START MODULE
Topics at a glance
• Introduction on pain
• Management of pain
• The usage of NSAIDs in pain management
• Summary
2
Introduction on pain
Definition and classification
• Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant
sensory and emotional experience associated with actual or potential tissue damage, or described
in terms of such damage”.1
• Pain can be classified based on the following factors2:
Acute pain
Acute on chronic
pain
Noncancer
Mechanism Nociceptive
Neuropathic
3
Introduction on pain
Differences between acute and chronic pain
• It is important to differentiate between the various types of pain as each has its own way of being
managed. The table shows the characteristics of acute versus chronic pain.2
Acute Chronic
Onset Sudden Insidious
Duration Less than 3 months More than 3 months
A warning signal of actual or potential Not a warning signal of
Function
tissue damage damage
Severity Correlates with the extent of damage Out of proportion of damage
Central nervous system • CNS intact • CNS may be dysfunctional
(CNS) involvement • Acute pain is a symptom • Chronic pain is a disease
• Headache
• Surgery
• Low back pain
Common causes • Fracture
• Arthritis pain
• Myocardial infarction
• Cancer pain
4
Management of pain
Assessing and managing acute pain
• Tools that can be used to assess pain2:
The Ministry of Health (MOH) pain scale for children older than 6 years of age and adults who
are not cognitively impaired.
Wong-Baker Faces Pain Rating Scale or Face, Legs, Activity, Cry, Consolability
(FLACC) pain scale for children younger than 6 years of age and adults who are cognitively impaired.
• Flow chart for acute pain management in adults2:
Pain
No No Record
Check Analgesia Order score <4
notes ordered analgesics
Reassess
Inform nurse Pain
Acute Under after
to serve score >4–6
pain APS 30 minutes
medication
to 1 hour
Call
Informed by Greet Pain Review
specialist/ Pain
nurse patient assessment Yes refer APS Yes analgesics
score >6
Chronic Manage as
pain chronic pain
5
Management of pain
• Management of chronic noncancer pain in adults2:
Patient complains
Regular/known of the same Refer to Pain
patient in the symptoms and Service
emergency pain site
department, Medical – usually
surgical or done by a pain 1. Emphasize self-
orthopaedic ward specialist management and
Patient with
confirmed chronic long-term benefits.
pain
Patient complains 2. Form a management
of pain in a Physical – usually plan together with the
different site Investigation done by a patient that includes the
or has different physiotherapist following:
New patient
symptoms • Pharmacotherapy
• Nerve blocks and
other interventions
Psychological • Active physiotherapy
– usually done • Psychological therapy
by a clinical
psychologist or
psychiatrist
• Principles for analgesic use in the ward2:
Prescribe oral analgesics (eg, tramadol 50–100 mg QID + paracetamol 1 g QID).
Give antineuropathic agents if neuropathic pain is suspected.
Avoid giving nonsteroidal anti-inflammatory drugs (NSAIDs) for more than 1–2 weeks due to risk of renal failure and
cardiovascular problems.
Avoid injectables (eg, pethidine) as they have high addictive potential.
QID=four times daily
6
Management of pain
Analgesic ladder for the management of pain2,3:
Uncontrolled
Refer to pain specialist for:
• PCA; or
• Chronic pain • Epidural; or
• Nonmalignant pain Severe (pain score >6) • Other forms of analgesia
Regular:
• Cancer pain • IV/SC morphine 5–10 mg/4 hr;
or
• Aqueous morphine 5–10 mg/
4 hr; or
Moderate (pain score 4–6) • IR oxycodone 5–10 mg/4–6 hr; ±
Regular: • PCM 1 g QID; ±
• Opioid tramadol 50–100 mg • NSAID
Mild (pain score <4)
TDS or QID; ± PRN:
Regular:
• No medication; or • PCM 1 g QID; ± • IV/SC morphine 5–10 mg;
• NSAID or
• PCM 1 g QID
• Aqueous morphine 5–10 mg/
PRN: PRN:
4 hr; or
• PCM; and/or • Additional tramadol 50–100 mg
• IR oxycodone 5–10 mg
• NSAID (maximum dose 400 mg/day)
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The usage of NSAIDs in pain management
NSAIDs are effective for pain Analgesic (mg) NNT 95% CI
management
Ibuprofen 800 1.6 1.3–2.2
The most effective NSAID would have
Ketorolac 20 1.8 1.4–2.5
a low number needed to treat (NNT) of
approximately two, which means that for
†
Rofecoxib 50 1.9 1.8–2.1
