26. Effect of Time to CV events
• Within the first 10-30 days of Rx
• Cumulative effect with time
• Risk persists 30 days after
27. ยา Coxibs ใด มีผลข้างเคียงทาง CVS
น้อยทีสุด
่
• A. ทุกตัวในกลุ่ม ทำาให้เกิด thrombosis
มากพอๆกัน
• B. Lumiracoxib
• C. Etoricoxib
• D. Celecoxib
• E. Parecoxib
28. Coxibs : Cardiovascular Risk
• Drug : Class effect ? No
Individual properties ? :
Ye Dose-
Dose s related
Yes
Molecule/Chemistry
Yes
Half-life
Ye
Effect to BP & sodium s
Ye
• Duration of Rx s
34. COX-2 Inhibitors : COX-Selectivity
More GI side toxicity
Anti-thrombotic
Less GI side effect
Thromboxane Inhibition
( COX-1 mediated )
Prothrombotic
Prostacyclin Inhibition
( COX-2 mediated )
Rofecoxib Diclofenac Ibuprofen ASA
Celecoxib Naproxen
Etoricoxib
Lumiracoxib
35. ยา NSAIDs ใด
มีผลข้างเคียงทาง CVS มากทีสุดใน
่
กลุ่ม
• A. ทุกตัวในกลุ่ม ทำาให้เกิด thrombosis
มากพอๆกัน
• B. Diclofenac
• C. Ibuprofen
• D. Meloxicam
• E. Naproxen
36. EMEA : June 2005
• Coxibs should not be used in pts with
established CAD, stroke and/or peripheral
arterial disease
• Caution when prescribing Coxibs in pt with
CAD risk ( HT, hyperlipidemia,
DM, smoking )
• Use the lowest effective dose & shortest
duration
39. ชายอายุ ปี เป็น คุมได้ดี
120/80 พึ่งได้รับยา Etoricoxib 1
สัปดาห์ รักษา OA knee ซึ่งได้
acetaminophen ไม่ดขึ้น มาพบท่าน
ี
เนื่องจาก ขา 2 ข้างบวมกดบุ๋ม ไม่มี
อาการอื่น BP 140/100 ท่านจะปฏิบัติ
• A. ตรวจ U/A และ renal function ทันที
อย่างไรเป็นลำาดับแรก
• B. ตรวจ LFT และ ดู albumin ในเลือด
• C. ยาเดิม เพิ่ม furosemide prn. และ follow
up
• D. แนะนำาว่ามันเป็นเช่นนีเอง เพราะเป็น HT ให้
้
40. Renal side effect
• Incidence up to 1-5%
• Risk
Volume-contracted states
Low cardiac output
Other condition compromised renal functions
Aging, septicemia, DM, premature baby etc.
44. Hematologic : Bleeding
• GI
• Hemorrhagic stroke
• Intra / post-operative bleeding
Significant in GU surgery
Tosillectomy
Underlying bleeding disorder
Discontinuation before surgery ASA 7-10 days
NSAIDs 3-5 x T1/2
50. Is an NSAID needed ?
Inflammation ? Yes
No
Use non-pharmacologic Is there a contraindication to NSAID ?
or other pharmacologic Rx Yes - Renal insufficiency ( CrCl < 30 )
- Allergic reaction
- Concurrent GI injury
No
Is there a reason that a classical NSAID cannot be used ?
- GI risk+ & Bleeding risk
No Yes
Use classical NSAID Use COX-2 inhibitor
( or classical NSAID + PPI+)
No Is patient at increased risk for CV events ? Yes
Select NSAID on the basis of GI risk Avoid NSAID esp. COX-2 inhibitor
52. ชายอายุ 66 ปี มีโรค angina pectoris
ได้ยา ASA อยู่ ล้มสะโพกคราก 1 วัน
ไม่มีกระดูกหัก
ท่านจะสั่งการรักษาอย่างไร
• A. เพิ่ม ASA จาก 75 mg/d เป็น 75 mg tid.
• B. เพิ่ม Naproxen 500 mg/d + Omeprazole
• C. เพิ่ม Naproxen 500 mg/d + off ASA
• D. เพิ่ม Celecoxib 400 mg/d
• E. ส่ง PM&R ให้ทำากายภาพบำาบัด ให้
Parecoxib ฉีดลดปวด prn
53. ชายอายุ 66 ปี มีโรค angina pectoris
ได้ยา ASA อยู่ ล้มสะโพกคราก 1 วัน
ไม่มีกระดูกหัก
ท่านจะสั่งการรักษาอย่างไร
• A. เพิ่ม ASA จาก 75 mg/d เป็น 75 mg tid.
