56.Mazhar, H., Samudrawar, R., Tamgadge, P. et al. Preemptive Oral Ketorolac with Local Tramadol Versus Oral Ketorolac in Third Molar Surgery: A Comparative Clinical Trial. J. Maxillofac. Oral Surg. (2020). https://doi.org/10.1007/s12663-020-01400-4

1. ORIGINAL ARTICLE
Preemptive Oral Ketorolac with Local Tramadol Versus Oral
Ketorolac in Third Molar Surgery: A Comparative Clinical Trial
Heena Mazhar1 • Ratna Samudrawar2 • Prashant Tamgadge1 • Rashmi Wasekar3 •
Rahul Vinay Chandra Tiwari4 • Heena Tiwari5
Received: 7 August 2019 / Accepted: 19 June 2020
The Association of Oral and Maxillofacial Surgeons of India 2020
Abstract
Aims To assess preemptive analgesic efficacy of oral
ketorolac with submucous placebo versus oral ketorolac
with submucous tramadol during impacted mandibular
third molar surgery.
Methodology A double-blind, split-mouth clinical study
was carried on 40 patients having bilateral impacted
mandibular third molars. They were divided as group A
comprising of 40 patients in whom oral ketorolac with
submucous tramadol was administered and group B com-
prising of 40 patients in whom oral ketorolac with sub-
mucous placebo was administered. The study parameters
included were pain intensity scores, duration to take 1st
rescue analgesia, need of analgesic intake during the first
24 h postoperatively and patient’s experience.
Results The patient’s experience was found to be better in
the group A as compared to group B while evaluating mean
pain intensity scores (VRS, VAS); need of postoperative
analgesics and drug-related complications.
Conclusion Preemptive oral ketorolac with tramadol in
comparison to oral ketorolac results in better pain relief,
longer pain free intervals with minimum rescue analgesics
requirement lesser postoperative analgesics
consumption.
Keywords Impacted third molars Ketorolac Preemptive
analgesics
Introduction
Surgical extraction of impacted mandibular third molar is
the most common minor surgical procedure which involves
mild to moderate trauma to bone, periosteum and muscles
causing postoperative algesia, edema and trismus. This
postoperative pain-induced anxiety makes the patient more
apprehensive by altering the harmony between circulatory
and endocrine system [1, 2]. The literature advocated
numerous drugs in various combinations via different
routes to achieve acceptable analgesia with minimum side
effects. [3–6] Among the various modalities used, Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs) are most
preferred due to their ease in availability and high patient’s
compliance rate. However, it presents with a range of side
effects, the commonest being are gastrointestinal [7, 8].
Hence arises, the requirement of a new strategy which
efficiently reduces postoperative pain with reduction in
frequency of intake of NSAIDs in addition to reducing the
adverse effects [9, 10].
Crile noted that by inhibiting the pain transmission
before giving surgical incision using preemptive analgesia,
we can reduce the postoperative mortality as it prevents our
central nervous system to become hyper-excitable to
afferent inputs [11, 12]. Therefore, it enhances effective
Heena Mazhar
drheenatiwari@gmail.com
1
Department of Oral Maxillofacial Surgery, Chhattisgarh
Dental College and Research Institute, Rajnandgaon,
Chhattisgarh, India
2
Oral Medicine Radiology, EJHS Wellness Center,
Adilabad, Telangana, India
3
Department of Oral Medicine and Radiology, Swargiya
Dadasaheb Kalmegh Smruti Dental College and Hospital,
Wadhamna Road, Hingna, Nagpur, Maharashtra, India
4
Department of Oral and Maxillofacial Surgery, Sri Sai
College of Dental Surgery, Vikarabad, India
5
CHC Makdi, Kondagaon, Chhattisgarh, India
123
J. Maxillofac. Oral Surg.
https://doi.org/10.1007/s12663-020-01400-4

2. pain management with the minimum need of analgesic
requirements postoperatively [13, 14]. Ketorolac (NSAIDs)
is a potent analgesic with rapid onset of action, good oral
bioavailability, short duration of action in addition to
causing minimal gastrointestinal side effects [7, 15].
