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Int. J. Oral Maxillofac. Surg.

2004; xxx: xxx–xxx


doi:10.1016/j.ijom.2003.09.015, available online at http://www.sciencedirect.com

Clinical Paper
Oral Medicine
K. S. Ong1, J. M. L. Tan2
Preoperative intravenous 1
Department of Oral & Maxillofacial Surgery,
Faculty of Dentistry, National University of
Singapore, Singapore;

tramadol versus ketorolac for 2


Anesthesiology, National University Hospital,
Singapore

preventing postoperative pain


after third molar surgery
K. S. Ong, J. M. L. Tan:Preoperative intravenous tramadol versus ketorolac for
preventing postoperative pain after third molar surgery. Int. J. Oral Maxillofac.
Surg. 2004; 33: xxx–xxx. # 2004 International Association of Oral and
Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Abstract. The objective of this study was to compare the analgesic efficacy of a
single-dose of preoperative intravenous tramadol versus ketorolac in preventing
pain after third molar surgery. 64 patients undergoing elective third molar surgery
were randomly assigned into one of the two groups (32 in each group): Group I
received tramadol 50 mg, and Group 2 received ketorolac 30 mg intravenously
preoperatively before the surgery. After injection of the study drugs, a standard
intravenous sedation technique was administered and the impacted third molars
were removed under local anesthetic. The difference in postoperative pain was
assessed by four primary end-points: pain intensity as measured by a 100-mm
visual analogue scale hourly for 12 h, median time to rescue analgesic,
postoperative acetaminophen consumption, and patient’s global assessment.
Throughout the 12-h investigation period, patients reported significantly lower
pain intensity scores in the ketorolac versus tramadol group (P ¼ 0:05, Mann–
Whitney U-test). Patients also reported significantly longer median time to rescue
analgesic (9.0 h versus 7.0 h, P ¼ 0:007, log rank test), lesser postoperative
acetaminophen consumption (P ¼ 0:02, Mann–Whitney U-test) and better global Key words: pain prevention; oral surgery;
assessment (P ¼ 0:01, Chi-square test) for the ketorolac versus tramadol analgesia; preemptive.
group. Preoperative intravenous ketorolac 30 mg is more effective than tramadol
50 mg in the prevention of postoperative dental pain. Accepted for publication 18 September 2003

Tramadol is a synthetic analogue of to be effective for postoperative dental promote pain. Oral and parenteral ketor-
codeine. It is a central analgesic with a pain2,10. olac has been shown to be effective for
low affinity for opioid receptors13. Much Ketorolac is a member of the pyrrolo- postoperative dental pain3,6,16.
of its action is due to inhibition of the pyrrole group of nonsteroidal anti- Comparative studies of analgesic effi-
neuronal uptake of norepinephrine and inflammatory drugs (NSAIDs). It pos- cacy between intravenous analgesics for
serotonin at synapses in the descending sesses analgesic, anti-inflammatory, and third molar surgery are rare. To the best
inhibitory pain pathways13. The side- antipyretic activity. The primary action of our knowledge, we are not aware of
effect profile of tramadol appears to be of ketorolac appears to be inhibition of any studies that compare the efficacy of
more acceptable to ambulatory surgical the cyclooxygenase enzyme that metabo- intravenous tramadol versus ketorolac in
patients compared with the traditional lizes arachidonic acid to endoperoxide third molar surgery. Since the type of
opioids. Oral tramadol has been found intermediates and prostaglandins that surgery may influence the efficacy of
0901-5027/000001+05 $30.00/0 # 2004 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
2 Ong and Tan