• B. เพิ่ม Naproxen 500 mg/d + Omeprazole
• C. เพิ่ม Naproxen 500 mg/d + off ASA
• D. เพิ่ม Celecoxib 400 mg/d
• E. ส่ง PM&R ให้ทำากายภาพบำาบัด ให้
Parecoxib ฉีดลดปวด prn
54. หญิงอายุ 38 ปี แพ้ยาซัลฟา เป็น
โรค psoriatic arthritis ปวดมากต้องรับ
ประทานยาแก้ปวดหลายชนิด หลัง
กินยามีผื่นทั่วตัว ยาใดน่าจะเป็น
สาเหตุมากที่สุด
• A. Etoricoxib
• B. Indomethacin
• C. Nimesulide
• D. Meloxicam
• E. All of above
55. หญิงอายุ 38 ปี แพ้ยาซัลฟา เป็น
โรค psoriatic arthritis ปวดมากต้องรับ
ประทานยาแก้ปวดหลายชนิด หลัง
กินยามีผื่นทั่วตัว ยาใดน่าจะเป็น
สาเหตุมากที่สุด
• A. Etoricoxib
• B. Indomethacin
• C. Nimesulide
• D. Meloxicam
• E. All of above
56. ชายอายุ 19 ปี วินิจฉัยเป็น ASA-
induced asthma มี acute tendinitis ท่านจะ
ให้ยาใด
• A. Indomethacin
• B. Naproxen
• C. Etoricoxib
• D. None of above
57. ชายอายุ 19 ปี วินิจฉัยเป็น ASA-
induced asthma มี acute tendinitis ท่านจะ
ให้ยาใด
• A. Indomethacin
• B. Naproxen
• C. Etoricoxib
• D. None of above
65. Strategies to Prevent
GI Complications of NSAIDs
General
Use least ulcerogenic NSAID, short duration
Identify risk factors
Low-risk : no risk factor
Moderate-risk : 1-2 risk factors
High-risk : ≥ 3 risk factors, use of ASA
or anticoagulant
Very high-risk : previous ulcer complications
Apply appropriate prevention
Co-therapy with gastroprotective drugs
Coxib
66. Which non-selective NSAID has lowest
GI side-effects?
A. Aspirin
B. Diclofenac
C. Ibuprofen
D. Indomethacin
E. Piroxicam
67. Relative Risk of
GI Complications with NSAIDs
Ibuprofen 1
Fenoprofen 1.6
ASA 1.6
Diclofenac 1.8
Sulindac 2.1
Diflusinal 2.2
Naproxen 2.2
Indomethacin 2.4
Tolmetin 3
Piroxicam 3.8
Ketoprofen 4.2
Azopropazon 9.2
Ketorolac
1 2 3 4 5 6 7 8 9 10
Relative risk Henry D. BMJ 1996;312:1563-66
69. Strategies to Prevent
GI Complications of NSAIDs
General
Use least ulcerogenic NSAID, short duration
Identify risk factors
Low-risk : no risk factor
Moderate-risk : 1-2 risk factors
High-risk : ≥ 3 risk factors, use of ASA
or anticoagulant
Very high-risk : previous ulcer complications
Apply appropriate prevention
Co-therapy with gastroprotective drugs
Coxib
70. Risk Factors of
Ulcer Complications from NSAIDs
Prior GI events 2.5-4.8
Multiple NSAIDs
(including ASA)
2-4
Age (>65) 2-3.5
Anticoagulant 3
Steroid therapy 2
Co-morbid illness 2
H.pylori infection 2
1 2 3 4 5 6
Relative risk
71. Risk Factors of
Ulcer Complications from NSAIDs
Prior complicated PU 13.5
Multiple NSAIDs (including ASA) 9
High-dose NSAID 7
Anticoagulant 6.4
Prior uncomplicated PU 6.1
Age >70 yr 5.6
H.pylori infection 3.5
Steroid therapy 2.2
1 3 5 7 9 11 13 15
Relative risk
72. Number of Risk Factors &
Incidence of Ulcer Complications
% NNH 5
20 18
15
NNH 12
10 8
NNH 50
5 NNH 125
2
0.8
0
No Risk 1-2 Factors 3 Factors 4 Factors
Factor
Silverstein FE. Ann Intern Med 1995;123:241-9
73. Strategies to Prevent
GI Complications of NSAIDs
General
Use least ulcerogenic NSAID, short duration
Identify risk factors
Low-risk : no risk factor
Moderate-risk : 1-2 risk factors
High-risk : ≥ 3 risk factors, use of ASA
or anticoagulant
Very high-risk : previous ulcer complications
Apply appropriate prevention
Co-therapy with gastroprotective drugs
Coxib
74. Strategies to Prevent
GI Complications of NSAIDs
General
Use least ulcerogenic NSAID, short duration
Identify risk factors
Low-risk : no risk factor
Moderate-risk : 1-2 risk factors
High-risk : ≥ 3 risk factors, use of ASA
or anticoagulant
Very high-risk : previous ulcer complications
Apply appropriate prevention
Co-therapy with gastroprotective drugs
Coxib
75. Which co-therapy is most effective in
reducing NSAID-associated ulcer
complications?
