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Int. J. Oral Maxillofac. Surg.

2006; 35: 613617


doi:10.1016/j.ijom.2006.01.026, available online at http://www.sciencedirect.com

Clinical Paper
Therapeutics

Premedication with T. Aoki1, H. Yamaguchi2, H. Naito3,


K. Shiiki3, K. Izawa4, Y. Ota4,
H. Sakamoto1, A. Kaneko4

cyclooxygenase-2 inhibitor
1
Department of Oral and Maxillofacial
Surgery, Tokai University Hachioji Hospital,
Hachioji, Tokyo, Japan; 2Department of
Anesthesia, Ryugasaki Saiseikai Hospital,

meloxicam reduced Ryugasaki, Ibaragi, Japan; 3Department of


Oral and Maxillofacial Surgery, Iwaki Kyoritsu
General Hospital, Iwaki, Fukushima, Japan;
4

postoperative pain in patients


Department of Oral and Maxillofacial
Surgery, Tokai University School of Medicine,
Isehara, Kanagawa, Japan

after oral surgery


T. Aoki, H. Yamaguchi, H. Naito, K. Shiiki, K. Izawa, Y. Ota, H. Sakamoto, A. Kaneko:
Premedication with cyclooxygenase-2 inhibitor meloxicam reduced postoperative
pain in patients after oral surgery. Int. J. Oral Maxillofac. Surg. 2006; 35: 613617.
# 2006 International Association of Oral and Maxillofacial Surgeons. Published by
Elsevier Ltd. All rights reserved.

Abstract. The efficacy of the selective cyclooxygenase-2 (COX-2) inhibitor


meloxicam for treatment of postoperative oral surgical pain was assessed in a
randomized controlled trial. Patients undergoing unilateral mandibular 3rd molar
extraction surgery were allocated to 3 groups, A, B and C. After oral premedication
of meloxicam 10 mg in group A, ampiroxicam 27 mg in group B and placebo in
group C, surgery was completed within 30 min under local anaesthesia using 2%
lidocaine. For postoperative pain relief the patients were allowed to take oral
loxoprofen (60 mg per tablet). Postoperative pain was evaluated at the clinic on the
1st, 7th and 14th postoperative day (POD) using a visual analogue scale (VAS), as
was the number of loxoprofen tablets consumed, and the results were compared
among the 3 groups with statistical significance of P < 0.05. VAS scores on 1 POD
Key words: meloxicam; cyclooxygenase-2
were significantly lower in group A than in group C. Loxoprofen consumption on
(COX-2) inhibitor; postoperative pain; oral
the day of surgery and 1 POD was significantly lower in group A than in group C surgery; local anaesthesia.
(P < 0.01). Total analgesic consumption was significantly lower in groups A and B
than in group C (P < 0.02). The COX-2 inhibitor, meloxicam 10 mg used for Accepted for publication 30 January 2006
premedication reduced postoperative pain compared with control in oral surgery. Available online 15 March 2006

Post-traumatic or postsurgical pain occa- elucidated8,20 and a number of interven- Cyclooxygenase-2 (COX-2) activity,
sionally develops into chronic pain, hyper- tions have been attempted to prevent or induced by cytokines, nitric oxide and
aesthetic pain or allodynia, which may reduce postoperative pain2,4,13,14,23,24. other substances and released in response
limit a patients daily activity level and Non-steroidal anti-inflammatory drugs to inflammatory processes, synthesizes
sometimes require regular analgesic med- (NSAIDs) are one of the exam- prostaglandin, sensitizes peripheral noci-
ication. The pathophysiological mechan- ples2,4,13,14,23,24, but are still controver- ceptor terminals and produces localized
isms of such neuropathic pain have been sial2,3,13,14. hypersensitivity10,25. Recently, COX-2

0901-5027/070613 + 05 $30.00/0 # 2006 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
614 Aoki et al.