individual analgesic, we found it worth- 2 ml with saline. Both solutions were experience throughout the investiga-
while comparing the analgesic efficacy prepared in an identical syringe by the tion time periods7.
of preoperative tramadol versus ketoro- independent investigator. An intrave- 2. Median time to remedication
lac in preventing postoperative pain in a nous cannula was inserted into the Time to remedication is defined as
relatively homogenous sample of third antecubital fossa or dorsum of the hand the time from the end of surgery until
molar surgical patients. of all patients for the administration of the intake of rescue medication be-
drugs. For the ketorolac group, a single came necessary for the patient. Once
bolus dose of ketorolac 30 mg was a subject received a rescue medication
Methods
given intravenously before the surgery. (acetaminophen 1000 mg), the time
The protocol for the study was approved For the tramadol group, a single bolus of this event was recorded and the
by the ethics committee of the local insti- dose of tramadol 50 mg was given subject was excluded from further
tution and informed written consent was intravenously before the surgery. After pain intensity measurements. Their
obtained from all participating patients. administration of the analgesic, a stan- previous VAS recordings for pain
Using the principal variable, the visual dard intravenous sedation technique intensity were extrapolated over the
analogue scores (VAS) for postoperative was administered. Single agent midazo- remaining time points5. Percentage
pain and considering a difference of lam was titrated to a clinical end-point, of patients not taking rescue medica-
20 mm as clinically significant and an characterized by slurred speech, patient tion were estimated as a survival
estimated mean standard deviation of 15– self-reports of relaxation or drooping distribution using the Kaplan–Meier
25 mm for VAS scores, the sample size eyelids. At this point, an inferior dental method.
was calculated as 30 patients in each nerve block was given with local 3. Total analgesic consumption
group with a type I error of 0.05 and a anesthetic 2% lidocaine with 1:100,000 Total amount of analgesic (acetami-
statistical power of 90%. This sample size epinephrine for the regional anesthesia. nophen tablets) consumed during the
matches a previous study, which studied The surgical removal of the impacted full recovery period (5 days) was
the analgesic efficacy of ketorolac versus mandibular third molar was then com- recorded.
diclofenac in maxillofacial surgery15. pleted with a standardized technique 4. Global assessment
Sixty-four patients who required elec- by the surgeon. Pulse and SaO2 were Patients were asked to provide an
tive surgical removal of impacted man- continuously monitored during the overall evaluation of the efficacy of the
dibular third molars in an outpatient duration of the surgery and recovery surgery with regard to pain on a five-
setting participated in the study. All using a pulse oximeter. Demographic point categorical scale, at the end of
patients were ASA I over 16 years old and surgical data, including age, the trial. The categories of scale were
and had at least one impacted mandibu- weight, gender, duration of surgery, 0 ¼ poor, 1 ¼ fair, 2 ¼ good, 3 ¼ very
lar third molars based on orthopantomo- and amount of local anesthetic used was good and 4 ¼ excellent. Excellent ¼
gram evidence. All patients had no recorded. minimum pain versus poor ¼ lots of
infection, pain or other problems in the pain.
week before the surgery. Patients were
Pain assessment
excluded, if they had a history of hyper-
Statistical analysis
sensitivity to ketorolac and tramadol or In contrast to most analgesic trials,
if they were taking analgesics or seda- which evaluate the ability to treat pain, All statistical analysis was done with the
tives. Allocation of treatment regimens this study assessed the ability of the NCSS 2001 statistical analysis system
was randomized and double blind. drug treatments to prevent pain. Hence, for windows statistical package (website
Restricted randomization was used to the standard measures of pain-reducing www.ncss.com/). Data were presented as
decide the treatment regime. Allocation of analgesic activity based on a difference the mean with their standard deviations
treatment was done by the sealed envel- from baseline were not used (for exam- and 95% confidence intervals for the
ope technique. Envelopes with cards ple, pain intensity difference or pain mean where applicable. Demographic
detailing which drug to give, was allo- relief). Analgesic efficacy was assessed data, duration of operation, and amount
cated to patients on the day of surgery. An on the basis of four key end-points, of local anesthetic used, were evaluated
independent investigator, who would be which the patients were required to with unpaired Student’s t-test. The dif-
administering the study drugs opened the record on a pain diary: ference in pain scores and total post-
envelope and gave either ketorolac or operative analgesic consumption were
tramadol preoperatively according to 1. The pain intensity in the form of visual analyzed using the Mann–Whitney
the randomized cards. This independent analogue scales (VAS) U-test. The comparison of time to taking
investigator was also responsible for Patients were asked to record on a of rescue analgesic was based upon log
administering the sedation for the surgery. plain serial 100 mm VAS, the pain rank test. The proportion of patients tak-
The study drugs, ketorolac and trama- intensity every hour for 12 h after the ing rescue analgesia was analyzed with
dol (1 ml formulation),a were diluted to surgery. Anchor points were 0 ¼ no Fisher’s exact test. Survival curves were
pain and 100 ¼ worst pain possible. plotted to indicate the proportion of
Ketorolac trometamol (Toradol1) in the
a Serial VAS recorded over the 12-h patients in each group who had received
form of 30 mg injectable ampoule was used. investigation periods were complied no rescue analgesia by a given time
Made in Switzerland by F. Hoffman-La into a graph of pain (mm) versus time after the surgery. The global assessment
Roche Ltd, Basel. (h). The area under the graph (AUC) was assessed by Chi-square statistic.
Tramadol hydrochloride (Tramal1) in the was measured using the trapezoidal Violin plots were constructed to show
form of 50 mg injectable ampoule was used. method and recorded as AUC0–12. the median, spread and density trace of
Licensed to: Sanofi-synthelabo by: Grunenthal Such a measure gives an overall the data. All tests were 2 sided and level
GmbH Aachen, Germany. assessment of each patient’s pain of significance was set at 0.05.
Preoperative ketorolac provides better analgesic efficacy than Tramadol 3

