KPPIA

1. THE ROLE OF PARECOXIB AS
OPIOID SPARRING AGENT IN
MULTIMODAL ANALGESIA FOR
POST-OPERATIVE PAIN
I Putu Pramana Suarjaya
Department of Anesthesiology and Intensive Care
Sanglah Hospital – Faculty of Medicine Udayana University
Bali - Indonesia

2. Even nowadays postoperative pain
remains poorly managed
2
1. Adapted from Apfelbaum JL, et al. Anesth Analg. 2003;97:534-40.
2. Adapted from Gan TJ, et al. Curr Med Res Opin. 2014;30:149-60.
82
13
47
21 18
86
25
45
23
8
0
20
40
60
80
100
Any Slight Moderate Severe Extreme
Patients
(%)
Pain Severity
Postoperative pain 24–48h after hospital discharge
from same-day surgery1,2
Apfelbaum 2003 Gan 2014

3. Inadequate post-op pain control
3
1. Oderda G. Pharmacotherapy. 2012;32(9 Pt 2):1S-5S.
2. Stephens J, et al. Rheumatology. 2003;42(Suppl. 3):iii40-52.
3. Filos KS, Lehmann KA. Eur Surg Res 1999;31:97-107.
4. Massad IM, et al. East Mediterr Health J. 2013;19:485-9.
5. VanDenKerkhof EG, et al. Pain Res Manag. 2006;11:41-7.
6. Schug SA, Chong C. Curr Opin Anaesthesiol. 2009;22:738-43.
 The most intense pain is reported in the first 48 hours
following surgery1
 Postoperative pain is often the consequence of
inadequate analgesic regimens2–4
 Inadequate pain control is reported both inpatient5
and outpatient surgeries6
 Over 80% of patients experience moderate to severe
pain
24–48 hours after hospital discharge1

4. Persistent postoperative pain is a risk
factor for the development of chronic
pain1,2
4
1. Dunwoody CJ, et al. Pain Manag Nurs. 2008;9(1 Suppl.):S11-S21.
2. Schug SA, et al. (eds). Acute pain management: Scientific evidence, 4th Edition 2015. ANZCA & FPM, Melbourne.
Long-term physical
consequences
Long-term psychological
consequences
Socioeconomic
consequences
Increased healthcare
costs
Chronic
Pain
syndromes
Neuronal
sensitisation
Unresolved
acute pain

5. Multimodal analgesia1,2
5
 Adapted from Kumar S, et al. OA Anaesthetics. 2014;2:2.
 Adapted from Julius D, Basbaum A. Nature. 2001;413:203-10.
• NSAIDS
• COX-2 inhibitors
• Topical local
anaesthetics
Transduction • Epidural block
• Regional anaesthesia
Conduction/Transmission
• Opioids
• COX-2 inhibitors
• Ketamine
• Alpha-2-Delta ligands
• Alpha-2 agonists
Modulation
• Opioids
• COX-2 inhibitors
• Paracetamol
Perception

6. Parecoxib
mechanism of action – selective COX-2 inhibition1
6
COX, cyclooxygenase
1. Adapted from Gajraj NM. Anesth Analg. 2003;96:1720-38.
Arachidonic Acid
COX-1 COX-2
Nonspecific
NSAID
Body Homeostasis
• Gastric integrity
• Renal function
• Platelet aggregation
• Inflammation
• Pain
Parecoxib
COX-2
Specific Inhibitor
X X
X

7. Parecoxib pharmacokinetic profile
7
1. Adapted from Karim A, et al. J Clin Pharmacol. 2001;41:1111-9.
2. Dynastat Prescribing Information, Pfizer Malaysia; 20 Nov 2015.
 The pro-drug parecoxib is rapidly and almost completely
converted to valdecoxib with a plasma half-life ≈22 min2
Single-dose plasma concentration pharmacokinetics in
healthy adult males aged 18–45years (n=56)1
Plasma
Concentration
(ng/mL)
Time(hours)
Prodrug parecoxib 40mg IM
Valdecoxib
100
10
1
0
1000
2000
0 2 4 8 10 12
6

8. Efficacy of single-dose
parenteral analgesics1
8
CI, confidence interval; NNT, number needed to treat
1. Barden J, et al. BMC Anesthesiol. 2003;3:1.
Systematic review ≥50% Pain reduction 4−6h post-dose
Drug and dose n NNT (95% CI)
Parecoxib 40mg IV 349 2.2 (1.8 to 2.7)
Morphine 10mg IM 946 2.9 (2.6 to 3.6)
Parecoxib 20mg IV 346 3.0 (2.3 to 4.1)
Ketorolac 30mg IM 359 3.4 (2.5 to 4.9)
Morphine 4mg IV NA NA

