12 12 12 10 12
Ratio (M: F) 1:1.5 1:1.5 1:1.5 1:2 1:1.5
Degree of bony impaction
Partial (%) 38 41 40 40 43
Complete (%) 62 59 60 60 57
Educational status
Illiterate 2 1 1 2 3
Literate 28 29 29 28 27

Table 2. Amount of local anesthetic used and duration of surgery (mean  SEM).
Placebo Paracetamol Serratiopeptidase Ibuprofen Betamethasone
Amount of anesthetic used (ml) 50 5.13  0.09 5.37  0.09 5.1  0.27 50
Duration of surgery (min) 28.07  0.75 29.07  1.84 29.27  1.08 25.6  1.3 28.5  1.17

Table 3. Mean of four distances (cm) measured over the swelling using tape measure method (mean  SEM).
Treatment groups Day 0 Day 1 Day 3 Day 5 Day 7
Placebo 43.3  0.43 46.84  0.51 45.71  0.5 45.13  0.48 44.54  0.42
Paracetamol 43.30  0.53 45.63  0.58 44.60  0.62 43.97  0.59 43.37  0.53
Serratiopeptidase 43.03  0.36 45.23  0.38 44.17  0.33 43.40  0.35 43.23  0.36
Ibuprofen 42.36  0.46 44.10  0.43** 43.30  0.43** 42.77  0.43** 42.50  0.46*
Betamethasone 43.34  0.38 44.68  0.37* 43.92  0.35 43.54  0.36 43.37  0.38
*,  -p < 0.05; **,  -p < 0.01; ***,  -p < 0.001.
* Significance of various treatment groups in comparison with placebo on respective days.

Intragroup comparison of day 1, 3, 5 and 7 with day 0.

determine statistical significance for dif-
ferences in bleeding, healing and adverse
drug reactions. P < 0.05 was considered
statistically significant. The statistical ana-
lysis was performed with the SPSS 7.5
software package.
Results
150 patients who required prophylactic
removal of impacted lower third molars
were randomly distributed to one of the
five study groups. The treatment groups
had similar demographic and baseline
characteristics (Table 1). All the enrolled
patients completed the study. The mean
time taken for surgery and the amount of
local anesthetic required was statistically
similar among all the groups (Table 2).
The mean of the 4 distances (tragus to
outer corner of mouth, tragus to progo-
nion, tragus to angle of mandible, lateral
corner of eye to angle of mandible) mea-
sured was calculated (Table 3). The mean
preoperative measurement (baseline) of
all distances was found to be similar in
all the groups (range 42–43.5 cm). In the
placebo, paracetamol (p < 0.05) and ser-
ratiopeptidase (p < 0.001) groups there
was a significant increase in the mean
distances compared with baseline until
day 7. In the ibuprofen group the measured
distance was significantly greater
(p < 0.001) compared with baseline until
day 5 (Table 3). In the betamethasone
group, swelling was significantly greater
(p < 0.001) compared with baseline until
day 3. On all the days, the mean distance in
the placebo group remained higher than in
the other treatment groups (Table 3).
In all the groups, the maximum pain
score occurred on day 0 (Table 4).

Table 4. The mean pain score (mm) on the day of surgery (day 0) (mean  SEM).
Treatment groups Immediate postoperative 30 min after surgery 1 h after surgery Afternoon Evening
Placebo 10.67  2.99 18  3.97 37  5.45 61  4.58 58.67  4.76
Paracetamol 4.67  2.43 28  6.69 36  5.92 44  5.79 33.67  6.74
Serratiopeptidase 2.67  1.26 12  3.85 23.33  5.86 49.33  5.82 40.67  6.62
Ibuprofen 3.67  1.46 13  4.77 28.67  5.16 39.67  3.43** 36  5.54*
Betamethasone 4  2.27 19.33  4.60 31.67  5.97 47.83  4.75 39  5.39
* -p < 0.05; ** -p < 0.01; *** -p < 0.001.
* Significance of various treatment groups in comparison with placebo.
 Drugs and postsurgical oral pain. 353

0.67  0.46yyy
Females experienced more pain. In the was significantly higher than on the non-

5.0  1.91yyy
Day 7
placebo group, the mean pain score was
significantly less (p < 0.001) from day 3
onwards (Table 5). Pain scores were sig-
operated side in all groups; the maximum
rise occurred in the placebo group. No
significant difference was found between

0
0
nificantly less on day 4 in the serratiopep- the groups.
tidase (p < 0.001) group. In the Pre- and postoperative hemoglobin
paracetamol group, significantly low levels were comparable in all groups. In
1.33  0.93yyy
1.56  1.08yyy
6.11  2.0yyy