Tramadol is an opioid analgesic (synthetic codeine)
whose efficacy for mild to moderate pain was found
comparable to morphine. It shows 100% bioavailability on
intramuscular administration. But, its primary metabolite,
O-demethylated is two to four times more potent than the
parent drug and is responsible for its analgesic effect
[7, 16, 17]. This study is conducted to assess preemptive
analgesic efficacy of oral ketorolac with submucous pla-
cebo versus oral ketorolac with submucous tramadol dur-
ing impacted mandibular third molar surgery.
Methodology
In 40 patients belonging to the age group of 18–30 years, a
double-blind, split-mouth placebo-controlled clinical study
was conducted after getting approval of the institutional
ethical committee. All patients who required surgical
removal of identical bilateral mandibular third molars,
during January 2015 to October 2016 were included. All
patients with ASA grade I category, having an asymp-
tomatic bilateral identical impacted mandibular third
molars along with grade II or III difficulty of extraction
were included. Following thorough case history, hemato-
logical and radiographic examination was performed for all
patients who satisfied the inclusion criteria. Written
informed consent was taken.
Those patients were excluded who failed to give written
informed consent for the study, having uncontrolled dia-
betes, peptic ulcers, Gastro-esophageal reflux disorder
(GERD), autoimmune disease, lactation or pregnant, under
oral contraceptive use, acute infections, history of seizure
disorder, respiratory disorders, impaired renal or hepatic
function, had taken analgesic 24 h prior to the surgical
procedure and known allergy to the drugs used in this
study.
The patients were randomly divided into two groups.
Each patient was tested for allergy to mixture of tra-
madol ? 2% lignocaine through subcutaneous injection of
test dose of 0.02–0.05 ml under standard observation
technique, a wheal reaction of [ 3 mm would be consid-
ered hypersensitive and excluded from the study. All
patients are advised to undergo impaction surgery on two
separate visits with a refractory period of 1 month. They
were given preemptive analgesics 30 min before surgery,
{tramadol or a placebo (normal saline) are administered in
the same area using an insulin syringe} as per their groups
as follows: GROUP A: oral ketorolac 10 mg with
submucous local tramadol 50 mg (1 ml solution).GROUP
B: oral ketorolac 10 mg with submucous local placebo
(1 ml saline solution). In every patient one side belonged to
Group A and the other side belonged to Group B. (Figs. 3,
4).
• All surgical cases was done out by the single same
operator and postoperative parameters were assessed by
another investigator.
• After giving local anesthesia (2% Lignocaine with
1:80,000 adrenaline) study drugs were administered in
the same area using an insulin syringe.
After achieving adequate local anesthesia, incision was
given and following mucoperiosteal flap reflection, disto-
buccal bone guttering with rotary cutting instruments under
copious saline irrigation was done. Once tooth was
removed, smoothing of bone margins, wound toilet of
extraction socket with betadine and normal saline was
done. After achieving homeostasis, primary closure was
done using 3–0 black braided silk suture.
Intraoperatively, time from giving incision to final
suturing was recorded. Following which immediate post-
operative medications and instructions was given to the
patient. The patients were given four oral ketorolac
(10 mg) tablets and were advised to have one tablet as
rescue analgesic and should be taken at 6 h interval only if
needed.
An evaluation format was given to each patient and
explained in their vernacular language about the markings
on the self-analysis pain performa, to document the time of
taking the first ketorolac after the surgery and also to
mention the total number of analgesic ketorolac 10 mg
consumed in the next 24 h. They were also asked to note
any postoperative complications like nausea; vomiting;
headache; dizziness; pain on injection of tramadol/saline;
erthyema; itching or other.
After assessment period of 24 h postoperative, the
patients had to return the unused ketorolac. The number of
consumed tablets was counted and noted. On the evening
of operative day, all the patients were evaluated for any
adverse events or symptoms, either from medications or
surgical procedures. Double blinding was done with the
patient and the investigator.