9. Parecoxib increases the duration
of analgesia1
9
1. Adapted from Kyriakidis AV, et al. Hernia. 2011;15:59-64.
 Parecoxib was more effective than equivalent doses of lornoxicam
and diclofenac in level and duration of analgesia
Hernia Repair
6
8
11
0
5
10
15
Diclofenac 75mg IM bid
(N=110)
Lornoxicam 8mg iv bid
(N=140)
Parecoxib 40mg IV bid
(N=260)
Mean
duration
of
analgesia
(h)
*P<0.001 vs diclofenac and lornoxicam
*

10. Parecoxib reduces postoperative
pain scores1
10
1. Adapted from Sindhvananda W, et al. J Med Assoc Thai. 2005;88:1557-62.
 Parecoxib 40mg IV was superior to tramadol 50mg IV in patients
undergoing open, uncomplicated appendectomy
Appendectomy
*P=0.01 vs tramadol
0
2
4
6
8
10
6h 12h 24h
Median
VAS
Scores
Time after surgery
Tramadol 50mg IV (N=25)
Parecoxib 40mg IV (N=25)
*

11. 3.09
1.81
1.05
0.81 0.74
0.48
0
2
4
6
8
10
2 12 24
Mean
pain
10-cm
VAS
score
Hour after procedure
Post-procedural pain
Placebo (n=43) Parecoxib (n=42)
ERCP, endoscopic retrograde cholangiopancreatography
1. Adapted from Amornyotin S, et al. J Pain Res. 2012;5:251-6.
11
55.8
21.4
0
10
20
30
40
50
60
Placebo (n=43) Parecoxib (n=42)
Patients
(%)
Pethidine use
Parecoxib 40mg reduces pain and
pethidine consumption1
ERCP
*P<0.001 vs placebo
*

12. Parecoxib improves pain; pre-incisional
parecoxib reduces morphine consumption1
12
1. Adapted from Pandazi A, et al. World J Surg. 2010;34:2463-69.
 Pre- and post-incisional parecoxib 40mg IV had comparable analgesic
efficacy
Colorectal Cancer Surgery
0
10
20
30
40
1h 6h 18h 24h
Mean
morphine
consumption
(mg)
Time after surgery
Preincisional parecoxib (N=20) Postincisional parecoxib (N=20)
*P=0.044 vs preincisional parecoxib; **P=0.02 vs preincisional parecoxib; ***P=0.001 vs
preincisional parecoxib
*
*
*
***

13. Parecoxib significantly reduces postoperative
pain
13
1. Adapted from Chen H, Luo A. Pain Pract 2015;16:467-72.
0
1
2
3
4
5
6
0H 1H 2H 4H 6H 8H 12H 24H
10cm
VAS
Score
Comparison ofVAS scores of patients at different time points1
Placebo (n=33) Parecoxib (n=31)
Endonasal Surgery
*P<0.05 vs placebo; **P<0.01 vs placebo
*
*
**
**
**

14. 42.2
32.4
39.1
0
5
10
15
20
25
30
35
40
45
Placebo
(N=38)
Perioperative
parecoxib
(N=37)
Postoperative
parecoxib
(N=38)
Mean
post-anaesthesia
care
unit
length
of
stay
(min)
Parecoxib reduces length of stay
1. Adapted from Shuying L, et al. Int J Surg. 2014;12:464-8.
14
47
19
34
0
5
10
15
20
25
30
35
40
45
50
Placebo
(N=38)
Perioperative
parecoxib
(N=37)
Postoperative
parecoxib
(N=38)
Proportion
of
patients
requiring
additional
analgesics
(%)
Parecoxib reduces need for
additional analgesics
Parecoxib reduces length of stay and need for
additional analgesics1
Laparoscopic
Cholecystectomy
*P<0.017 perioperative parecoxib vs placebo; **P<0.017 perioperative parecoxib vs postoperative parecoxib
*
**
*