(p < 0.01) scores occurred on day 5. In all the groups, the total leukocyte count
Day 6

the ibuprofen group, patients experienced preoperatively ranged from 6700 to

significantly (p < 0.001) less pain from 7900 mm3 and was not significantly dif-
day 3 onwards and the score was zero ferent. On day 1 only, the counts were
0
0

from day 4 onwards. In the betamethasone significantly raised in all the groups. The
group the score was significantly less counts were significantly higher
6.11  2.12yyy
5.55  2.24yy

(p < 0.001) from day 2 (Table 5). Pain (p < 0.05) in the betamethasone group
5.0  2.36yyy
Day 5

scores were lower in the serratiopeptidase
group compared with the placebo and
paracetamol groups on all postoperative
0
0
compared with placebo. Such difference
in total leukocyte count was not observed
on day 5. The neutrophil count was

days, but the values were not statistically increased on day 1 in all the groups,
significant. Betamethasone was signifi- although the difference was not statisti-
cantly superior to placebo on day 1 cally significant. The lymphocyte count
10.55  2.73yyy

11.67  3.54yyy

3.11  0.98yyy
16.22  4.13

(p < 0.05) and day 2 (p < 0.01). Ibupro- showed no statistically significant differ-
fen was significantly superior to placebo, ence in any group, although a slight fall in
Day 4

paracetamol and serratiopeptidase on day lymphocyte count was observed on day 1.

3 and day 4. The lymphocyte count on day 5 in the
0**+##

Percentage reduction in mouth opening
ability on days 3 and 5 in the placebo and
serratiopeptidase groups was comparable.
Ibuprofen and paracetamol treatment
2.0  0.93yyy***++###
ibuprofen (p < 0.05) group was signifi-
cantly lower than in the placebo group.
Eosinophil and monocyte counts were
comparable in all the groups.

benefited the patients, but the difference Data regarding the use of rescue med-
was not significant compared with placebo ication in the treatment group is presented
on either day. Betamethasone (p < 0.01) in Table 7. The requirement for tramadol
Day 3

significantly improved mouth opening was significantly greater in the placebo

19.67  2.97yyy

9.22  2.36yyy
21.33  4.87
15.55  3.36

ability on day 3, and showed further group compared with the paracetamol
improvement on day 5. Betamethasone and ibuprofen groups. A significant dif-
was significantly superior to serratiopep- ference was seen in the serratiopeptidase
* Significance of various treatment groups compared with placebo on respective days.

tidase (p < 0.001) and paracetamol
(p < 0.05) on day 3. On day 5, betametha-
sone (p < 0.05) was better than paraceta-
mol (Table 6).
10.78  1.88**
Table 5. The mean pain score (mm), day 0 through day 7 (mean  SEM).
group compared with the paracetamol and
ibuprofen groups.
20 (13%) patients experienced adverse
drug reactions; all were mild and did not

29.44  4.67
26.33  5.39
19.44  3.45
14.89  3.75

Wound healing was similar and require any alteration in the treatment. The
Day 2

straightforward in all groups. Bleeding most common were vomiting 11 (55%),

was reported only on the day of operation sleepiness 6 (30%), dizziness 4 (20%) and
in 37 (21%) patients; 73% of these patients headache 3 (15%). In the placebo group, a
Intragroup comparison of day 1, 2, 3, 4, 5, 6 and 7 with day 0.
-p < 0.05; yy,**,++,## -p < 0.01; yyy,***,+++,### -p < 0.001.

reported mild bleeding. No significant majority of patients (53%) reported the

difference was found between groups. postoperative events to be more than
Lower buccal cavity temperatures, expected. In the ibuprofen (60%), beta-
17  2.91*
34.44  4.45
27.55  4.86
22.89  3.44
21.44  5.07

recorded preoperatively and on postopera- methasone (40%), serratiopeptidase

Day 1

tive days 3, 5 and 7, on the control and test (37%) and paracetamol (37%) groups,
side were comparable in all groups. On patients reported the events to be less than
Significance compared with serratiopeptidase.

day 1, the temperature on the operated side expected.

# Significance compared with paracetamol.
37.07  3.12
29.27  3.98
25.60  3.39
24.20  3.09
28.37  3.33
Day 0

Table 6. Percent reduction in mouth opening ability (mean  SEM).