every two patients who receive the drug, Diclofenac 100 1.9 1.6–2.2
one patient will get at least 50% pain Piroxicam 40 1.9 1.2–4.3
relief due to the treatment.4
*Lumiracoxib 400 2.1 1.7–2.5
• NSAIDs are commonly used for pain
Diclofenac 50 2.3 2.0–2.7
management.4
• From the table, it is clear that NSAIDs Naproxen 440 2.3 2.0–2.9
are effective analgesics. However, Oxycodone IR 15 2.3 1.5–4.9
the efficacy varies between different Ibuprofen 600 2.4 2.0–4.2
drugs in the same class and is also
Ibuprofen 400 2.4 2.3–2.6
dose-dependent.4
Aspirin 1200 2.4 1.9–3.2
†
Off market
*Not available in Malaysia
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The usage of NSAIDs in pain management
Different NSAIDs have different selectivity *Lumiracoxib
for COX-1 and COX-2 enzymes †
Rofecoxib
Etoricoxib
>50-fold COX-2 selective
The graph shows the selectivity of various
NSAIDs for cyclooxygenase (COX) enzymes. *Etodolac
Traditional NSAIDs non-selectively inhibit both Meloxicam
COX-1 and COX-2, whereas the newer COX-2 Celecoxib 5–50-fold COX-2 selective
inhibitors are more COX-2 selective.5 Diclofenac
†
Sulindac
• NSAIDs suppress the COX function of
prostaglandin H synthase and formation of *Fenoprofen <50-fold COX-2 selective
prostaglandin E 2 and prostaglandin I 2. This Ibuprofen
brings about relief from pain (analgesia) and Naproxen
Aspirin
reduced inflammation (anti-inflammatory). 5
Indomethacin
• The analgesic and anti-inflammatory effects of Ketoprofen
NSAIDs are mediated by inhibition of COX-2, Flurbiprofen
and their gastrointestinal (GI) side effects Ketorolac
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The usage of NSAIDs in pain management
Cardiovascular risk The relative risk of acute AMI in patients using
• Higher risk of acute myocardial infarction different NSAIDs.6
(AMI) is associated with6:
NSAIDs Relative risk (RR) 95%CI
Higher doses of commonly used NSAIDs.
A history of coronary heart disease. Etoricoxib 1.97 1.35–2.89
• The risk of AMIs varies between different *Etodolac 1.55 1.16–2.06
drugs in the same class.6
Indomethacin 1.40 1.21–1.62
• For diclofenac and rofecoxib, the risk of
AMI was found to be increased at both Diclofenac 1.38 1.26–1.52
low and high doses.6 †
Rofecoxib 1.34 1.22–1.48
• Low and high doses of naproxen are not
Meloxicam 1.25 1.04–1.49
associated with an increase in AMI risk.6
Ibuprofen 1.14 0.98–1.31
Celecoxib 1.12 1.00–1.24
Naproxen 1.06 0.94–1.20
†
Off market
*Not available in Malaysia
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The usage of NSAIDs in pain management
Cardiovascular (CV) and upper GI complication risks
The relative risks of major vascular events and upper GI complications in patients using different NSAIDs
compared with placebo are shown below.7
A Coxibs C Ibuprofen (800 mg 3 times a day)
Absolute annual excess
10 10 10 10
7 9
6
5 5 4
5 5
2 2 2 3 2
0 0 0 0
D Naproxen (500 mg twice a day)
B Diclofenac (75 mg twice a day) 20 20
Absolute annual excess
• All NSAIDs increase the risks of cardiac and GI adverse events but each drug has a different risk level7:
Naproxen – least cardiac adverse effect, worst adverse GI effect.
Diclofenac – worst cardiac adverse effect, least adverse GI effect.
Vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs.
SE=standard error
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The usage of NSAIDs in pain management
Renal risk
• The risk of acute renal failure exists even when the drug is used for a relatively short period of time.8
• Generally, the use of NSAIDs is associated with a three-fold increase in the risk of acute renal failure compared
with non-NSAID use (95% CI, 1.8–5.8).9
• Additionally, the risk increases with long-term use and higher doses.8,9
The risk of renal failure due to various NSAIDs8 The risk of acute renal failure increases
9
8.05
with the duration of NSAID use8
8
7 Days RR
Relative risk*
6
5 1–30 2.65
4
3.12 2.98
3 2.64 31–365 2.42
1.89
2
1 366–730 4.33
0
Meloxicam Diclofenac Naproxen Ibuprofen Other NSAIDs†
>730 3.71
*The relative risk (RR) has been adjusted for age, sex, body mass index and various
comorbidities.
†
Includes aceclofenac, acemetacin, azapropazone, etodolac, fenoprofen, flurbiprofen,
indomethacin, ketoprofen, mefenamic acid, nabumetone, piroxicam, tenoxicam,
tiaprofenic acid and sulindac.
