RATIONAL USE OF

NSAIDs IN
MANAGEMENT OF PAIN

I Nyoman Suarjana
Division of Rheumatology Department of Internal Medicine
Faculty of Medicine University of Lambung Mangkurat
Ulin General Hospital Banjarmasin
Definition

Pain is defined by IASP as ‘an

unpleasant sensory and
emotional experience associated
with actual or potential tissue
damage, or described in terms of
such damage
 Classifications of Pain
Nociceptive

Pathophysiology Mixed

Neuropathic

Acute

Duration
Chronic
Nociceptive pain

Nociceptive pain is the term for pain that is detected
by specialized sensory nerves called nociceptors

These nerves are located throughout the soft tissues,

such as muscles and skin, as well as the internal
organs

There are two types of nociceptive pain :

= Somatic pain (joints, bones, muscles & other soft
tissues)
= Visceral pain (internal organs)
 Presentation Across Pain States Varies

Nociceptive Pain Neuropathic Pain

Mixed Pain Pain initiated or caused by a
Pain caused by injury to
Pain with primary lesion or dysfunction
body tissues
neuropathic and in the nervous system
(musculoskeletal,
nociceptive (either peripheral or
cutaneous or visceral)2
components central nervous system)1

Examples Examples
Examples
Peripheral
• Low back pain with • Postherpetic neuralgia
• Pain due to inflammation radiculopathy
• Limb pain after a fracture • Trigeminal neuralgia
• Cervical • Diabetic peripheral neuropathy
• Joint pain in osteoarthritis radiculopathy
• Postoperative visceral pain • Postsurgical neuropathy
• Cancer pain • Posttraumatic neuropathy
• Carpal tunnel Central
Common descriptors2 syndrome
• Aching • Poststroke pain
• Sharp Common descriptors2
• Throbbing • Burning
• Tingling
• Hypersensitivity to touch or cold
1. International Association for the Study of Pain. IASP Pain Terminology.
2. Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57
 Perception
The Pain Pathway
Pain

Medulation
Descending
modulation Dorsal Horn
Ascending Dorsal root Transmission
input ganglion

Transduction
Spinothalamic Peripheral
tract nerve

Trauma
Peripheral
nociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
 Analgesia and the pain pathway

Opioids
Alpha-2-agonist
Centrally acting analgesics
Ascending NSAIDs
input Descending
modulation Local anesthetics
Opioids
Alpha-2-agonist
NSAIDs
Dorsal root
ganglion
Spinothalamic
tract Local anesthetics
Peripheral
nociceptors
Local anesthetics
NSAIDs

Modified from Gottschalk A, Smith DS. Am Fam Physician 2001;63:1979-1984, 1986-1986

 Goals in Managing Pain

Reduce pain

Control acute pain

Protect the patient from further injury
while encouraging progressive
exercise
Management of Pain

A. Pharmacological

B. Nonpharmacological
PHARMACOLOGICAL THERAPIES
Opioid analgesics Nonopioid analgesics Adjuvant drugs
• Codeine Nonselective NSAIDs Antidepressants
• Aspirin • Doxepin
• Oxycodone
• Ibuprofen • Amitriptyline
• Morphine • Naproxen • Imipramine
• Hydromorphone • Fenoprofen • Nortriptyline
• Levorphanol • Indomethacin • Desipramine
• Methadone • Ketorolac (parenteral) • Venlafaxine
COX-2–selective inhibitors Anticonvulsants
• Meperidine
• Celecoxib • Phenytoin
• Butorphanol • Etoricoxib • Carbamazepine
• Fentanyl Preferentially COX-2 • Gabapentin
• Tramadol • Na. diclofenac
Others Local analgsic
• Acetaminophen drugs
• Clonidine
• Local anaesthetics
• Ketamine
• Topical agents
Prostaglandin Systhesis
Arachidonic Acid & COX Inhibitions

Arachidonic Acid

Cyclooxygenase (COX)

COX-1 COX-2
COX-2
selective

X Non-specific
NSAIDs X Inhibitor
(coxibs)

Body Homeostasis Inflammation

• Gastric integrity Pain
• Renal function
• Platelet function
Fitzgerald GA et al. N Engl J Med 2001;345:433-42
 Classification of NSAIDs

