Preemptive Analgesia in Total Knee Arthroplasty: Comparing the Effects of Single Dose Combined Celecoxib With Pregabaline and Repetition Dose Combined Celecoxib With Pregabaline (Double Blind Controlled Clinical Trial)
Phase: PHASE2
Conditions: Acute Pain
Sponsor: Fakultas Kedokteran Universitas Indonesia

PREEMPTIVE ANALGESIA IN TOTAL KNEE ARTHROPLASTY: 
COMPARING THE EFFECTS OF SINGLE DOSE COMBINED CELECOXIB WITH 
PREGABALINE AND REPETITION DOSE COMBINED CELECOXIB WITH 
PREGABALINE (DOUBLE BLIND CONTROLLED CLINICAL TRIAL) 
Rangga Bayu Valentino Rawung, Andri M. T. Lubis, Aida Rosita Tantri 
Document date information: 10th May 2018 
 
ABSTRACT 
Introduction. Acute Pain is the most common early complication after total knee arthroplasty 
that caused delayed mobilization, demands of morphine, and higher operative cost. There were 
many researches that had been done in analgesia method to find the most effective analgesia, 
lowest side effect, and easy to apply. Preemptive analgesia of combined celecoxib and 
pregabalin were reported to give a promising outcome. 
Method. In a randomized, double blind controlled clinical trial, 30 subjects underwent surgery 
for total knee arthroplasty using 15-20mg bupivacaine 5% epidural anesthesia. All subjects were 
divided into three groups. First group was given celecoxib 400mg and pregabaline 150mg 1 hour 
before operation, second group was given celecoxib 200mg and pregabaline 75mg twice daily 
started from 3 days before operation, and the last group was given placebo. The outcome was 
measured with VAS, knee ROM, and post-operative mobilization. 
Results. There was a significant difference in post-operative morphine usage between the groups 
taken preemptive analgesia and the placebo group, but there was no any significant difference 
found between first and second group that consumed preemptive analgesia with different dosage. 
ROM and post-operative mobilization were not significantly different among three groups. 
Discussion and Conclusion. Preemptive analgesia had been proven to reduce post-operative 
usage of morphine regardless of the dosage. We recommend the usage of combined celecoxib 
and pregabaline as the preemptive analgesia in total knee arthroplasty procedure. Nausea side 
effect was found in 2 subjects of the first group, 1 subject in the second group, and 1 subject in 
the third group. 
Keywords: preemptive analgesia, celecoxib, pregabaline, morphine, VAS 
 
 
 

INTRODUCTION 
Total knee arthroplasty is one of the most satisfactory operation procedure in orthopaedic 
field.1 There were many researches that had been done to prove that TKA procedure increase the 
Quality of Life of the patients.2,3 Crowder, Duffy, and Trousdale,4 reported that after 10 years of 
follow up, 99% of the patients that underwent TKA procedure showed good functional outcome. 
TKA procedure was indicated for patients had chronic pain caused by severe damage of the joint. 
Although this procedure was frequently giving a good outcome, it is still followed by few 
complications.5 
Acute pain following TKA has been reported as one of the most common complication of 
the procedure.6,7 There are many factors that contribute to emerging pain sensation, such as 
infection, inflammatory reaction caused by the procedure, and racial factor. Post-operative pain 
management is a crucial factor that must be considered. The demands of opioid usage that 
increased regarding this phenomenon cause the increasing of drug side effect, impeding the 
rehabilitation process and causing longer hospital stay period that associated with increasing 
treatment cost and lowering satisfaction of the patients.8,9 
The usage of multimodality of analgesia intra-operative and post-operatively has been 
reported recently.10,11 Epidural, peripheral nerve block, and local articular injection has been 
reported to give a good result but associated with many side effects such as headache, 
hypotension, neurologic bladder, and contra lateral numbness.12,13 Patient Control Analgesia 
(PCA) using morphine also reported to reduce post-operative acute pain but also associated with 
nausea and vomitting.14,15 The usage of multimodality analgesia is rational considering that there 
is no any single analgesia that can cover all type of pain.16 
Preemptive analgesia is a pharmacological therapy to cope pain sensation before 
operative procedure. The aim of this therapy is to prevent central pain sensitization through the 
inhibition of pain stimuli and afferent signaling from operation site.17,18,19 A literature review by 
Katz20 showed the benefit of preemptive analgesia in many surgical procedure. There was a 60% 
cases of decreasing pain sensation and lower post-operative analgesia usage. Many preemptive 
analgesia could be taken post-operatively, such as NSAID, NMDA, local anesthesia, and 
systemic antiepileptic drugs.16 