Table 1. Demographic details and operation data of patients


Variable Tramadol group Ketorolac group
Number of subjects 32 32
Number of dropouts 2 2
Male:female 14:16 13:17
Age (years) 26.9  4.4 27.1  4.7
Weight (kg) 61.1  11.6 60.7  10.3
Amount of local anesthetic used (ml) 5.6  1.0 5.4  0.9
Mean operating time (min) 18.1  3.6 17.5  3.7
Where appropriate, results are expressed as mean  SD.
No significant difference (P > 0:05) between the two groups in demographic and operation
Fig. 3. Violin plot comparing the median, the
variables.
spread, and the distribution pattern of the time
to rescue analgesia between the ketorolac- and
tramadol-treated groups. The median is shown
by the circle, the interquartile range (IQR) is
shown by the length of the thick line, and the
distribution of data is shown by the density
trace. Mean ¼ 9:5, median ¼ 9:0 for the keto-
rolac-treated group. Mean ¼ 7:6, median ¼
7:0 for the tramadol-treated group.

the survival curve. The curves show that


more patients in the ketorolac group sur-
vived for longer time without the need
for rescue analgesia than the tramadol
Fig. 2. Survival curves for the ketorolac- and group (Fisher’s exact test, P ¼ 0:01).
tramadol-treated groups, representing the pro- Figure 3 shows a violin plot comparing
Fig. 1. Mean pain intensity scores (in mm) as portion of patients in each group who had not the median, spread, and distribution pat-
recorded on a 100-mm plain VAS throughout required any rescue analgesia after surgery. tern of the time to rescue analgesia
the 12-h investigation period for the ketoro- Patients who survived longer than the 12-h of between the two groups. The ketorolac
lac- and tramadol-treated groups. investigation period are assigned a value of group reported a longer time to rescue
13. P < 0:01 by log-rank test for ketorolac- analgesic (median 9.0 h) compared with
vs. tramadol-treated groups. the tramadol group (median 7.0 h) (log
Results
rank test, P ¼ 0:007). The mean time
Of the 64 patients entered into the study, Fig. 1. Patients in the ketorolac group to rescue analgesic for the ketorolac
4 were excluded from the analysis due experienced significantly less pain group was 9.5 h after surgery as com-
to incomplete pain diary form. Thus, throughout the 12-h investigation period, pared with the 7.6 h for the tramadol
data was obtained from 60 patients (30 than when they received tramadol (Mann– group. Hence, the results showed that
in each group). Demographic details of Whitney U-test, 0.05). ketorolac provided approximately 2-h
the patients and efficacy parameters Percentage of patients taking rescue longer duration of preventive analgesia
recorded in the investigation are shown medication throughout the 12-h investi- compared with tramadol.
in Tables 1 and 2. Both groups were gation period is shown in the survival The total postoperative analgesic con-
balanced for the demographic variables curve in Fig. 2. The curves indicate the sumption for the ketorolac group
and there was no significant difference proportion of patients in each group who (median ¼ 4, range 0–12) was also sig-
(P > 0:05) between the two groups for had not received any rescue analgesia nificantly less than the tramadol group
operating time and amount of local by a given time after the surgery. Those (median ¼ 6, range 0–16) (Mann–Whit-
anesthetic used for the surgery. The patients who had not required rescue ney U-test, P ¼ 0:02). Figure 4 shows a
mean pain intensity scores and AUC for analgesia by 12 h after the surgery con- violin plot comparing the total number
VAS scores throughout the 12-h investi- tinued without needing analgesia for of tablets of postoperative acetamino-
gation period are shown in Table 2, and 24 h and were assigned a value of 13 on phen consumption for the two groups.