NSAIDs

Selective COX-2
Non-selective COX Preferential COX-2
Inhibitors
Inhibitors Inhibitors
(Coxibs)

Aspirin,
Ibuprofen Diclofenac Celecoxib
Naproxen Aceclofenac Etoricoxib
Indomethacin Meloxicam Lumiracoxib
Peroxicam Nimesulide Parecoxib
Mefenemic acid
 COX inhibitors

Non-selective
COX-1/COX-2
NSAIDs Inhibitors
(peroxicam)

COX-2 COX-3
Inhibitors inhibitors
• Selective (coxibs) •Antipyretic
• Preferential analgesics
(Na. diclofenac) (paracetamol)
 COX-1 vs COX-2
COX-1 COX-2
• Constitutive • Inducible (in most tissues)
• Present in most tissues • Induced mainly at sites of
• Synthesizes PGs that regulate inflammation by cytokines
physiologic processes • Synthesizes PGs that mediate
• Especially important in inflammation, pain, and fever
– gastric mucosa • Constitutive expression
– kidneys primarily in
– platelets – brain
– vascular endothelium – kidneys

Needleman P et al. J Rheumatol. 1997;24(suppl 49):6-8.

Dubois RN et al. FASEB J. 1998;12:1063-73.
Role of COX-1 & COX-2
NSAIDs for Acute & Post Operative Pain

Less GI side effects

More GI side effects

PIROXICAM Diclofenac Coxibs

Ketorolac Ketoprofen

preferentially non- preferentially

COX-1 COX-1 COX-2 COX-2
selective
selective selective selective selective
COX
inhibitor inhibitor inhibitor inhibitor
inhibitor

anti-inflammatory
analgesic
Rational Use of Drugs –5 R’s

The Right drug at

The Right dose by

The Right route at

The Right time for

The Right patient
 Guidelines for Prevention of
NSAID-Related Ulcer Complications
(ACG Practice Guidelines 2009)

CV risk Gastrointestinal risk

Low Moderate High

Low CV risk NSAID alone NSAID + Alternative

(the least ulcerogenic PPI/Misoprostol therapy if possible
NSAID at the lowest or COX-2 inhibitor
effective dose) + PPI/Misoprostol

High CV risk Naproxen + Naproxen + Avoid NSAIDs or

(low dose PPI/Misoprostol PPI/Misoprostol COX-2 inhibitors.
aspirine Use Alternative
required) therapy

Lanza FL et al. Am J Gastroenterol 2009;104:728-738

Contraindications of NSAIDs
 Active bleeding or a history of
gastrointestinal bleeding
 Gastroduodenal ulcer
 Cerebrovascular bleeding
 Bronchial asthma
 History of hypersensitivity to NSAIDs
 Severe dysfunction of liver, kidney or
heart
 Gestation
 Breast-feeding
 Severe hypertension
 Adverse Side Effects of NSAIDs
GI : Dyspepsia, ulcers & ulcer complications,
bleeding, exacerbates colitis

Renal : Salt-water retention, hypertension, edema,

hyperkalemia, ARF, papillary necrosis,
type IV RTA

Hepatic : Elevates AST & ALT, Reye’s symdrome

Hematologic : Cytopenia, bleeding

 Adverse Side Effects of NSAIDs

Nervous : Dizziness, confusion, drowsiness,

seizure, aseptic meningitis, tinnitus
(aspirin)

CVS : HT, ↑CHF, thrombosis

Skeletal : Reduced fracture healing

Pulmonary: Asthma/allergic
GI Side Effects of NSAIDs
 NSAIDs and GI Toxicity

Dyspepsia

Abdominal pain 10 % to 60 %

Flatulence

Gastric ulcer

Bleeding 1.5 % to 4 %

Perforation

Greater risk with non-selective NSAIDs as compared to

Selective COX-2 inhibitors (Coxibs)
Risk Factors for NSAID-induced ulcer diseases

1. Advanced age (> 65 years)

2. Prior ulcer disease or ulcer complications
3. High dose, multiple NSAIDs (including low
dose ASA)
4. Concomitant steroid & anticoagulant
5. Serious systemic diseases