The usage of oral analgesia as preemptive analgesia has been reported to give promising 
result.21 Celecoxib and Pregabaline could be used as preemptive analgesia. Their synergic effect 
could inhibit pain stimuli in different ways. Celecoxib has a better analgesia effect with lower 
rate of side effect compared to ibuprofen, and pregabaline has similar analgesia effect with lower 
rate of side effect compared to gabapentine.22,23 A study by Niruthisard et al. showed the 
combination of celecoxib and pregabaline taken 1 hour before TKA procedure capable in 
decreasing pain during motion and post-operative anxiety.24 In spite of these promising effect, 
the research about repetitive dose of preemptive analgesia in TKA procedure has not been done 
until recently. The aim of this research is to compare the therapeutic effect of single dose and 
repetitive dose of combined celecoxib and pregabaline. 
 
MATERIALS AND METHODS 
             All procedures undertaken in this study have been approved by The Ethical Committee 
of Faculty of Medicine Universitas Indonesia No.851/UN2.F1/ETIK/2015. Verbal and written 
informed consents were obtained before the study. The study was carried out in accordance of 
the approved guidelines. 
 
The study design that was used in this study was double blind control clinical trial 
design. This study was executed from July 2015 to December 2016. Total 30 subjects of the 
study were collected by consecutive sampling from adults who underwent TKA procedure and 
fulfilled the inclusion criteria. The inclusion criteria are 55-80 years old patients who come to 
orthopaedic polyclinic, underwent TKA procedure, have osteoarthritis, and consumed pain killer 
and anti-inflammatory drugs routinely. The exclusion criteria are patients with psychiatric 
disorder, have history of renal disease, history of chronic neuropathic, have genu arthritis that 
caused by rheumatoid arthritis and infection., diabetic and obesity, coagulopathy, and patients 
with severe pain that needed immediate analgesia regimen.  
 
 

All surgeries were done by one experienced orthopaedic surgeon. The tested subjects 
were allocated randomly into three groups, which are group 1 (taking single dose of celecoxib 
400mg and pregabaline 150mg), group 2 (taking repetitive dose of celecoxib 200mg and 
pregabaline 75mg twice daily, since 3 days pre-operatively), and group 3 (taking placebo). All 
groups of subjects underwent same procedure of epidural anesthesia with 15-20mg bupivacaine 
5% before TKA procedure. Two hours after the procedure, post-operative analgesia that consist 
of paracetamol 1000mg + PCA morphine 2mg/kg BW administration with maximal dose of 
6mg/hr and 5 minutes interval were given.  
The efficacy of preemptive analgesia among the groups were measured in post-operative 
follow up that consist of 4 parameters, which are total morphine consumption 3 days post-
operative, VAS 0-24 hours, 25-48hours, 49-72 hours post operative, range of motion, and 
mobilization exercise. All the side effect of post-operative therapy were monitored and treated.  
Outcome Parameters 
Total Morphine Consumption. This is the main outcome parameter to measure the efficacy of the 
preemptive analgesia of combined celecoxib and pregabaline. In this study, morphine is given by 
patient control analgesia (PCA). 
Post-operative Pain. The acute pain is measured and evaluated by Visual Analogue Scale every 
morning before the patients begin their rehabilitation program. This parameter is measured from 
the first day until the third post-operative day.   
Knee functional outcome. Measured by knee range of motion. The measurement is done in the 
morning from the first day until the third post-operative day. The patient is asked to move the 
knee joint actively, and the knee angle is measured by goniometer. 
Mobilization. The patient is expected to be able to do sitting motion on the first day, standing on 
the second day, and walking on the third day.   
 
 
 

Statistical Analysis  
 
The outcome of this research was counted as numerical variable that included total of 
morphine consumption, VAS, range of motion, and mobilization exercise. The differences 
among the three groups were measured within the first day until the third post-operative day. 
Statistical analysis was performed with SPSS software version 20. The normality of 
distribution for numeric variables was assessed by Saphiro-Wilk test. According to normally 
distributed or not, the variables are presented as means with SD or medians with inter-quartile 
range (95%CI). The data will be tested using One-way ANOVA if the data were normally 
distributed, and tested with Kruskal-Wallis if it were not normally distributed. If there are Any 
significant difference found by one-way ANOVA, it then will be analyzed by Bonferroni post 
hoc test to assess the significance of each group.  
 