activation has been reported to play an The degree of difficulty of the procedure the degree of difficulty of the procedure
important role in the centrally generated was evaluated using the following 4-grade and the number of loxoprofen tablets used
inflammatory pain hypersensitivity pro- scale presented by CAMPBELL et al.4: (i) for postoperative wound pain were com-
cess9,18. Preoperative administration of simple tooth extraction, (ii) bone removal pared among the 3 groups using the Krus-
COX-2 inhibitors could be expected to or tooth division, (iii) bone removal and kalWallis rank test followed by Mann
prevent postoperative pain5,15. Meloxicam tooth division and (iv) the same as (iii) but Whitney U-test. The areas under the curve
is a COX-2 inhibitor available for clinical very difficult. After surgery, the patients (AUC) for VAS and the number of lox-
use. It has not been reported whether were discharged from the hospital with a oprofen used during the 14-day postopera-
meloxicam premedication has a preemp- prescription of loxoprofen tablets, 60 mg tive period were determined and compared
tive analgesic effect when used in oral per tablet, for postoperative pain relief. among the 3 groups using ANOVA with
surgery under local anaesthesia. In this All the patients were scheduled to come Tukeys correction. Statistical analyses
randomized prospective double-blind to the clinic on the 1st, 7th and 14th days were performed using SPSS version 10.0
study, it was tested whether meloxicam after surgery. At the clinic, dentists who (SPSS Inc., Chicago, IL, USA). P < 0.05
premedication prevented postoperative were not informed of the patients group- was considered statistically significant.
pain in patients undergoing unilateral ing evaluated the wound pain, incidence of
mandibular 3rd molar extraction under adverse effects and mouth-opening range
Results
local anaesthesia. (mm). Postoperative pain at rest was eval-
uated using a 10-cm visual analogue scale The surgical procedure was completed
(VAS) of 0 (no pain) to 10 (worst pain within 30 min for each patient. No patient
Methods
imaginable) and the number of loxoprofen complained of wound pain or discomfort
After approval of the study protocol by the tablets used for wound pain relief during during surgery or needed additional local
local Ethical Committee in both the the postoperative period. Adverse effects anaesthesia.
Department of Oral Surgery, Tokai Uni- were evaluated if the patients had nausea Seven patients were excluded from
versity School of Medicine, and the and/or vomiting, dizziness or somnolence. group A (3 with dry socket, 2 due to
Departments of Oral Surgery and Anaes- Patients who developed postoperative wound infection after surgery and 2 lost
thesia, Iwaki Kyoritsu General Hospital, infections or chronic alveolar osteitis to follow-up). Eight patients were
this study was carried out in a randomized (dry socket), or who did not come to excluded from group B (4 due to dry
prospective double-blinded fashion. A the clinic on either the 1st, 7th or 14th socket, 2 lost to follow-up, 1 due to tem-
total of 114 consecutive ASA physical postoperative day (POD) were excluded poromandibular joint disorder after sur-
status I or II patients undergoing unilateral from further statistical analysis. gery and 1 due to the administration of
mandibular 3rd molar extraction surgery The primary outcomes were the degree loxoprofen for the reason other than post-
were enrolled. Written informed consent of postoperative pain determined by VAS operative pain). Eight patients were
was obtained from each patient after score and the number of loxoprofen tablets excluded from group C (3 due to dry
explanation of the study protocol. Patients used during the 14-day postoperative per- socket, 3 lost to follow-up, 1 due to wound
who were given any analgesic agents or iod. The sample size of the study (38 infection and 1 due to inferior alveolar
tranquilizers within a week prior to the patients in each group) was estimated nerve paresthesia). A dry socket is an
surgery were excluded from the study. At using a 2-sided level of 0.05 and a power affected extraction site filled initially with
an initial consultation, patients were of 0.75 based on preliminary data. Patient a dirty grey clot that is lost, leaving a bare
divided into 3 groups, A, B and C, using demographic data and the incidence of bony socket, with exposed and extremely
random numbering cards. Group A adverse effects were compared among sensitive bone. Patients with postoperative
patients (n = 38) were premedicated with the 3 groups using the KruskalWallis infections suffer more intense pain due to
oral meloxicam 10 mg approximately rank test and analysis of variance an inflammatory reaction not only in the
90 min before surgery. Group B patients (ANOVA) as applicable. VAS values, healing process but also during infection
(n = 38) were premedicated with oral
ampiroxicam 27 mg approximately
90 min before surgery. Group C patients Table 1. Demographic data, degree of difficulty (grade) of the procedure, and range of mouth
(n = 38) were premedicated with placebo opening
containing ascorbic acid 500 mg approxi- Group A B C
mately 90 min before surgery. The pre- n (M/F) 31 (12/19) 30 (10/20) 30 (12/18)
medication agents were prepared in Age (years) 26.0  1.1 24.0  1.0 25.0  1.1
capsule form by the oral surgeons who Side (R/L) 14/17 18/12 11/19
had the responsibility for patient grouping Surgery (min) 11.7  1.3 13.8  1.6 12.7  1.3
and were given to the patients by a nurse Grade
assistant who had no information about I 6 3 3
their content or the patient grouping. II 17 19 15
The surgery was performed by 2 oral III 7 5 9
surgeons with more than 10 years clinical IV 1 3 3
experience and no information on patient Range of mouth opening (mm)
grouping, under local anaesthesia in the 0 POD 47.0  1.3 46.0  1.3 47.6  1.1
form of blocks to both the inferior alveolar 1st POD 40.0  2.0* 39.1  1.7* 34.4  1.7*
and buccal nerves with 2% lidocaine con- 7th POD 44.3  1.6 43.8  1.8 44.4  1.8
taining 1:80,000 epinephrine, approxi- 14th POD 47.5  1.4 46.4  1.4 47.5  1.4
mately 1.8 ml. The same extraction Values are number of patients or mean  SE. Side, operative side; POD, postoperative day.
*
technique was employed for all patients. P < 0.01 vs 0 POD. See text for details.
COX-2 inhibitor and postoperative pain 615