• Misoprostal
• PPI
• H2-RA
• Sucralfate
• Rebamipide
76. Prophylaxis of NSAID-induced Gastropathy
Meta-Analysis
H2-RA PPI Misoprostal
Serious GI No No ↓
events
Symptomatic No ↓ ↓
ulcers
Endoscopic ↓ ↓ ↓
ulcers (double dose)
Mortality No No No
Rostom A. Cochrane database of systematic reviews 2007
77. GI Side Effects of Coxib VS. ns-NSAID
Meta-analysis
Endoscopic ulcers RR 0.26 [0.23-0.30]
Ulcer complications RR 0.39 [0.31-0.50]
Ulcer complications RR 0.89 [0.52-1.53]
(ASA users)
0.1 0.2 0.5 1 2 5 10
Favours coxibs Favours ns-NSAID
Rostom A. Clin Gastroenterol Hepatol 2007;5:818-28
78. Coxib VS. ns-NSAID
Endoscopic Ulcers
Rostom A. Clin Gastroenterol Hepatol 2007;5:818-28
79. Coxib VS. ns-NSAID
Clinically Ulcers
Rostom A. Clin Gastroenterol Hepatol 2007;5:818-28
80. 65 YO woman had Hx of UGIB following NSAID use 2
years ago
Now she requires NSAID for severe OA
What is the most appropriate
management?
A. Ibuprofen + misoprostal
B. Ibuprofen + PPI
C. Coxib
D. Coxib + PPI
E. No NSAID/Coxib
81. Efficacies of Each Preventive Strategies in
Very High-Risk Patients
Chan FKL. NEJM 2001; 344: 967-73
Chan FKL. NEJM 2002; 347: 2104-10
Chan FKL. Lancet 2007; 369: 1621-6
NSAID + Hp eradication
COXib
NSAID + PPI
COXib + PPI
82. Prophylaxis of NSAID-induced Gastropathy
Recommendation
GI Risk 6 mo GI complications
rate (%)
Low-risk 0.8
• No risk factor
Moderate-risk 2
• 1-2 risk factors
High-risk 8
• ≥ 3 risk factors
• on anticoagulant
• on ASA*
Very high-risk 18
• Prior PU complication
83. Prophylaxis of NSAID-induced Gastropathy
Recommendation
GI Risk Low CV Risk High CV Risk
Low-risk
• No risk factor Least ulcerogenic
NSAID, lowest
effective dose
Moderate-risk
• 1-2 risk factors
High-risk
• ≥ 3 risk factors
• on anticoagulant
• on ASA*
Very high-risk
• Prior PU complication
Chan FKL. AP&T 2004;19:1051-61
84. Prophylaxis of NSAID-induced Gastropathy
Recommendation
GI Risk Low CV Risk High CV Risk
Low-risk
• No risk factor Least ulcerogenic
NSAID, lowest
effective dose
Moderate-risk
• 1-2 risk factors
High-risk
• ≥ 3 risk factors
• on anticoagulant
• on ASA*
Very high-risk
• Prior PU complication
Chan FKL. AP&T 2004;19:1051-61
85. Prophylaxis of NSAID-induced Gastropathy
Recommendation
GI Risk Low CV Risk High CV Risk
Low-risk
• No risk factor Least ulcerogenic
NSAID, lowest
effective dose
Moderate-risk
• 1-2 risk factors NSAID + PPI/MSP
Coxib
High-risk
• ≥ 3 risk factors
• on anticoagulant
• on ASA*
Very high-risk
• Prior PU complication
Chan FKL. AP&T 2004;19:1051-61
86. Prophylaxis of NSAID-induced Gastropathy
Recommendation
GI Risk Low CV Risk High CV Risk
Low-risk
• No risk factor Least ulcerogenic
NSAID, lowest
effective dose
Moderate-risk
• 1-2 risk factors NSAID + PPI/MSP
Coxib
High-risk
• ≥ 3 risk factors Coxib + PPI/MSP
• on anticoagulant
• on ASA* *NSAID + PPI/MSP
Very high-risk
• Prior PU complication
Chan FKL. AP&T 2004;19:1051-61
87. Prophylaxis of NSAID-induced Gastropathy
Recommendation
GI Risk Low CV Risk High CV Risk
Low-risk
• No risk factor Least ulcerogenic
NSAID, lowest
effective dose
Moderate-risk
• 1-2 risk factors NSAID + PPI/MSP
Coxib
High-risk
• ≥ 3 risk factors Coxib + PPI/MSP
• on anticoagulant
• on ASA* *NSAID + PPI/MSP
Very high-risk
• Prior PU complication Coxib + PPI/MSP
Chan FKL. AP&T 2004;19:1051-61
88. Coxib in Patients with CV Risk
Important Issues
Increased risk of thrombosis risk of Coxib
Aspirin decrease GI safety of Coxib
Aspirin is like another NSAID
89. FitzGerald Hypothesis
Platelet Endothelial
Arachinodic acid
COX-1 COX-2
Thromboxane Prostacyclin
TXA2 PGI2