15. Parecoxib improves pain scores at rest and
on coughing1
15
1. Adapted from Ling XM, et al. J Thorac Dis. 2016;8:880-7.
 Parecoxib, as part of multimodal analgesia, improves postoperative
analgesia provided by thoracic epidural analgesia, relieves stress response
after thoracotomy, and may restrain the development of chronic pain
Thoracotomy
PostoperativeVAS score
0
1
2
3
4
5
6
7
2h 4h 8h 24h 48h 72h
VAS
Scores
Time after surgery
0
1
2
3
4
5
6
7
2h 4h 8h 24h 48h 72h
VAS
Scores
Time after surgery
Placebo Parecoxib 40mg
At rest* On coughing*
*P<0.01 for parecoxib vs placebo in the 72h after surgery

16. Parecoxib reduces morphine use and lowers
opioid-related distress vs placebo1
16
1. Adapted from Dirkmann D, et al. BMC Anesthesiol. 2015;15:31.
 Parecoxib significantly reduces pain severity and pain interference
 Parecoxib significantly lowers mean overall benefit of analgesia
score
Prostatectomy
57.1
43.1
0
10
20
30
40
50
60
Placebo
(n=48)
Parecoxib
(n=48)
Mean
dose
(mg)
Morphine in 48h
-24.4%
*
*P=0.02 vs placebo
Parecoxib IV 40mg then 20mg every 12h until 48h after skin closure
Patients having radical open prostatectomy using patient controlled
analgesia with morphine up to 40mg/4h

17. Pain Ther (2017) 6:61–72
DOI 10.1007/s40122-017-0066-5
Results: Pain scores were significantly lower in the parecoxib group (n = 142)
compared with placebo (n = 139) on day 2 (-22%; p0.001)
and day 3 (-17%; p = 0.004).
Pain interference with function scores were also significantly lower in the
parecoxib group on day 2 (-32%; p0.001) and day 3 (-27%; p = 0.003)
relative to placebo. Additionally, significantly less supplemental
morphine was required in the parecoxib group relative to placebo through 24
h (-28%; p = 0.008) and 48 h (-33%; p0.001).
Patients in the parecoxib group had a reduced risk of experiencing opioid-
related symptoms

18. Fig. 2 Mean SPI-24 scores following surgery. **p0.001; *p0.010
versus placebo. Day 2 is the day after surgery. SD standard
deviation, SPI-24 summed pain intensity over 24 h
Pain Ther (2017) 6:61–72
DOI 10.1007/s40122-017-0066-5

19. Fig. 4 Cumulative morphine consumption following initial
dose of study medication. **p0.001 versus placebo;
*p0.010 versus placebo. SD standard deviation
Pain Ther (2017) 6:61–72
DOI 10.1007/s40122-017-0066-5

20. Fig. 3 Mean mBPI-sf composite pain interference with function scores
following surgery. **p0.001 versus placebo; *p0.010 versus placebo.
Day 2 is the day after surgery. SD standard deviation, mBPI-sf modified
brief pain inventory-short form
Pain Ther (2017) 6:61–72
DOI 10.1007/s40122-017-0066-5

21. NS non-significant, RR relative risk
a Parecoxib compared to placebo
b It was not possible to calculate the RR since no patients in the parecoxib group experienced
retching/vomiting
Pain Ther (2017) 6:61–72
DOI 10.1007/s40122-017-0066-5

22. Parecoxib is effective in other types of surgery
22
1. Gehling M, et al. Br J Anaesth. 2010;104:761-7.
2. Neuss H, et al. J Surg Res. 2010;162:88-94.
Thyroidyroidectomy
 Postoperative parecoxib reduces pain and rescue
medication use after thyroidectomy1
 Parecoxib, alone or in combination with
acetaminophen, significantly reduced pain and
piritramide use vs acetaminophen alone at 24h1
Radical axillary lymph node dissection
 Preoperative parecoxib 40mg IV is effective in
radical axillary lymph node dissection in patients
with melanoma2
 Reduced pain after mobilisation, fatigue, and use
of rescue medication vs placebo (P≤0.05 for all)2

23. Parecoxib common adverse events1*
23
1. European Medicines Agency. Dynastat: EPAR – Product Information. Updated 7 July 2015. Available from:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000381/WC500038843.pdf. Accessed Sep 2016.
(May affect more than 1 in 10 people)
Nausea
(May affect up to 1 in 100 people)
Hypertension Abdominal pain Dry mouth
Hypotension Vomiting Pruritis
Back pain Constipation Pharyngitis
Peripheral oedema Dyspepsia Alveolar osteitis (dry socket)
Bradycardia Flatulence Rash
Dizziness Oliguria Hyperhidrosis
Insomnia Increased blood creatinine
Overall Safety
*Please refer to local prescribing information