occurring as a complication. Since this


study examined postoperative pain in
patients who exhibited normal wound
healing process, these patients were
excluded. As a result, statistical analyses
were carried out on the data from 91
patients: groups A (n = 31), B (n = 30)
and C (n = 30).
No significant differences in the demo-
graphic data or the degree of difficulty of
the procedure were found among the 3
groups (Table 1). The range of mouth
opening was determined on the day of
surgery (0 POD) and the 1st, 7th and
14th days after surgery. The range on 1
POD was found to be significantly smaller
than that on 0 POD in all groups, but the
changes in range of mouth opening were Fig. 2. Comparison of postoperative analgesic consumption following 3rd molar extraction
not significantly different among the between the 3 groups. #Lox. indicates the number of loxoprofen tablets used for postoperative
groups (Table 1). pain relief in each patient during the indicated period. The analgesic consumption on the day of
The distribution of VAS scores on 1 surgery in group A was significantly less than that in group C (P < 0.01), and that on 1 POD in
POD in group A was significantly smaller groups A and B each was significantly less than that in group C (P < 0.01). AUC of analgesic
consumption for groups A and B was significantly less than for group C (P < 0.01 and
than that in group C (P < 0.05, Fig. 1).
P = 0.013, respectively).
The AUC of the VAS scores in group A
was significantly smaller than those in
groups B and C (P < 0.05, Fig. 1). At clinic on 1 POD, 1 patient in group B relief than the control group. Group B
The number of loxoprofen tablets used and 2 patients in group C reported nausea (preoperative administration of ampirox-
for postoperative pain relief on 0 POD in but no vomiting after surgery, and no icam 27 mg) exhibited no significant dif-
group A was significantly smaller than patient in the 3 groups reported dizziness ference in VAS score but showed less
that in group C (P < 0.01, Fig. 2). The or somnolence after surgery. The inci- postoperative analgesic use compared
number of loxoprofen tablets used for dence of adverse effects was not signifi- with group C. Meloxicam is a COX-2
postoperative pain relief on 1 POD in cantly different among the 3 groups inhibitor with tmax 7.00  3.29 h and t1/2
groups A and B was significantly smaller (P > 0.05). 27.59  7.30 h3. The COX-1 and COX-2
than that in group C (P < 0.01, Fig. 2). inhibitory activity of meloxicam, using
AUC of the number of loxoprofen tablets human platelets and synovial cells, respec-
Discussion
used for postoperative pain relief during tively, is 4663. Ampiroxicam is a non-
the study period in groups A and B was The results of this study show that patients selective COX inhibitor with tmax
significantly smaller than that in group C premedicated with meloxicam 10 mg had 4.0  0.0 h and t1/2 40.9  2.4 h12. Oral
(P < 0.01 and P = 0.013, respectively; reduced postoperative pain and needed administration of meloxicam or ampirox-
Fig. 2). fewer analgesics for postoperative pain icam 90 min before surgery was used
because the drug would, in this way, reach
a sufficient concentration in the blood
during operation, on the basis of its phar-
macokinetics. The non-selective COX
inhibitor ampiroxicam 27 mg is a long-
acting drug similar to meloxicam 10 mg,
with shorter tmax and longer t1/2. The
longer duration of analgesic action of
ampiroxicam may contribute to the sig-
nificantly less postoperative analgesic use
on 1 POD and AUC value compared with
control. Postoperative pain, however, was
more effectively alleviated in group A
than in group B. One of the reasons for
this may be the inhibition of central sen-
sitization by COX-2 inhibitors5,9,18,22. In
the spinal cord, COX-1 immunoreactivity
is located in the axon within the dorsal root
ganglion but is not present in the grey
matter of spinal cord22. COX-2 is gener-
Fig. 1. Comparison of VAS scores and AUC for the changes in VAS score at rest following 3rd ally considered to be an inducible enzyme,
molar extraction between the 3 groups. Values are expressed as mean  SE in AUC. Group A but immunocytochemistry of sections of
showed significantly lower VAS scores on 1 POD than group C (P < 0.05). AUC of VAS in normal rat spinal cord incubated with
group A was significantly smaller than that in groups B and C, respectively (P < 0.05). specific COX-2 antiserum exhibited
616 Aoki et al.

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