All patients recalled after 24 h to assess self assessment
Performa and for noting any local complications due to the
surgical procedure. The self analysis sheets will be asses-
sed and confirmed verbally. Pain scale will be evaluated
according to visual analog scale and verbal response scale
at 1st hour, 2nd hour, 3rd hour, 4th hour, 6th hour and at
12th hour postoperatively. After a week, suture removal
was done.
J. Maxillofac. Oral Surg.
123

3. Results
For the statistical analysis of the data, the SPSS version
16.0 was employed. Frequency distribution and Chi-square
tests at 95% confidence interval were calculated for ana-
lyzing the results. Z test, unpaired t test to find difference
between two means, v2
Chi-square test for comparison of
qualitative data between the groups were used.
Demographic features and other variables were found to
be similar among both the groups (Tables 1, 2). The
postoperative pain intensity scores according to Verbral
Response Scale (VRS) Table 3, Fig. 1. The patients
experienced significantly lower pain intensity scores from
1st to 12th postoperative hours with oral ketorolac plus
local tramadol in group A as compared to group B of oral
ketorolac plus local saline as placebo. (Table 3, Fig. 1)
According to Visual Analog Scale (VAS), both the
groups had nearly equal effect for up to 2 h postopera-
tively. But, at 3rd hour, highly significant pain relief was
noted which gradually persists to give a significant pain
Table 1 Age and genderwise
distribution of patients
Age Male Female Total Z value P value and significance
No. % No. % No. %
B 20 10 41.7 6 37.5 16 40.0 Z = 0.46 P [ 0.05, not significant
21–25 10 41.7 9 56.2 19 47.5
26–30 4 16.6 1 6.3 5 12.5
Total 24 100.0 16 100.0 40 100.0
Mean ± SD 22.30 ± 3.2 21.86 ± 3.1 22.10 ± 3.15
There is no statistical significance difference of age among males and females
Table 2 Duration of surgery
Duration of surgery in minutes Group A Group B Total Z value P value and significance
No. % No. % No. %
15–20 8 41.7 7 37.5 15 40.0 Z = 0.43 P [ 0.05, not significant
21–25 3 41.7 5 56.2 5 47.5
26–30 10 16.6 10 6.3 20 12.5
31–35 5 100.0 2 100.0 7 100.0
36–40 6 100.0 8 100.0 14 100.0
[ 40 8 16.6 8 6.3 16 12.5
Total 40 100.0 40 100.0 80 100.0
Mean ± SD 32.15 ± 10.73 33.25 ± 10.25 32.70 ± 10.48
There is no statistical significance difference of duration of surgery in group A and group B
Table 3 Comparison of mean
pain intensity between the
groups using VRS
Time period Group A Group B t test values P value significant
Mean ± SD Mean ± SD
1st hour 0.8 ± 0.46 1.0 ± 0.22 t = 2.45 P = 0.017, S
2nd hour 1.0 ± 0.22 1.17 ± 0.44 t = 2.23 P = 0.030 S
3rd hour 1.47 ± 0.55 1.92 ± 0.57 t = 3.57 P = 0.001 HS
4th hour 2.17 ± 0.54 2.62 ± 0.54 t = 3.69 P = 0.000 HS
6th hour 2.57 ± 0.50 2.25 ± 0.49 t = 2.92 P = 0.005 S
12th hour 2.27 ± 0.45 2.57 ± 0.50 t = 2.82 P = 0.006 S
24th hour 2.2 ± 0.40 2.3 ± 0.46 t = 1.02 P = 0.308 NS
S significant, NS not significant, HS highly significant
J. Maxillofac. Oral Surg.
123

4. relief at hours 3rd, 4th, 6th postoperatively. (Table 4). It
means that patients reported a significantly lower pain
intensity scores at hours 3rd, 4th, 6th postoperatively in
group A as compared to group B.
The pain-free interval was found to be significantly
longer in the group A (6.96 ± 1.47 h) (highly significant
P 0.001) as compared to group B (4.59 ± 0.99 h) as
assessed by mean time to take first rescue analgesic.