12
The usage of NSAIDs in pain management
Managing the risk of adverse events
• Choose a COX-2 inhibitor over a traditional NSAID if the patient has upper GI disease or is on antiplatelet therapy.10
• As CV risk is increased in these particular groups of patients, avoid using NSAIDs or use minimal dose in those
with congestive cardiac failure, hypertension, prior MI, CV disease, atheroma disease, rheumatoid arthritis,
chronic renal disease or chronic obstructive airways disease and in elderly patients.11
Moderate/high
Celecoxib + H2 antagonist
GI risk
Yes
Celecoxib
Low GI risk
CV Risk Naproxen
Any COX-2 inhibitors
Moderate/high
GI risk
Any traditional NSAIDs + PPIs
No Any COX-2 (avoid naproxen, ibuprofen)
inhibitors
Low GI risk
Any traditional
NSAIDs
An algorithm recommended by the CPD reviewer, adapted from Manolis A.10 PPIs=proton pump inhibitors
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Summary
• It is vital to differentiate between different types of pain as each has its own unique
management plan.
• Analgesia is a class effect of NSAIDs. However, the analgesic efficacy differs between
various drugs in the class.
• NSAIDs also vary in their risk of adverse effects. For instance:
Naproxen has a lower risk of adverse cardiac events but higher risk of adverse GI events
compared with diclofenac.
Celecoxib has lower adverse cardiac effect compared with enterocoxib.
• When choosing an NSAID for pain management, it is important to know both the patient
and drugs well for an accurate risk stratification. Remember to:
Take into account the patient’s baseline renal, CV and GI risks.
Start with the lowest dose.
Prescribe for short duration only.
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Summary
• Consider paracetamol plus opiate12,13
Combining the two medications extends the duration of analgesia.
At a higher dose (1,000 mg paracetamol plus 60 mg codeine), more patients experience
adequate pain relief.
Oxycodone is two to three times stronger than codeine.
At the dose of 650 mg paracetamol plus 10 mg oxycodone, the analgesic efficacy is
similar to commonly used NSAIDs but lasts longer.
• Consider an NSAID plus paracetamol14
The combination of ibuprofen plus paracetamol provides better analgesia than
either drug alone.
The combination is also associated with lesser side effects.
• Consider an NSAID plus opiate15
The combination of ibuprofen 400 mg plus codeine 25.6 to 60 mg has better analgesic
efficacy than either drug alone.
15
References
1. International Association for the Study of Pain (IASP) Taxonomy. Available at: http://www.iasp-pain.org/Taxonomy. Accessed on 19 Oct 2015. 2. MOH Malaysia. Pain as
the 5th Vital Sign Guidelines: 2nd Edition. Available at: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&uact=8&ved=0CB0QFjAAahUKEwjN
h9_L-c3IAhWDPo4KHYbyA5M&url=http%3A%2F%2Fwww.moh.gov.my%2Fpenerbitan%2FPain%2520As%2520The%2520Fifth%2520Vital%2520Sign%2520Guidelines.
pdf&usg=AFQjCNGE_nvMmezA9u0DNhJbkhWXJhcAFg. Accessed on 19 Oct 2015. 3. Vargas-Schaffer G. Can Fam Physician 2010;56:514–517. 4. Ong CK. Clin Med Res
2007;5:19–34. 5. Herndon CM. Pharmacotherapy 2008;28:788–805. 6. Varas-Lorenzo C. Pharmacoepidemiol Drug Saf 2013;22:559–570. 7. Coxib and traditional NSAID
Trialists' (CNT) Collaboration. Lancet 2013;382:769–779. 8. Fine M. Am J Manag Care 2013;19:s267–s272. 9. Huerta C. Am J Kidney Dis 2005;45:531–539. 10. Manolis
A. Hospital Chronicles 2015;10:63–70. 11. Solomon DH. Arthritis Rheum 2008;59:1097–1104. 12. Toms L. Cochrane Database Syst Rev 2009;1:CD001547. 13. Gaskell H.
Cochrane Database Syst Rev 2009;3:CD002763. 14. Derry CJ. Cochrane Database Syst Rev 2013;6:CD010210. 15. Derry S. Cochrane Database Syst Rev 2015;3:CD010107.
Editorial development by MIMS Medica. The opinions expressed in this publication are not necessarily those of the reviewer, editor, publisher or sponsor. Any liability or obligation for loss
or damage howsoever arising is hereby disclaimed. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all
information and data before treating patients or employing any therapies described in this educational activity. ©2017 MIMS Medica. All rights reserved. No part of this publication may be
reproduced by any process in any language without the written permission of the publisher.
Enquiries: MIMS Medica Sdn Bhd (891450-U), 2nd Floor, West Wing, Quattro West, No.4, Lorong Persiaran Barat, 46200 Petaling Jaya, Selangor, Malaysia.