Table 2. Operation details and efficacy parameters recorded in the investigation


Variable Tramadol group Ketorolac group P-value
a
VAS (mm) 20.0  10.1 (13.4–26.3) 15.1  7.7 (10.2–20.1) 0.05
AUC0–12 (intensity) (mm/h) 220.5a 168.0 0.05
Mean time to rescue analgesic (h) 7.6  2.7a (6.7–8.7) 9.5  3.0 (8.4–10.6) 0.007
Median time to rescue analgesic (h) 7.0a (6.7–8.7) 9.0 (8.4–10.6) 0.007
Percentage of patients not taking rescue analgesic 16.7a 36.7 0.01
during the 12-h investigation period (%)
Total analgesic consumption (tablets) 6.4  3.8a (5.0–7.8) 4.4  3.1 (3.2–5.6) 0.02
Global assessment scores 2.6  0.9a (2.3–3.0) 3.1  0.9 (2.8–3.5) 0.01
Results are expressed as a mean  SD and 95% confidence intervals for the mean are shown in brackets where applicable.
a
Significant difference between tramadol and ketorolac groups.
4 Ong and Tan

usually most severe between 6 and 8 h surgery3. In contrast, tramadol does not
after the surgery14. This analgesic tech- appear to have the ceiling effect com-
nique provides adequate analgesic cover- mon to many NSAIDs. MOORE &
age during the 8 h peak pain period and MCQUAY10 reviewed 18 studies, which
is an advantage. When tramadol was demonstrated that all doses of tramadol
administered preoperatively in this were superior to placebo in relieving
study, it has a median analgesic duration postsurgical dental pain, and showed
of 7.0 h. The analgesic effect of the drug a dose–response effect. However, at
would be reducing at the time when the higher doses, the incidence of side
postoperative pain would be at its peak. effects like nausea and vomiting appears
Analgesia after impacted third molar to be more common.
surgery is necessarily a balance between Hence, one of the reasons for the
Fig. 4. Violin plot comparing the total post- achieving adequate pain relief, whilst positive effect of ketorolac over trama-
operative analgesic consumption (number of causing minimum side effects. Use of a dol in our study may be due to the
tablets of acetaminophen) between the ketor- long-acting local anesthetic would also higher dose of ketorolac used. It may be
olac- and tramadol-treated groups. The med-
be able to control the peak pain period possible that higher doses of tramadol
ian is shown by the circle, the IQR is shown by
the length of the thick line, and the distribution
at 6–8 h after the surgery. The analgesic may have a better analgesic effect than
of data is shown by the density trace. effect of bupivacaine infiltration for ketorolac. However, the incidence of
Mean ¼ 4:4, median ¼ 4:0 for ketorolac-trea- third molar surgery has been reported to side effects, particularly nausea and
ted group. Mean ¼ 6:4, median ¼ 6:0 for the be about 8 h1,4. However, the use of vomiting may be high. The other reason
tramadol-treated group. long-acting intraoral local anesthetic can for the positive effect may be that the
cause difficulty with speech and swal- pathogenesis of dental pain and general
lowing. Many authors consider that surgical pain are different. The type of
these unwanted effects detracts from its surgery may influence the efficacy of
usefulness4,9. MELLOR et al.9 found no individual analgesics. Dental pain is lar-
significant difference in analgesia gely inflammatory, and evidence-based
between patients receiving bupivacaine medicine has shown that NSAIDs are
infiltration versus intravenous ketorolac the best analgesic for dental pain8,11.
after third molar surgery. However, The duration of the analgesic effect
patients who received ketorolac reported after a single dose of ketorolac and tra-
Fig. 5. Patient’s overall global assessment at a higher overall patient satisfaction com- madol is about 6 h6,13. In this study, the