Prothrombotic Antithrombotic
State State
90. FitzGerald Hypothesis
Platelet Endothelial
Arachinodic acid
COX-1 COX-2
× NSAID ×
Thromboxane Prostacyclin
TXA2 PGI2
Prothrombotic Antithrombotic
State State
91. FitzGerald Hypothesis
Platelet Endothelial
Arachinodic acid
COX-1 COX-2
Coxib ×
Prostacyclin
PGI2
Thromboxane
TXA2
Prothrombotic Antithrombotic
State State
93. Question 1
A 51-year-old man presents with a one-day
history of moderately severe low back pain that
began after lifting a heavy box. He has a
normal neurological examination. He has
epigastric pain off and on and has history of
allergy to sulfa.
What analgesics would you offer?
4. Are NSAIDs an appropriate choice of
medication in this patient?
5. If so, which NSAIDs will you prescribe & why?
6. If not, why?
Vimolluck Sanansilp, Siriraj
94. Question 2
A 72-y-o man underwent an explor-lap with
bowel resection. He has Lt hemiplegia. He
gets IV morphine for postoperative pain relief
but still has pain score of 7-8.
3. Would you add any NSAIDs to enhance
analgesia for this patient?
4. If so, which NSAIDs will you prescribe & why?
5. If not, why?
Vimolluck Sanansilp, Siriraj
95. Question 3
A 70-y-o woman underwent Total Knee
Arthroplasty. Parecoxib 40 mg i.v. x 3 d,
etoricoxib 60 mg p.o. x 5 d. are prescribed.
POD 1, drainage = 400 ml blood, BP 120/70
mmHg, PR 96/min, urine output 460 ml/24 h.
POD 2, BP 180/100 mmHg, BUN 20, Cr 2.6,
edema 2+.
What do you think is(are) the problem(s)?
Vimolluck Sanansilp, Siriraj
96. NSAIDs and coxibs
• Non-selective NSAIDs and coxibs reduce pain
safely and effectively in many patients
• Neither are as safe as initially thought
• Both have similar cardiorenal profiles should
be reserved for patients at low risk for cardiac fai
lure or thromboembolic events
• CV safety profile: coxibs are contraindicated in
patients with known atherosclerotic disease and
those at risk of CV thromboembolic events
Vimolluck Sanansilp, Siriraj
97. NSAIDs and coxibs
• Induced perioperative bleeding small added risk
• Surgeons - reluctant to use NSAIDs in some types
of surgery:- endoscopic/microscopic or involving th
e airway, head & neck, plastics, urology and neuros
urgery, where bleeding interfere surgical field / in
crease the level of risk
• Devoid of bleeding risk, coxibs = more safely, pre-
or intra-operatively,
analgesia + reduce strong opioid rescue pain relief
in postoperative period (opioid sparing effect)
Vimolluck Sanansilp, Siriraj
100. • Act by inhibition of COX-2
• May be sufficient for moderate pain,
• An adjunct in a multimodal regimen to reduce
opioid requirements, to improve pain relief and r
educe opioid associated side-effects (:- N/V)
101. • Traditional non-selective NSAIDs associated with
GI complications: dyspepsia & gastric erosions
complications
serious ulcer bleeds and perforations
• COX-2 selective inhibitors (coxibs) was
developed to improve GI safety in long term anti-
inflammatory analgesic therapy
• Concerns over the CV safety of coxibs and
NSAIDs in some postoperative patients
102. • Recommendations and strict guidelines -
implemented for the use of coxibs, primarily for
long-term indications
• Efficacy and safety evaluation for the short-term
use, focusing on the issues relevant to the surgic
al setting:- bleeding risk, and GI safety
103. International multicentre study of 1671 patients,
CV events (including myocardial infarction,
cardiac arrest, stroke and pulmonary embolism
) were significantly more frequent among the p
atients given parecoxib and valdecoxib than tho
se receiving placebo.