RESULTS 
 
Thirty subjects that mostly consist of more than 65 years old female were divided into 
three groups. Each group consist of ten randomized subjects. The characteristics of the patients 
can be seen in table 1. 
No 
Variable 
Group 1 (N=10) 
Group 2 (N=10) 
Group 3 (N=10) 
1 
Gender  
Man (3) Woman (7) 
Man (3) Woman (7) 
Man (1) Woman (9) 
2 
Age (years) 
66.1 ± 7.79 
65.9 ± 5.82 
68.2 ± 6.35 
 
Total Morphine Consumption 
 
On the third day post-operatively, the morphine consumption of all subjects from each 
group were being measured by PCA. There was a significant difference of total morphine 
consumption among the groups (p<0.001). The results of morphine consumption measurement 
can be seen on table 2. 
 
 

 
 
 
 
 
 
 
 
 
The post-hoc Bonferroni test concluded a significant difference of total morphine 
consumption between the first and third group (p<0.001), between the second and the third 
group (p<0.001), but there was no significant difference between the first and the second group.  
Post-Operative Pain 
 
Post-operative pain was measured with VAS. The measurement was done on the first day 
until the third day. The VAS within each group was generally decreased from day-one until 
day- three. From this research, it was found that there were a significant differences of VAS 
comparison among the groups (p<0.001) on the first day, second day, and the third day. The 
third group showed higher score of VAS than the first and the second group. 
VAS measurement among the groups after underwent TKA procedure that evaluated from the 
first day until the third day  
 
VAS  D-1 
VAS D-2 
VAS D-3 
p-value* 
 
N=10 
 
N=10 
N=10 
 
 
 
 
 
 
Group 1 (1 hr preemptive analgesia) 
2 (2-3) 
1 (1-2) 
1 (1-2) 
<0,001 
Group 2 (72 hrs preemptive analgesia) 
2.5 (2-3) 
2 (1-2) 
1.2 (1-2) 
0,001 
Group 3 (Placebo) 
4(2-5) 
3 (2-4) 
3 (2-3) 
0,001 
The data were not normally distributed 
The p-value was measured using Kruskal-wallis non-parametric test 
   
Total Morphine Consumption (PCA) among the groups after underwent TKA 
procedure 
 
Group 1 (1 hr 
preemptive 
analgesia) 
Group 2 (72 hrs 
preemptive 
analgesia) 
 Group 3 
(Placebo) 
p-value* 
 
N=10 
N=10 
N=10 
 
Morphine (PCA) 
10.60(2.675) 
9.90(1.524) 
30.20(5.308) 
<0.001 
The data were normally distributed 
The p-value was measured using ANOVA parametric test  

 
 
The post-hoc Bonferroni test concluded a significant difference of total morphine 
consumption between the first and third group (p<0.001), between the second and the third 
group (p<0.001), but there were no significant differences between the first and the second 
group.  
Knee Functional Outcome 
The outcome was defined by the measurement of knee range of motion. In general, the 
range of motion in all groups was getting better from day-one until day-three. The results of this 
parameter were a little different from the previous parameters. It was found that there was no 
significant difference of ROM among all groups) on the first day (p=0.886), on the second day 
(p=0.131), and on the third day (p=0.011). Nevertheless, the clinical outcome showed a 
different result. The ROM were getting better significantly each day. 
 
ROM  D-1 
ROM D-2 
ROM D-3 
 
N=10 
 
N=10 
N=10 
 
 
 
 
Group 1 (1 hr preemptive analgesia) 
15 (10-30) 
60 (15-60) 
90 (60-90) 
Group 2 (72 hrs preemptive analgesia) 
15 (15-20) 
30 (30-60) 
60 (45-90) 
Group 3 (Placebo) 
15(15-20) 
30 (30-60) 
60 (60-90) 
p-value  
 
 
0.886 
 
0.131 
 
0.011 
The data were not normally distributed 
The p-value was measured using Kruskal-wallis non-parametric test 
   
Mobilization 
 
The outcome was defined by the capability of doing motion on the first, second, and third 
day. Almost all of the subjects from each group can do sitting motion on the first day, standing 
motion on the second day, and walking motion on the third day. There was no significant 
difference among the groups (p=1.00) 
 

Mobilization measurement among the groups after underwent TKA procedure that evaluated from 
the first day until the third day  
 
Motion  D-1 
(sitting) 
Motion D-2 
(standing) 
Motion D-3 
(walking) 
p-value* 
 
N=10 
 
N=10 
N=10 
 
 
 
 
 
