Pain Management in General Surgery

Reference Slide
Inadequate pain control is reported by the majority of
patients

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 by the majority of patients
who undergo both inpatient5 and outpatient surgeries6
Over 80% of patients experience moderate to severe pain
24–48 hours after hospital discharge1

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.
2
Persistent postoperative pain is a risk factor for the
development of chronic pain1,2

Neuronal Long-term physical

sensitisation consequences

Long-term psychological
Chronic consequences
Unresolved Pain
syndromes Socioeconomic
acute pain
consequences

Increased healthcare
costs

1. Dunwoody CJ, et al. Pain Manag Nurs. 2008;9(1 Suppl.):S11-S21.

3
2. Schug SA, et al. (eds). Acute pain management: Scientific evidence, 4th Edition 2015. ANZCA & FPM, Melbourne.
Even nowadays postoperative pain remains poorly managed

Postoperative pain 24–48h after hospital discharge

from same-day surgery1,2
Apfelbaum 2003 Gan 2014
100
82 86
80
Patients (%)

60
47 45
40
25 21 23
20 18
13
8
0
Any Slight Moderate Severe Extreme

Pain Severity

1. Adapted from Apfelbaum JL, et al. Anesth Analg. 2003;97:534-40.

4
2. Adapted from Gan TJ, et al. Curr Med Res Opin. 2014;30:149-60.
Impact of inadequately managed acute postoperative pain1

Impact on Patients
Intense postoperative pain Psychological impact
– Increases risk of developing chronic pain – Anxiety
– Depression
Immunosuppression from
unrelieved pain Delayed ambulation
– Slows wound healing – Increased risk of thromboembolic events
– Delays recovery – Delays hospital discharge
– Increases risk of postsurgical infection
Sympathetic activation
– Predisposes patients to adverse events

Impact on Hospitals
Extended length of stay
Increased risk of readmission
Increased cost of care

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1. Oderda G. Pharmacotherapy. 2012;32(9 Suppl.):6S-11S.
Multimodal management

Multimodal analgesic technique offers multiple benefits:1

– for the patient
– for the healthcare system
– aligns with the goals of modern ambulatory (day-case) surgery
Multimodal analgesia improves pain control while eliminating
opioid-related side-effects (e.g. gastrointestinal and bladder
dysfunction)1

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1. Elvir-Lazo OL, White PF. Curr Opin Anesthesiol. 2010;23:697-703.
Multimodal analgesia1,2 Perception
• Opioids
• COX-2 inhibitors
• Paracetamol

Transduction
Conduction/Transmission
• NSAIDS
• COX-2 inhibitors • Epidural block
• Topical local anaesthetics • Regional anaesthesia

Modulation
• Opioids
• COX-2 inhibitors
• Ketamine
• Alpha-2-Delta ligands
• Alpha-2 agonists

1. Adapted from Kumar S, et al. OA Anaesthetics. 2014;2:2. 7

2. Adapted from Julius D, Basbaum A. Nature. 2001;413:203-10.
Parecoxib mechanism of action – selective COX-2 inhibition1

Arachidonic Acid

COX-1 COX-2

Nonspecific
X NSAID X
Parecoxib
X COX-2
Body Homeostasis Specific Inhibitor
• Gastric integrity
• Renal function • Inflammation
• Platelet aggregation • Pain

COX, cyclooxygenase
8
1. Adapted from Gajraj NM. Anesth Analg. 2003;96:1720-38.
Parecoxib pharmacokinetic profile

Single-dose plasma concentration pharmacokinetics in

healthy adult males aged 18–45 years (n=56)1
2000
Prodrug parecoxib 40mg IM
1000 Valdecoxib
Plasma Concentration

100
(ng/mL)

10

1
0
0 2 4 6 8 10 12

Time (hours)