Nussmeier NA, Whelton A, Brown MT, Langford RM, Joshi G, Verburg KM.
Safety of parecoxib and valdecoxib in the treatment of pain following
coronary artery bypass surgery. N Engl J Med 2005;352:1081—91.
104. 462 patients, undergoing CABG, reported
CABG
proportionately more serious CVS sequelae in t
he patients who received parecoxib/valdecoxib
postoperatively.
Ott E, Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC et al.
Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valde
coxib in patients undergoing coronary artery bypass surgery.
J Thorac Cardiovasc Surg 2003;125:1481—92.
105. By contrast, in a similarly designed study of
1050 non-cardiac major surgery patients, the gr
oup randomised to receive parecoxib and valde
coxib did not differ from the placebo patients in
any of the four safety categories: cardiovascula
r events, renal events, surgical wound complica
tions, and GI complications.
complications
Nussmeier NA, Whelton A, Brown MT, Langford RM, Joshi G, Singla NK et
al. Safety and efficacy of the cyclooxygenase-2 inhibitors parecoxib and
valdecoxib after noncardiac surgery. Anesthesiology 2006;104(3):518—26.
106. A combined analysis of 6979 patients in 19
cardiac and non-cardiac surgery studies (10 ort
hopaedic surgery, 5 gynaecological surgery, 2
general surgery, 2 CABG), in which parecoxib i
n doses ranging from 20 to 80 mg was administ
ered, the CV thromboembolic event rates were
comparable to placebo [parecoxib 20—80 mg/d
ay 1.0% (39/3821) and placebo 0.9% (27/3158)
].
Schug S. Poster presentation. ESA; 2006.
107. • Choice of selective COX-2 inhibitor for the
acute pain setting is narrow.
• Both parecoxib and oral lumiracoxib are
licensed for the management of post-oper
ative pain.
pain
• Lumiracoxib being limited to orthopaedic
and gynaecological surgery.
108. Usual recommended dose for
Cox-2 inhibitors in postop. pain
Celecoxib Parecoxib Etoricoxib Lumiracoxib
(Celebrex®) (Dynastat®) (Arcoxia®) (Prexige®)
200-400 mg/tab 40 mg/amp 60, 90, 120 100, 400
mg/tab mg/tab
first day: 400 mg 20-40 mg 120 mg Leaflet:
single dose IV/IM q 12 h once daily 400 mg
followed by 200 (short period) once daily not
mg after 12 h if (Can keep exceed 5
needed, diluted med in consecutive
then 200 mg b.i.d. room temp for days
as needed 24 h)
Vimolluck Sanansilp, Siriraj
109. …cancelled the registration of lumiracoxib
in Australia due to concerns that it may
cause liver failure.
…8 reports of serious liver adverse
reactions to the drug, including two deaths
and two liver transplants.
Vimolluck Sanansilp, Siriraj
111. NSAIDs and Asthma
• Study of stable asthmatics given diclofenac
orally (Short et al. 2000)
• Measured PEFR and FEV 1 pre- and post
administration
• 56% had drop in values but max 15%
• None had to increase their medication
• Suggest - acceptable in stable asthmatics
Vimolluck Sanansilp, Siriraj
112. Safety Information for COXIBs
• Contraindications
– Pregnancy and lactating women, Age < 16 y
– Patients with Sulfonamide allergy history
– Experienced angioneurotic edema, urticaria or allergic-
type reactions after taking acetylsalicylic acid or NSAIDs
or other COX-2 selective inhibitors
– Patients who undergone Coronary Artery Bypass Graft
(CABG) surgery
– Patients with IHD or stroke, CHF
– Currently GI bleeding / Active peptic ulceration
– Patients who have cardiovascular risks
– Patients with renal and hepatic impairment
Vimolluck Sanansilp, Siriraj
117. Preemptive analgesia
Noxious stimuli Initiating analgesic regimen
before onset of noxious stimuli
Neurons of dorsal horn
of spinal cord
n t
“windup/central sensitizationv
e
(process)”
p re
Neurons of dorsal
horn of spinal cord
become “sensitized”
Level of pain Limit subsequent pain
Vimolluck Sanansilp, Siriraj
118. Analgesic choices - based on level of pain
in
pa
iv
e
Strong opioid
severe
at
+/- adjuvant
er
op
+/- NSAIDs
st
Po
Weak opioid
moderate +/- adjuvant
+/- NSAIDs
mild Non-opioid/NSAIDs
+/- adjuvant
Vimolluck Sanansilp, Siriraj
119. Multimodal Analgesia
Morphine ₪Improved antinociception
Codeine due to synergistic/
Tramadol
additive effects
Potentiation ₪Reduce dose of each
analgesic
NSAIDs,α2 agonist,
acetaminophen,
regional blocks
₪May reduce severity of
side effects of each drug
Kehlet H, Dahl JB. Anesth Analg. 1993;77:1048–56.