Tel: (603) 7623 8000 Fax: (603) 7623 8188 E-mail: enquiry.my@mims.com Web site: www.mims.com MY-PFI-347
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This course is sponsored as a service to the medical profession by Pfizer (Malaysia) Sdn. Bhd. This
educational programme is not intended in any way to influence any healthcare professional’s (HCP’s)
judgement and attitude towards the treatment of his/her patients or prescribing decision.
Neither is it intended to influence the purchase of Pfizer’s drugs by any HCPs.
Day 7 Day 14
73.5 72.8
Change from
baseline ±2.63
28.6 32.0
(LS mean)
-18.4 ±3.05
±2.75 ±2.70
Baseline Day 3 ‡¶ -25.0
‡
-27.7 -26.4
‡
±3.06
-42.8* -39.4 §
‡
-35.0
Celecoxib 400 mg loading dose + 200 mg BID Celecoxib 400 mg loading dose + 200 mg at 8 hours (Day 1) + 200 mg BID (n=98)
ns-NSAIDs† Naproxen 500 mg BID (n=100)
Placebo (n=108)
* Difference between the two groups was 3.39 mm (95% CI: -0.76, 7.55). p<0.05 vs placebo
‡
† ns-NSAIDs included diclofenac 100–200 mg, nimesulide 200 mg, ibuprofen 800–1,600 mg,
¶
p=ns vs celecoxib
§
A statistically significant difference was not observed for naproxen vs placebo at Day 14.
meloxicam 15 mg, piroxicam 20–40 mg, ketoprofen 100–200 mg, naproxen 1,100 mg,
cholestyramine diclofenac 150 mg, or tiaprofenic acid 600 mg.
LS=least squares; VAS=visual analogue scale; ns-NSAIDs=nonselective nonsteroidal anti-inflammatory drugs
References: 1. Cardenas-Estrada E, et al. J Int Med Res 2009;37:1937–1951. 2. Petri M, et al. J Rheumatol 2004;31:1614–1620.
anaemia of defined GI origin, acute GI haemorrhage of unknown origin including presumed small-bowel haemorrhage, and clinically significant anaemia of presumed occult GI origin including possible
small-bowel blood loss.1
OA=osteoarthritis; RA=rheumatoid arthritis
References: 1. Chan FK, et al. Lancet 2010;376(9736):173–179. 2. Cryer B, et al. Am J Gastroenterol 2013;108(3):392–400. 3. Bell AD, et al. Can J Cardiol 2011;27:S1–S59. 4. Wilner KD, et al. J Clin Pharmacol
2002;49(9):1027–1030. 5. Shi W, et al. Clin Drug Investig 2004;24:89–101. 6. Soni P, et al. Curr Res Med Opin 2009;25(8):1841–1851. 7. Whelton A, et al. Kidney Int 2006;70(8):1495–1502.
6
Multi-centre, double-blind, randomized, 6-month trial in patients with OA or RA at increased
GI risk. Patients tested negative for Helicobacter pylori and were aged 60+ years or 18+ years
5 with previous GD ulceration. Patients were randomized 1:1 to receive celecoxib 200 mg BID or
diclofenac slow release 75 mg BID plus omeprazole 20 mg QD. Patients and investigators were
4 masked to treatment allocation. Primary endpoint was a composite of clinically significant upper
or lower GI events adjudicated by an independent committee.1
3
Over 87% of the
2 CONDOR study
1 population was
60 years or older.1
0
0 30 60 90 120 150 180 210
Time (months)
2.0% 2.1%
el /day
el /day
el /day
da c
da n
)
d n
se
da
do b
m xib
m ib
m ib
m ib
eb
g/ a
g/ e
y
1, Na ay
y
g/ e
i
m n
m x
n x
0 x
0 x
0 x
m f
g/
reviewed and adapted according to country-
0 ro
ac
0 ro
0 fe
o
00 co
20 co
40 co
80 co
Celecoxib 400 mg twice daily (n=3,987)
y
ec
40 up
15 lo
00 p
Pl
e
specific regulation and b) referenced with and in
(a
c
el
el
Ibuprofen 800 mg three times daily (n=1,985)
2, b
<2
0– i
10 D
C
I
Diclofenac 75 mg twice daily (n=1,996) accordance to the local celecoxib prescribing
information (PI). 3. Soni P, et al. Curr Res Med
*Hepatobiliary adverse events included all hepatic- or biliary-related categories according to the World Health Organization Opin 2009;25(8):1841–1851.
dictionary of adverse reactions.
Celecoxib incidence of increased serum creatinine (>0.5 mg/dL) †
p=0.21 vs celecoxib (any dose)
p=0.0001 vs celecoxib (any dose)
or serum creatinine >1.5 mg/dL was comparable to ns-NSAIDs1
‡
§
p=0.006 vs celecoxib (any dose)
¶
p=0.03 vs celecoxib (any dose)
23