 
Group 1 (1 hr preemptive analgesia) 
9(90%) 
8 (80 %) 
10 (100%) 
<0,001 
Group 2 (72 hrs preemptive analgesia) 
8 (80%) 
7 (70 %) 
7 (70%) 
0,001 
Group 3 (Placebo) 
9 (90%) 
7 (70%) 
8 (80%) 
0,001 
The data were not normally distributed 
The p-value was measured using Kruskal-wallis non-parametric test 
 
 
DISCUSSION 
 
Osteoarthritis are often involved in geriatric patients. The incidence are increasing by age 
and more often affected women than men.25 These demographic characteristic are similar about 
the findings in this study. Because more than half subjects of TKA procedure come from late 
adult or geriatric patients that would rather have more complication rate, intensive evaluation are 
often needed in the usage of analgesia.26,27  In this study, The usage of morphine has been found 
significantly lower in the groups that received preemptive analgesia regardless of the duration 
compared to the placebo group. These results are supported by the study that has been done by 
Lee et al.28 and Huang Yu et al.29 said that the usage of celecoxib (400mg) combined with 
pregabaline (150mg) given 1 hour prior to the TKA procedure were proven lowering the usage 
of morphine and post-operative pain. However, in this study we found that there was no 
significant difference whether the preemptive analgesia combination was given 1 hour or 72 
hours prior to the procedure. 
 
This study also use VAS to measure the efficacy of preemptive analgesia. We found that 
VAS in the groups that were taken preemptive analgesia was lower than the placebo group. This 
result was similar with the study that has been done by Buvanendran et al.19 and Carmichael et 
al.30 that said the using of repetitive dosage of celecoxib and pregabaline succeed in lowering 

acute and chronic post-operative pain. Even in this study we did not measure the outcome of 
chronic pain among the groups, it was found that in general, there was a decreasing VAS score 
from day-one to day-three that significantly different from the group that used either single dose 
or repetitive dose of preemptive analgesia compared to placebo group. Another confounding 
such as racial, gender, and the method of VAS measurement should be considered in later study. 
 
Rehabilitation program hold a significant portion in post-operative outcome of the 
patients. It has been reported that the early mobilization after TKA procedure gives a better 
outcome with lower morbidity and hospital stay period of the patients. Range of Motion is 
important to ensure early mobilization of patients. The fact that ROM is directly affected with 
pain conclude that lowering the post-operative pain with preemptive analgesia should increase 
ROM and early mobilization rate of the patients. In this study, ROM is proven to be increasing 
from day to day but we found that there was no significant difference of ROM between subjects 
that were given preemptive analgesia compared to placebo group. According to the study that 
has been done by Miner et al.31 and Jacobsen et al.32 the using of ROM as the parameter of TKA 
procedure outcome is still controversial. Their study reported that many factors like knee soft 
tissue, knee alignment, knee muscle strength, psychological condition, pre-operative ROM, and 
operative procedure determined the post-operative ROM. The result of our study supports the 
fact that ROM is not only affected by pain but also by multifactorial aspects that were not been 
studied in our research. 
 
Preemptive analgesia also expected to permit the early mobilization of post-operative 
patients. With early mobilization, a complication like DVT could be avoided, besides with early 
mobilization the healing process and functional outcome of the patients are expected to be 
better.33,34 In this study, it was found that there was no significant differences of mobilization 
period among the groups. Bade reported that pre-operative mobilization directly affected post-
operative mobilization outcome. There are many factors that affect the post-operative 
mobilization such as age, comorbidity, muscle strength, and psychological factors. The result of 
our study supported the fact that patient’s mobilization is not only affected by post-operative 
pain, and the possibility that preemptive analgesia only lowering static post-operative pain, not 
lowering the pain sensation during mobilization. 
 
 

In our study, we also monitored the side effect of preemptive analgesia. And we found 
that the side effect were dose dependent and often emerge in prolonged using of celecoxib 
combination with pregabaline. Buvanendran19 reported that the using of 300mg pregabaline 1 
hour post-operatively has been followed by sedative, confusing, and dry mouth side effect. Lee 
et al.28 in their study compare the using of 400mg celecoxib and 150mg pregabaline combination 
with 400mg celecoxib alone and found that the side effect were emerge in the combination 
group. In our study, we found that 2 subjects in first group, 1 subject in second group, and 1 
subject in third group were having nausea. 
 
CONCLUSION 
 
Preemptive analgesia with the combination of celecoxib and pregabaline are effective in 
decreasing acute pain sensation after TKA procedure regardless of the dose and repetition. This 
combination preemptive analgesia also proven ineffective in decreasing pain sensation during 
motion. In this study, the using of combination preemptive analgesia didn’t show any significant 
side effects. 
 
 
 
 
 
 
 
 
 
 

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