Vimolluck Sanansilp, Siriraj
120. Treatment for common menstrual
cramps (primary dysmenorrhea)
• Lie down at the first sign of pain
• Current recommendations = not only adequate rest and
sleep, but also regular exercise (especially walking)
• Nonpharm. strategies: heating pad, massage, yoga, etc.
For mild cramps: aspirin / acetaminophen, or
acetaminophen + diuretic
For moderate menstrual cramps: main agents are NSAIDs,
NSAIDs
which lower the production of PG and lessen its effect:-
ibuprofen; naproxen sodium; and ketoprofen
http://www.medicinenet.com/menstrual_cramps/article.htm Vimolluck Sanansilp, Siriraj
121. NSAIDs - Route of administration
• Oral
• IV
• IM
• Rectal suppository1
diclofenac (suppo) 50 mg x3 or placebo 1x3 during
the first 24 h postoperatively
reduces the need for opioids significantly with
maintained or improved analgetic effect
reduce negative side-effects of systemic opioids
1
Olofsson. Eur J Obstet Gynecol Reprod Biol 2000;88:143-6.
Vimolluck Sanansilp, Siriraj
122. NSAIDs - Route of administration
• Oral
• IV
• IM
• Rectal suppository
• Peri- & intra-articular1
Improve early analgesia and mobilization
vs contin. Fem. n. block in TKA under
spinal anesthesia
1
Toftdahl et al. Acta Orthopaedica 2007;78:172-9. Vimolluck Sanansilp, Siriraj
123. NSAIDs - Route of administration
Continuous intrawound infusion of diclofenac
• Oral
demonstrates a greater opioid sparing effect and
• IV
better postoperative analgesia than the same dos
• IM administered as an intermittent intravenous bolu
e
s during the first 24 h after surgery.
• Rectal suppository
• Peri- & intra-articular
• Local infiltration – single/continuous1
Lavand’homme et al. Anesthesiology 2007; 106:1220–5.
1
Vimolluck Sanansilp, Siriraj
124. NSAIDs - Route of administration
• Oral
• IV
Intrathecal adm. of COX-1, but not COX-2,
• specific inhibitors given on postoperative day 1 ha
IM
s analgesic effects in an incisional model of posto
• Rectal suppository
perative pain in rat.
• Peri- & intra-articular
• Local infiltration – single/continuous
• Intrathecal (COX-1)1
Zhu et al. Anesth Analg 2005;100:1390 –3.
1
Vimolluck Sanansilp, Siriraj
126. Oral Analgesics for
Acute Nonspecific Pain
• The safest NSAID is ibuprofen in doses of 400 mg
• Higher doses may offer greater analgesia but with
more adverse effects
• Other NSAIDs fail to demonstrate consistently
greater efficacy or safety than ibuprofen
• Coxibs provide equivalent efficacy to traditional
NSAIDs but lack a demonstrable safety advantage
for the treatment of acute pain
Vimolluck Sanansilp, Siriraj
127. Oral Analgesics for
Acute Nonspecific Pain
Direct comparative studies between NSAIDs
and acetaminophen (1,000-mg dose) :
more effective than acetaminophen in some
situations (e.g., dental and menstrual pain)
pain
equivalent analgesia in others (e.g.,
orthopedic surgery and tension headache).1,2
headache
1. Scott D, Smith C, Lohmander S, Chard J. Osteoarthritis. Clin Evid 2003;(9):1301-26.
2. Hyllested M, Jones S, Pedersen JL, Kehlet H. Comparative effect of paracetamol,
NSAIDs or their combination in postoperative pain management: a qualitative review.
Br J Anaesth 2002;88:199-214. Vimolluck Sanansilp, Siriraj
Vimolluck Sanansilp, Siriraj
128. Oral Analgesics for
Acute Nonspecific Pain
Traditional NSAIDs
EFFICACY
• Dysmenorrhea1 :
ibuprofen=naproxen > acetaminophen/aspirin
• Postpartum perineal pain2 :
ibuprofen > acetaminophen+codeine+caffeine
1. Zhang WY, Li Wan Po A. Efficacy of minor analgesics in primary dysmenorrhoea: a
systematic review. Br J Obstet Gynaecol 1998;105:780-9.
2. Peter EA, Janssen PA, Grange CS, Douglas MJ. Ibuprofen versus acetaminophen
with codeine for the relief of perineal pain after childbirth: a randomized controlled trial.