The prodrug parecoxib is rapidly and almost completely

converted to valdecoxib with a plasma half-life ≈22 min2
1. Adapted from Karim A, et al. J Clin Pharmacol. 2001;41:1111-9.
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2. Dynastat Prescribing Information, Pfizer Malaysia; 20 Nov 2015.
Efficacy of single-dose parenteral analgesics1

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

CI, confidence interval; NNT, number needed to treat

10
1. Barden J, et al. BMC Anesthesiol. 2003;3:1.
 Hernia Repair

Parecoxib increases the duration of analgesia1

Parecoxib was more effective than equivalent doses of

lornoxicam and diclofenac in level and duration of analgesia
15
Mean duration of analgesia (h)

*
11
10

8
5 6

0
Diclofenac 75mg IM bid Lornoxicam 8mg iv bid Parecoxib 40mg IV bid
(N=110) (N=140) _x000d_(N=260)

*P<0.001 vs diclofenac and lornoxicam

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1. Adapted from Kyriakidis AV, et al. Hernia. 2011;15:59-64.
 Appendectomy

Parecoxib reduces postoperative pain scores1

Parecoxib 40mg IV was superior to tramadol 50mg IV in patients

undergoing open, uncomplicated appendectomy

10 Tramadol 50mg IV (N=25)

9 Parecoxib 40mg IV (N=25)
Median VAS Scores

8
7
6
5
4
3
2
*
1
0
6h 12h 24h
Time after surgery

*P=0.01 vs tramadol

12
1. Adapted from Sindhvananda W, et al. J Med Assoc Thai. 2005;88:1557-62.
 ERCP

Parecoxib 40mg reduces pain and pethidine consumption1

10 Post-procedural pain 60 Pethidine use

Placebo (n=43) Parecoxib (n=42) 55.8
50
Mean pain 10-cm VAS score

40
6

Patients (%)
30
4 3.09 *
20 21.4
1.81
2
0.81
1.05 10
0.74
0.48
0 0
2 12 24 Placebo (n=43) Parecoxib (n=42)
Hour after procedure

*P<0.001 vs placebo

ERCP, endoscopic retrograde cholangiopancreatography

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1. Adapted from Amornyotin S, et al. J Pain Res. 2012;5:251-6.
 Colorectal Cancer Surgery

Parecoxib improves pain; pre-incisional parecoxib reduces

morphine consumption1
Pre- and post-incisional parecoxib 40mg IV had comparable analgesic efficacy

Preincisional parecoxib (N=20) Postincisional parecoxib (N=20)

45
***
Mean morphine consumption

40
35 **
30
25
*
20
(mg)

15
10
5
0
1h 6h 18h 24h
Time after surgery

*P=0.044 vs preincisional parecoxib; **P=0.02 vs preincisional parecoxib; ***P=0.001 vs preincisional parecoxib

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1. Adapted from Pandazi A, et al. World J Surg. 2010;34:2463-69.
 Endonasal Surgery

Parecoxib significantly reduces postoperative pain

Comparison of VAS scores of patients at different time points1

Placebo (n=33) Parecoxib (n=31)
6
* ** **
5
**
10cm VAS Score

*
4

0
0H 1H 2H 4H 6H 8H 12H 24H

*P<0.05 vs placebo; **P<0.01 vs placebo

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1. Adapted from Chen H, Luo A. Pain Pract 2015;16:467-72.
 Laparoscopic Cholecystectomy

Parecoxib reduces length of stay and need for additional

analgesics1
Parecoxib reduces length of stay Parecoxib reduces need for ad-
ditional analgesics
45 50
Mean post-anaesthesia care unit

**

Proportion of patients requiring

40 42.2 45 47
39.1

additional analgesics (%)

40
length of stay (min)

35
30
*
32.4 35
30 34
25
25
20
20
15 *
19
15
10 10
5 5
0 0

*P<0.017 perioperative parecoxib vs placebo; **P<0.017 perioperative parecoxib vs postoperative parecoxib