(Fig. 2)
When total number of analgesic consumed in first 24 h
postoperatively were compared, a highly significant dif-
ference (P 0.001) was noticed with mean 1.29 ± 0.45
and 2.53 ± 0.66 for group A and group B, respectively.
This suggests that use of combination of analgesics (ke-
torolac ? tramadol) as preemptive analgesics proved
better than use of single analgesic (ketorolac) and needs
less consumption of analgesics postoperatively. (Table 5).
Complications like headache; nausea; vomiting; local
changes like itching, pain at injection site if experienced by
the patient were recorded. Headache were noticed in 5
patients of group A (12.5%) and in only one patient of
group B (2.5%). Whereas, 8 patients (20%) after injecting
tramadol complains of nausea and 3 patients (7.5%)
reported vomiting. They were prescribed antiemetic in
group A. Only 5 patients (12.5%) of group A had com-
pliant of local reactions like pain at injection site and 3
patients (7.5%) reported itching on tramadol injection as
compared to none of local reactions noted in group B.
(Fig. 3).
Fig. 1 Graph 1 showing
comparison of mean pain
intensity between the two
groups
Table 4 Comparison of mean
pain intensity between the
groups using VAS
Time period Group A Group B t test values P value significant
Mean ± SD Mean ± SD
1st hour 2.12 ± 0.33 2.12 ± 0.33 t = 0.04 P [ 0.05, P = 0.961 NS
2nd hour 2.71 ± 0.52 2.90 ± 0.80 t = 1.36 P [ 0.05, P = 0.157 NS
3rd hour 3.48 ± 1.07 4.59 ± 1.32 t = -3.818 P 0.001, P = 0.000 HS
4th hour 5.45 ± 1.62 6.50 ± 1.25 t = - 2.76 P 0.05, P = 0.012 S
6th hour 6.35 ± 1.57 5.35 ± 1.40 t = 2.278 P 0.05, P = 0.024 S
12th hour 5.45 ± 1.21 6.15 ± 1.20 t = 0.687 P 0.05, P = 0.494 NS
24th hour 5.22 ± 0.71 5.59 ± 1.02 t = - 1.54 P [ 0.05, P = 0.085 NS
S significant, NS not significant, HS highly significant
J. Maxillofac. Oral Surg.
123

5. Global assessment shows patients of group A, on 32
occasions of oral ketorolac with local tramadol treatment
and patients of group B, on 9 occasions of oral ketorolac
with local saline rated the overall surgical procedure as
good. (Fig. 4) There was statistically highly significance
difference of global assessment experienced between the
groups (P 0.001).
Discussion
Preemptive analgesia is an anti-nociceptive therapy to
block transmission of altered central processing of afferent
inputs from preoperative or intraoperative injuries (central
desensitization) which causes pain enhancement in post-
operative period. To attain its maximum effectiveness,
establishing an optimum level of analgesia before, during
and after injury period is necessary to reduce central sen-
sitization during inflammation [9, 10, 18].
Based on the intensity and severity of pain, a specific
analgesic drug can be chosen. The opioid and non-opioid
(NSAIDs) analgesic drugs mostly selected for moderate to
severe type of dental pain. Whereas, on reviewing litera-
ture, it had been shown that the combined usage of drugs
having different modes of action like morphine, meperidine
with NSAIDs gives more efficacy with even the reduced
dose of opioids and increases anti-nociceptive effects
[6, 19]. This was also proved in our study by the additive
agonism of oral ketorolac with local tramadol, reporting
increased pain free duration of 6.96 h postoperatively in
group A as compared to 4.59 h in group B where only oral
ketorolac was used. Thus, our study supports the syner-
gistic analgesic effective of ketorolac with tramadol as
suggested by various authors in the past.
[3–5, 14, 15, 20–22].