CMAJ 2001;165:1203-9. Vimolluck Sanansilp, Siriraj
129. Oral Analgesics for
Acute Nonspecific Pain
Traditional NSAIDs
SAFETY AND ADVERSE EFFECTS
• Ibuprofen excellent GI safety profile, not
different from placebo (dose 800-1,200 mg/d)1
• Higher doses of naproxen and ibuprofen
increased GI side effects similar to other NSAIDs2
1.Kellstein DE, Waksman JA, Furey SA, Binstok G, Cooper SA. The safety profile
of nonprescription ibuprofen in multiple-dose use: a metaanalysis. J Clin
Pharmacol 1999;39:520-32.
2.Bansal V, Dex T, Proskin H, Garreffa S. A look at the safety profile of over-the-
counter naproxen sodium: a meta-analysis. J Clin Pharmacol 2001;41:127-38.
Vimolluck Sanansilp, Siriraj
130. Oral Analgesics for
Acute Nonspecific Pain
COX-2 Selective NSAIDs
EFFICACY
• Theoretically, provide analgesia = traditional
NSAIDs without many of the side effects
• Meta-analysis of celecoxib, showed fair to good
efficacy for postoperative pain with an NNT of 4.5
(95% CI, 3.3 to 7.2) compared with placebo1
1. Barden J, Edwards JE, McQuay HJ, Moore RA. Single dose oral celecoxib for
postoperative pain. Cochrane Database Syst Rev 2004;(3):CD004233.
Vimolluck Sanansilp, Siriraj
131. Oral Analgesics for
Acute Nonspecific Pain
COX-2 Selective NSAIDs
SAFETY AND ADVERSE EFFECTS
• Greater numbers of thrombotic CV events
• May impair renal function and have no benefit
over traditional NSAIDs in this area
• In elderly patients with hypertension - may be
associated with edema and ↑ BP1
1. Whelton A, White WB, Bello AE, Puma JA, Fort JG, for the SUCCESS-VII Investigators.
Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or = 65 years of
age with systemic hypertension and osteoarthritis. Am J Cardiol 2002;90:959-63.
Vimolluck Sanansilp, Siriraj
132. Oral NSAIDs in the Treatment of Acute Pain
Medication Efficacy* Max dosage per day
Recommended
Ibuprofen (400 mg initially) Good 2,400 mg
Naproxen (Aleve) Good 1,376 mg
Alternative choices
Diclofenac (Voltaren) Good 150 mg
Piroxicam (Feldene) Good 20 mg
Ketorolac (Toradol) Good 40 mg
Meclofenamate (Meclomen) Good 400 mg
Meloxicam (Mobic) Good 7.5 mg
Nabumetone (Relafen) Good 2,000 mg
COX-2 inhibitors Fair to Celecoxib (Celebrex),
good 400 mg
* Poor: number needed to treat (NNT) > 6, Fair: NNT = 3 – 6, Good: NNT = <3
Sachs. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71:913-8
Vimolluck Sanansilp, Siriraj
133. Analgesic Side effects Dosage Comment
class
NSAIDs GI, 400 mg ibuprofen No
platelet safest inexpensive evidence
function choice; that any
inhibition, decreases some one NSAID
renal adverse GI events is more
dysfunction with misoprostol 800 effective
mg, H2 blockers, than
and PPI another
Selective Renal Once or twice per Expensive
COX-2 dysfunction; day, only advantage
inhibitors hypertension; over most traditional
thrombotic NSAIDs for acute
events pain
Sachs. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71:913-8
Vimolluck Sanansilp, Siriraj
134. Recommendation Label
Acetaminophen in doses up to 1,000 mg is the initial choice for B
most mild to moderate acute pain.
The first-line NSAID for safety, efficacy, and cost is ibuprofen in A
doses of 400 mg.
For moderate to severe pain, consider narcotic acetaminophen B
or narcotic ibuprofen combination.
Tramadol, propoxyphene, and codeine provide inferior A
analgesia to other recommended agents.
COX-2 inhibitors provide analgesia equal to NSAIDs at greater B
cost and may be reserved for patients who have a history of GI
bleeding and have failed treatment with acetaminophen.
A = consistent, good-quality patient-oriented evidence;
B = inconsistent or limited-quality patient-oriented evidence;
C = consensus, disease-oriented evidence, usual practice, opinion, or
case series.
Sachs. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71:913-8
Vimolluck Sanansilp, Siriraj
135. Acute and Postoperative Pain
A. Managing pain in the older patient:
• NSAIDs and COX-2 inhibitors in older
people requires extreme caution
• Acetaminophen is the preferred non-opioid
analgesic
Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.