24. Parecoxib is well tolerated1
24
1. Adapted from Barden J, et al. BMC Anesthesiol. 2003;3:1.
55
13
23
8
65
11
24
12
59
11
19
10
0
10
20
30
40
50
60
70
Any event Headache Nausea Vomiting
Patients
(%)
Placebo (n=132)
Parecoxib 20mg IV (n=132)
Parecoxib 40mg IV (n=131)
Systematic Review

25. Parecoxib does not have a significant
effect on platelet aggregation1
25
bid, twice daily; qid, four times daily
 Adapted from Noveck RJ, et al. Clin Drug Invest. 2001;21:465-76.
Haemostatic Safety
*p<0.001 for change from baseline vs ketorolac
**p<0.001 for change from baseline vs placebo
0
20
40
60
80
100
Baseline 30min Predose 2h Postdose 4h Postdose 6h Postdose
Platelet aggregation response to arachidonate1
Placebo Ketorolac 30mg QID IV (n=15) Parecoxib 40mg BID IV (n=15)
*
**
*
**
*
**
**
*
Platelet aggregation response to arachidonate in non-elderly patients1
Platelet
aggregation
(%)

26. 6
90
14
0
45
10
0
20
40
60
80
100
Placebo Ketorolac 15mg
QID
Parecoxib 40mg
BID
Patients
(%)
BID, twice daily; QID, four times daily
1. Adapted from Stolz RR, et al. Am J Gastroenterol. 2002;97:65-71.
2. Adapted from Harris SI, et al. J Clin Gastroenterol. 2004;38:575-80.
26
10
85
5
2
45
2
0
20
40
60
80
100
Placebo Ketorolac
30mg QID
Parecoxib
40mg BID
Patients
(%)
Parecoxib has a low incidence of upper
gastrointestinal events1
Gastrointestinal Safety
*P<0.05 vs parecoxib and placebo; **P<0.001 vs parecoxib and placebo
*
*
**
**
Incidence of upper GI events in
healthy adults aged 65–75 years1
Incidence of upper GI events in
healthy adults aged 18–64 years2
Gastric ulcer or erosion (hatched bars) Duodenal ulcer or erosion (solid bars)

27. Scientific Reports | (2021) 11:7362 |
https://doi.org/10.1038/s41598-021-86826-7
An opioid-sparing protocol with
intravenous parecoxib can
effectively reduce morphine consumption
after simultaneous
bilateral total knee arthroplasty
Hsuan-Hsiao Ma1,2, Te-Feng Arthur Chou1,2, Hsin-Yi Wang3,4, Shang-Wen
Tsai1,2*, Cheng-Fong Chen1,2, Po-Kuei Wu1,2 & Wei-Ming Chen1,2
Conclusion; the opioid-sparing protocol may be used as an
alternative modality for pain management following SBTKA. Similar
pain relief effects may be achieved utilizing a reduced cumulative
opioid dose, with few opioid related adverse events.

28. Table Comparison of clinical outcomes after simultaneous bilateral TKA
in both groups. *p < 0.05.

29. Table Adverse events in both groups.

30. Scientific Reports | (2021) 11:7362 |
https://doi.org/10.1038/s41598-021-86826-7
An opioid-sparing protocol with
intravenous parecoxib can
effectively reduce morphine consumption
after simultaneous
bilateral total knee arthroplasty
Hsuan-Hsiao Ma1,2, Te-Feng Arthur Chou1,2, Hsin-Yi Wang3,4, Shang-Wen
Tsai1,2*, Cheng-Fong Chen1,2, Po-Kuei Wu1,2 & Wei-Ming Chen1,2
Conclusion; the opioid-sparing protocol may be used as an
alternative modality for pain management following SBTKA. Similar
pain relief effects may be achieved utilizing a reduced cumulative
opioid dose, with few opioid related adverse events.

31. Summary of parecoxib for postoperative
pain management: orthopaedic surgery
31
 Parecoxib provides rapid and long-lasting pain control
 Parecoxib is indicated for the short-term management of
acute postoperative pain, and can be used concurrently
with opioid analgesics
 Parecoxib is an effective analgesic in many surgical
settings
 Effective in single1 and multiple doses9
 Effective as monotherapy9
 Effective as part of multimodal analgesia5

32. TERIMA KASIH

33. THANK YOU