Fig. 2 Graph 2 showing
comparison of mean time of first
dose of rescue analgesia
between the groups
Table 5 Comparison of number of total analgesics consumed in 24 h
postoperatively between the groups
No. of doses Group A Group B
No of cases % No of cases %
1 28 70.0 0 0.0
2 11 27.5 22 55.0
3 1 2.5 14 35.0
4 0 0.0 4 10.0
Total 40 100.0 40 100.0
There is statistically highly significance difference of total analgesics
consumed in 24 h PO between the groups
v2
= 21.36 P 0.001 very highly significant
J. Maxillofac. Oral Surg.
123

6. In our study, the mean pain intensity scores as per
Verbal Response Scale (VRS) reported a significant pain
relief from 1st to 12th hours postoperatively and according
to Visual Analog Scale (VAS), showed a significant pain
relief from 3rd to 6th hours postoperatively. It was
according to Mario A et al. who noted statistically
Fig. 3 Graph 3 showing
complications in both the
groups
Fig. 4 Graph 4 showing
comparison of overall
assessment between the two
groups
J. Maxillofac. Oral Surg.
123

7. significant difference in pain intensity score (VAS) mea-
sured at 6 h post-surgery between studied groups [23].
The mean time to take first rescue analgesic for group A
was found statistically significant with 6.96 h with oral
ketorolac along with local tramadol and 4.59 h with oral
ketorolac along with local saline as placebo in group B
which was found significant clinically as pain after third
molar surgery was most severe between 6 and 8 h. This
was in contrast to the study by Mario A et al. who reported
the mean time to take first rescue analgesic was of
approximately 5.13 min for both the groups which was not
found statistically significant (P [ 0.05) [23].
We found that 3 patient in group A needed no pain
medication within 10 h after surgery as compared with all
40 patients from group B. This finding was according to the
study by Mario A et al. who reported that only 1 patient in
group A needed no analgesic within 12 h postoperatively
as compared with 10 patients in group B [23]. This sug-
gests that use of combination of analgesics (ketoro-
lac ? tramadol) as preemptive analgesics proved better
than use of single analgesic (ketorolac) and needs less
consumption of analgesics after surgery.
But in terms of postoperative complications associated
with the study drugs, nausea, headache and vomiting are
the major adverse effects of tramadol same as suggested by
previous studies [19]. In our study, after receiving sub-
mucous tramadol, 5 patients (12.5%) complained head-
ache, 8 patients (20%) complained nausea and 3 patients
(7.5%) reported vomiting out of which only 3 demanded
the rescue antiemetic in group A. Intraoperative complaints
like respiratory depression and perspiration on injection of
tramadol was not reported in any patient in our clinical trial
which was consistent according to previous studies [24].
Local reactions like itching and pain on injection, erythema
were also reported with tramadol administration in our
study. This was consistent as reported in a meta-analysis on
a paracetamol and tramadol combination. [25].
By adapting such analgesic combination and preemptive
study design, postoperative quality of the life of patients
improves which can be assessed by doing Global assess-
ment. Our study shows that patients of group A, on 32
occasions and patients of group B, on 9 occasions, graded
the overall patients satisfaction as good which was found to
be consistent with the previous studies [26, 27]. Few
studies advocated that submucosal tramadol injection dur-
ing surgical procedure has remarkable effect to reduce
postoperative pain and extension of anesthetic duration of
articaine [28, 29].
Conclusion
Our clinical trial suggests that preemptive use of oral
ketorolac along with local tramadol are better tolerated
than ketorolac and can be used as an alternative for the
treatment of acute pain following surgical removal of third
molars. The patients experienced significantly lower pain
intensity scores in the immediate postoperative phase with
oral ketorolac plus local tramadol. The results of this study
also reveal that the drugs are associated with minimal side
affects or local reactions in addition to the need for less
number of analgesics consumed in first 24 h postopera-
tively providing a good patient compliance. Hence, it can
be concluded that preemptive oral ketorolac with tramadol
in comparison with oral ketorolac results in better pain
relief, longer pain free intervals with minimum rescue
analgesics requirement lesser postoperative analgesics
consumption.
Funding Self funded.
Compliance with Ethical Standards
Conflict of interest None.
Ethical Approval Institutional ethical clearance taken.
Informed Consent Patient consents taken.
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