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1. Adapted from Shuying L, et al. Int J Surg. 2014;12:464-8.
 Thoracotomy

Parecoxib improves pain scores at rest and on coughing1

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
Postoperative VAS score
7 At rest* 7 On coughing*
6 6
5
VAS Scores

VAS Scores
4 4
3 3
2 2
1 1
0 0
2h 4h 8h 24h 48h 72h 2h 4h 8h 24h 48h 72h
Time after surgery Time after surgery
Placebo Parecoxib 40mg
*P<0.01 for parecoxib vs placebo in the 72h after surgery

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1. Adapted from Ling XM, et al. J Thorac Dis. 2016;8:880-7.
 Prostatectomy

Parecoxib reduces morphine use and lowers opioid-related

distress vs placebo1
Parecoxib significantly reduces pain severity and pain interference
Parecoxib significantly lowers mean overall benefit of analgesia score

Morphine in 48h
60
50
57.1 -24.4%
Mean dose (mg)

*
40 43.1
30
20
10
0
Placebo Parecoxib
(n=48) (n=48)
*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

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1. Adapted from Dirkmann D, et al. BMC Anesthesiol. 2015;15:31.
Parecoxib is effective in other types of surgery

Thyroidectomy
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

1. Gehling M, et al. Br J Anaesth. 2010;104:761-7.

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2. Neuss H, et al. J Surg Res. 2010;162:88-94.
 Overall Safety

Parecoxib common adverse events1*

(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

*Please refer to local prescribing information

1. European Medicines Agency. Dynastat: EPAR – Product Information. Updated 7 July 2015. Available from:
20
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000381/WC500038843.pdf. Accessed Sep 2016.
 Systematic Review

Parecoxib is well tolerated1

70
Placebo (n=132)
65 Parecoxib 20mg IV (n=132)
60
59 Parecoxib 40mg IV (n=131)
55
50
Patients (%)

40

30

20 23 24
19
10 13 11 11 12 10
8
0
Any event Headache Nausea Vomiting

21
1. Adapted from Barden J, et al. BMC Anesthesiol. 2003;3:1.
 Haemostatic Safety

Parecoxib does not have a significant effect on platelet

aggregation1

PlateletPlatelet
aggregation response to
aggregation arachidonate
response in non-elderly patients 1
to arachidonate1
Placebo Ketorolac 30mg QID IV (n=15) Parecoxib 40mg BID IV (n=15)

100 *
90 * *
Platelet aggregation (%)

80 *
70
60
50
40
** **
30
** **
20
10
0
Baseline 30min Predose 2h Postdose 4h Postdose 6h Postdose

*p<0.001 for change from baseline vs ketorolac

**p<0.001 for change from baseline vs placebo

bid, twice daily; qid, four times daily

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1. Adapted from Noveck RJ, et al. Clin Drug Invest. 2001;21:465-76.
 Gastrointestinal Safety

Parecoxib has a low incidence of upper gastrointestinal

events1
Incidence of upper GI events in Incidence of upper GI events in
healthy adults aged 65–75 years1 healthy adults aged 18–64 years2
100
90* 100
85**
80 80

Patients (%)
Patients (%)

60 60
45* 45**
40 40

20 14 20
10 10
6 5
0 2 2
0 0
Placebo Ketorolac Parecoxib Placebo Ketorolac Parecoxib
15mg QID 40mg BID 30mg QID 40mg BID

Gastric ulcer or erosion (hatched bars) Duodenal ulcer or erosion (solid bars)

*P<0.05 vs parecoxib and placebo; **P<0.001 vs parecoxib and placebo

BID, twice daily; QID, four times daily

1. Adapted from Stolz RR, et al. Am J Gastroenterol. 2002;97:65-71.
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2. Adapted from Harris SI, et al. J Clin Gastroenterol. 2004;38:575-80.
Summary of parecoxib for postoperative pain management:
orthopaedic surgery

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

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