Treatment groups Day 3 Day 5
Placebo 53.65  1.88 45.42  1.77
Paracetamol 48.04  2.06 38.91  2.0
Serratiopeptidase 52.71  1.6 41.65  2.36
Treatment groups

Serratiopeptidase

Ibuprofen 44.11  3.54 35.44  3.27

Betamethasone

Betamethasone 31.83  4.75**y 19.07  5.44***y

Paracetamol

y, , 
* -p < 0.05; yy,**,  -p < 0.01; yyy,***,  -p < 0.001.
Ibuprofen
Placebo

* Significance of various treatment groups in comparison with placebo on respective days.

y, ,+,#

y
Significance compared with paracetamol.
*


Significance compared with serratiopeptidase.
+
y
354 Chopra et al.
Table 7. Requirement for rescue medication.
No. of
Treatment group patients (30)
Placebo 24*,§
Paracetamol 14
Serratiopeptidase 22y,z
Ibuprofen 12
Betamethasone 17
*
P < 0.01 vs. paracetamol group (x2 test).
§
P < 0.01 vs. ibuprofen group.
y Entegart DJ. Factors affecting the onset
P < 0.05 vs. paracetamol group.
z and severity of pain following the surgical
P < 0.01 vs. ibuprofen group.
Discussion
The dental pain model provides a useful
model for evaluating oral analgesics.
Third-molar surgery involves local tissue
damage. The initial pain includes the
release of various mediators into the local
environment, such as arachidonic acid
metabolites, 5-HT and bradykinin. These
mediators increase the responsiveness of
local nociceptors. The afferent activity is
relayed to the dorsal horn neurons in the
spinal cord, which relay to higher centers
where pain is perceived. The two other
pathways that may be important to pain
control are the descending inhibitory path-
way and the sympathetic nervous system,
which is implicated in the maintenance of
pain states22. The problem of dental pain
can be tackled using peripherally acting
drugs or a centrally acting analgesic.
The pattern of postsurgical pain experi-
enced by the patients was similar to pre-
vious reports; the greatest levels of pain
were experienced on the day of surgery
with a peak 3–5 hours after the operation4.
Females experienced more pain than
males; previous studies have reported
more pain perception by females18.
Paracetamol is commonly used for pain
relief following oral surgery. Paracetamol
provides a statistically significant benefit
when compared with placebo for pain
relief after third-molar surgery19,25. In
the present study, paracetamol was not
found to be superior to placebo. Compared
with a NSAID (ibuprofen), paracetamol
did not proved to be better either in terms
of pain scores and rescue medication
requirement. Other studies have reported
varying efficacy of paracetamol compared
with NSAIDs, depending on the surgical
procedure. NSAIDs are more effective in
dental surgery, but there seems to be no
difference in major and orthopaedic sur-
gery13.
In this study, serratiopeptidase admin-
istration resulted in less swelling com-
pared with placebo and paracetamol, but
the difference was not significant. The
mean pain scores were less compared with
placebo, but the difference was not statis-
tically significant. The amount of rescue
medication required by the serratiopepti-
dase group was less (73%) than for the
placebo group (80%). Serratiopeptidase
was not superior to ibuprofen or beta-
methasone. The role of serratiopeptidase
as an anti-inflammatory agent and in pain
relief has been described and its efficacy
evaluated12. ESCH et al conducted a double
blind study to determine the effect of
serratiopeptidase on postoperative swel-
ling and pain in 66 patients who were
treated for rupture of knee ligament. The
patients were given serratiopeptidase and
showed 50% reduction in swelling and
became pain free more rapidly compared
with the controls3. In a double-blind study,
serratiopeptidase was superior to placebo
for improvement of breast pain, swelling
and induration7. CHAIWAT et al evaluated
the effect of serratiopeptidase on post-
operative swelling and trismus following
removal of impacted third molars. The
authors found no significant difference
between the serratiopeptidase and control
groups2. No published, double-blind, pla-
cebo-controlled study has evaluated serra-
tiopeptidase in a dental pain model.
Published trials evaluating the efficacy
of serratiopeptidase are small and gener-
ally of poor methodological quality.
Ibuprofen was effective in reducing
swelling and pain. These results confirm
earlier studies6,9,17. Ibuprofen was effec-
tive on the day of operation when the
patients experienced peak pain, reflecting
the major contribution of peripheral pros-
taglandins to the pathophysiology of post-
operative dental pain22.
Previous studies investigating the effi-
cacy of corticosteroids following third-
molar surgery have yielded conflicting
result. These variations can be attributed
to different drug, doses, routes of admin-
istration, methods of evaluating swelling
and the length of the postoperative obser-
vation period21.
In the present study, the effect of beta-
methasone on postoperative pain, in con-
trast to ibuprofen, appeared from the first
postoperative day. This accords with stu-
dies that have shown that corticosteroids
produce analgesic action but with a
delay20.
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Address:
Deepti Chopra
Department of Pharmacology
Lady Hardinge Medical College
New Delhi 110001
Tel. +91 11 28532486
9818710237.
E-mail: drdeeptichopra@yahoo.co.in