Possible:
Smoking, alcohol consumption and H. Pylori
infection
 Risk of serious GI complication

1.Old age group (>70 yr-old) : OR = 5.6

2.Previous PU :
- uncomplicated ulcer : OR = 6.1
- past complicated ulcer : OR = 13.5
3. Anticoagulants : OR = 6.4
4. High dose & long duration Rx : OR = 7
5. Concomitant corticosteroid : OR = 2.2
6. Combination of NSAIDs : OR = 9
 Prevention of NSAID-induced
Gastroduodenal Ulcers: Cochrane Review
2006

1. Mesoprostol 800 ug/day superior to 400

ug/day (but main side effect diarrhea)

2. PPI

3. Standard dose of H2 blocker: reduced DU

but not GU, double dose reduced DU and
GU
Overuse of PPIs

 Increased cost of the treatment

 Risk associated with long term use of

PPIs

Renal failure

Increased risk of fractures (osteoporosis)

Clostridium difficile infection
Renal Complications of NSAID
NSAIDs and renal toxicity
Who are at risk?

Chronic renal
Monitoring
insufficiency
Serum creatinine at

Congestive heart baseline and within 3 to 7

days of drug initiation
failure

Severe hepatic disease

Nephrotic syndrome

Advancing age Recommendation

Diuretics
Prefer acetaminophen over
other NSAIDs

ACE inhibitors

Avoid combination of two

Cyclosporine NSAIDs

Aminoglycosides
 Caution when use with drugs
that causes renal toxicity and hyperkalemia

 Aminoglycosides
 Cyclosporin A
 ACEI
 K-sparing diuretic
Warfarin

Phenytoin

Kelley’s Textbook of Rheumatology 2005

Kelley’s Textbook of Rheumatology 2005
 Fixed dose combinations

• FDC of NSAID and NSAID

Diclofenac + Nimesulide

Diclofenac + Ibuprofen

• Justifiable..?

Risk of renal toxicity

Risk of hepatictoxicity

No added advantage of combination

Increased cost of treatment
Selective COX –2 inhibitors (Coxibs)

 Advantages over tNSAIDs

Less GI side effects, bleeding

Patients intolerant to conventional NSAIDs

Treatment for OA, RA

 Are Coxibs completely safe..?

Coxibs and toxicity

Rofecoxib & Valdecoxib

Risk of myocardial infarction and stroke

Banned

Cardiovascular
GI toxicity toxicity
Coxibs and toxicity

Demerits of Coxibs

Acute myocardial infarction

Stroke

Hypertension

Na and water retention

Heart failure

Renal toxicity
 Classification and
Basic Differences of COXIBs

Classification Drug Selectivity Chemical

structure

First Celecoxib 30 Sulfonamide

generation Rofecoxib 272 Sulfone

Second Valdecoxib 61 Sulfonamide

generation Etoricoxib 344 Sulfone
Lumiracoxib 433 Phenylacetic
acid derivative
 In Vitro Selectivity: COX-2/COX-1 Ratio
Lumiracoxib
Etoricoxib
Rofecoxib
Valdecoxib > 50-fold COX-2 selective
etodolac
nimesulide
diclofenac 5- 50-fold COX-2 selective
celecoxib
meloxicam

fenoprofen < 5-fold COX-2

ibuprofen selective
tolmetin
naproxen
aspirin
indomethacin
ketoprofen
flurbiprofen
ketorolac
-3 -2 -1 0 1 2 3

Increasingly COX-2 Increasingly COX-1

Selective Selective
Warner et al. FASEB J. 2004:18:790-804
 European Medicines Agency Approval

Etoricoxib has received approval from EMA as a COX-2 inhibitor

with therapeutic indications for patients with degenerative
chronic inflammation such as rheumatoid arthritis and
osteoarthritis
 Efficacy of etoricoxib, celecoxib, lumiracoxib, non-selective
NSAIDs, and acetaminophen in osteoarthritis: a mixed treatment
comparison
Stam W, Jansen J, Taylor S. Open Rheumatol J. 2012;6:6-20