the end of study. pared with patients who received bupi- median analgesic duration of ketorolac
vacaine. The bupivacaine infiltration and tramadol was 9.0 and 7.0 h, respec-
gave rise to more minor airway compli- tively. The longer duration of analgesic
Patient’s overall assessment of the cations and lower patient’s acceptability effect maybe due to a preemptive effect
surgery in relation to pain is shown in when compared to ketorolac. The results as they were given before the surgical
Fig. 5. The distribution of scores shows from our study shows that preoperative incision. In theory, the strategy of
that more patients in the ketorolac intravenous ketorolac could provide a administering the analgesic before sur-
group (43.3%) scored the surgery as median analgesic duration of 9.0 h and gery will pre-position the drug at the
excellent in relation to minimum pain this is comparable with the duration of surgical site and establish effective
after the surgery as compared with tra- analgesia after bupivacaine infiltration. blood levels for maximum analgesic
madol group (23.3%) (Chi-square test, However, ketorolac probably provides effect. These predicts not only less pain
P ¼ 0:01). better patient acceptability and less post- during the initial postoperative period,
Both intraoperative and postoperative operative local anesthetic related pro- but also lowers the intensity of pain dur-
subjective observations were done by blems than bupivacaine infiltration. ing the days after the surgery. By les-
the surgeon for any complications due By contrast a recent study has shown sening the pain during recovery, fewer
to the study drugs. No significant intrao- that intravenous tramadol was more analgesics will be consumed, which
perative and postoperative complications effective in reducing postoperative pain results in fewer drug adverse events
were seen for both groups of patients. than ketorolac in laparoscopic surgery12. complicating the post-operative course
The were no cases of postoperative However, in this study a mean dose of and delaying patient’s return to normal
bleeding problems associated with ketor- 100 mg of tramadol was compared with activities.
olac and no cases of vomiting associated 10 mg of ketorolac. There was evidence In conclusion, the results of the
with tramadol at the doses given in this showing that there would be a signifi- present study shows that preoperative
study. Adverse effects were mild and do cant increase in analgesic efficacy with intravenous ketorolac 30 mg is more
not required any treatment. 30 mg ketorolac when compared with effective than tramadol 50 mg for pre-
10 mg ketorolac in the oral surgery venting postoperative dental pain.
model3. Previous studies of patients after
Discussion
major surgery whose pain is typically of Acknowledgments. The authors gratefully
This study shows that preoperative intra- greater severity and duration than is that thank Associate Professor SB KENG,
venous ketorolac is better than tramadol of patients after oral surgery, have also National University of Singapore, Faculty
in preventing postoperative third molar demonstrated a dose–response relation- of Dentistry for reviewing the manuscript.
surgical pain. The median analgesic ship between 30 and 90 mg ketorolac17. The research is supported in part by a
duration of 9.0 h is clinically significant However, a plateau or ceiling effect research fund from Pacific Health Care
as pain for this type of procedure is occurs at 30 mg for ketorolac in oral (Singapore) to KS ONG.
Preoperative ketorolac provides better analgesic efficacy than Tramadol 5

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