Vimolluck Sanansilp, Siriraj
136. Acute and Postoperative Pain
B. Managing acute pain during pregnancy:
• Use of NSAIDs during pregnancy does not
seem to increase the risk of adverse birth
outcome, but ↑risk of miscarriage.
miscarriage
Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.
Vimolluck Sanansilp, Siriraj
137. Acute and Postoperative Pain
C. Managing pain in the puerperium
(perineal pain, breast and nipple pain):
1.Acetaminophen and rectal NSAIDs – effective in
perineal pain after childbirth.
2.Acetaminophen and NSAIDs – equally, but only
modestly, effective in treating uterine pain.
pain
3.Acetaminophen and several NSAIDs, in
particular ibuprofen, seem safe non-opioids in
lactation.
lactation
Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.
Vimolluck Sanansilp, Siriraj
138. Acute and Postoperative Pain
D. Abdominal pain of nonsurgical origin:-
dysmenorrhea, renal and biliary colic,
and irritable bowel syndrome:
1.Analgesics do not interfere with the diagnostic
process in acute abdominal pain.
2.NSAIDs – superior to opioids in the treatment of
renal colic.
3.Onset of analgesia is fastest with IV NSAIDs in
renal colic.
colic
4.NSAIDs + vitamin B1 – effective in the treatment
of primary dysmenorrhea.
Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.
Vimolluck Sanansilp, Siriraj
139. Acute and Postoperative Pain
E. Pain associated with acute orofacial
conditions:- sinusitis and oral ulceration:
1.NSAIDs and coxibs provide better analgesia with
fewer adverse effects than acetaminophen,
acetaminophen/opioid combinations,
acetaminophen/tramadol combinations,
tramadol, or weaker opioids after dental
extraction.
2.Aspirin and NSAIDs increase the likelihood of
reoperation for post-tonsillectomy bleeding.
bleeding
Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.
Vimolluck Sanansilp, Siriraj
140. Acute and Postoperative Pain
F. Pain management of acute headache
including migraine, cluster headache and post-
dural puncture headache (PDPH):
1.Aspirin-metoclopramide is effective in Rx of
migraine with mild symptoms.
2.Addition of caffeine to aspirin or acetaminophen
Add
improves analgesia in acute tension-type
headache.
3.Ibuprofen + acetaminophen are effective in the
treatment of migraine with mild symptoms.
4.Simple analgesics:- aspirin, acetaminophen, and
NSAIDs, either alone or in combination, are
combination
effective in the treatment of episodic tension-type
headache.
Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.
Vimolluck Sanansilp, Siriraj
141. Acute and Postoperative Pain
G. Acute musculoskeletal pain:
1.Understand that topical + oral NSAIDs improve
acute shoulder pain.
2.Treat pain with acetaminophen; if it is ineffective,
acetaminophen
NSAIDs may be used.
Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.
Vimolluck Sanansilp, Siriraj
142. Acute and Postoperative Pain
H. For nonselective NSAIDs and
acetaminophen, know:
1. Different routes & dosage (:- oral, IV, rectal).
2. How to modify doses or withhold NSAIDs in presence
of comorbidity (CHF, renal disease, ulcer disease,
coagulopathy).
3. How to select particular NSAIDs to lessen risk of
specific side effects (:- nonacetylated compounds for
platelet sparing; nabumetone to lessen gastrointestinal
blood loss).
4. There is a “plateau effect” = dosage increases beyond
effect
the recommended range increase the incidence of side
effects but do not improve analgesia.
Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.
Vimolluck Sanansilp, Siriraj
143. Acute and Postoperative Pain
H. For nonselective NSAIDs and
acetaminophen, know:
5. Efficacy + utility of NSAIDs when administered
via intra-articular, topical, local infiltration routes
6. Pharmacokinetic profiles of the NSAIDs
7. Controversies concerning NSAIDs and
orthopedic surgery
8. Efficacy of NSAIDs for acute pain: aspirin,
ibuprofen, diclofenac, piroxicam, naproxen, and
ketorolac
Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.
Vimolluck Sanansilp, Siriraj
144. Acute and Postoperative Pain
I. For the COX-2 inhibitors, know:
1. Structural differences between the agents and
conventional NSAIDs.
2. Selectivity for the COX-2 enzyme between
different agents.
3. Comparisons between COX-2 inhibitors and
nonselective NSAIDs in terms of analgesic
activity and side-effect profile.
4. The pharmaco-economic impact of COX-2
inhibitors.
5. Opioid-sparing effects.
effects
6. Controversies concerning COX-2 inhibitors
Charlton J E, editor. Core Curriculum for Professional Education in Pain. IASP Press, Seattle 2005.
Vimolluck Sanansilp, Siriraj