CONCLUSION:
The current study estimated the efficacy of acetaminophen, nsNSAIDs,
and COX-2 selective NSAIDs in OA and found that etoricoxib 30 mg is
likely to result in the greatest improvements in pain and physical
function
 Evaluation of two doses of etoricoxib, a COX-2 selective non-
steroidal antiinflammatory drug (NSAID), in the treatment of
Rheumatoid Arthritis in a double-blind, randomized controlled trial

Bickham K, et al. BMC Musculoskelet Disord. 2016; 17: 331

CONCLUSION:
Both etoricoxib 90 mg and 60 mg are superior to
placebo in relieving the symptoms of RA
Bickham K, et al. BMC Musculoskelet Disord. 2016; 17: 331.
 Efficacy and safety profile of treatment with etoricoxib 120 mg once
daily compared with indomethacin 50 mg three times daily in acute
gout: a randomized controlled trial

Rubin BR, et al. Arthritis Rheum. 2004;50(2):598-606

Conclusion
Etoricoxib at a dosage of 120 mg once daily was confirmed to be an
effective treatment for acute gout for 8 days. Etoricoxib was comparable
in efficacy to indomethacin at a dosage of 50 mg 3 times daily, and it was
generally safe and well tolerated
 Cardiovascular outcomes with etoricoxib and diclofenac in patients
with osteoarthritis and rheumatoid arthritis in the Multinational
Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a
randomised comparison

Cannon CP, et al. Lancet. 2006;368(9549):1771-81

RESULT Arterial thrombotic events
Thrombotic cardiovascular events

APTC events (myocardial infarction, stroke or vascular death)

Conclusion:
Rates of thrombotic cardiovascular events in patients
with arthritis on etoricoxib are similar to those in
patients on diclofenac with long-term use of these
drugs
 Pain Intensity among each group during 48 hour after surgery

Conclusions:
Etoricoxib is more effective than celecoxib and placebo for using as
preemptive analgesia for acute postoperative pain control in patients
underwent arthroscopic anterior cruciate ligament reconstruction
A randomized placebo-controlled trial comparing the efficacy of
etoricoxib 30 mg and ibuprofen 2400 mg for the treatment of
patients with osteoarthritis

Puopolo A, Boice JA, Fidelholtz JL, Littlejohn TW, Miranda P, Berrocal A, Ko A, Cichanowitz
N, Reicin AS. Osteoarthritis Cartilage. 2007;15(12):1348-56.

WOMAC pain subscale (PS) WOMAC physical function subscale (PFS)

Conclusion
Treatment with etoricoxib 30 mg q.d. provides superior efficacy vs
placebo and comparable clinical efficacy vs ibuprofen 2400 mg (800 mg
t.i.d.) for the treatment of OA of the hip and knee
 The global risk for each NSAID is determined by Global Risk
Method (GRM) and Maximum Risk Method (MRM)

The risk-type criteria, representing the probability that the patient may
develop a side effect (SE)

Moldeveanu LM, et al. non-steroidal anti-inflammatory drugs ranking by Nondeterministic

Assessment of Probabilistic Type. Applied Medical Informatics 2012;31(3):37-46.
Evaluation of the efficacy of etoricoxib in ankylosing spondylitis:
Results of a fifty‐‐two–week, randomized, controlled study

CONCLUSION:
Etoricoxib at doses of 90 mg and 120 mg demonstrated superior efficacy
compared with placebo over 6 weeks, and compared with naproxen over 1
year. These study results demonstrate that etoricoxib is generally safe, well-
tolerated, and efficacious for the treatment of AS

Van der Heijde D, et al. Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: results of a fifty-
two-week, randomized, controlled study. Arthritis & Rheumatism. 2015;52(4):1205-1215.
Summary

 Use NSAIDs considering risk

Gastrointestinal

Cardiovascular

Renal and Hepatic

 Use gastroprotective agents judiciously

with NSAIDs
 DO NOT use unjustifiable FDCs of NSAIDs
Summary

Etoricoxib

Second generation Coxib

Better selectivity

Better anti-inflammatory effectiveness

Good safety profile

Coxiron®
(Etoricoxib)
THANK YOU...