2022 lecture given to incoming internal medicine residents of the Department of Medicine, East Avenue Medical Center.

1. Sidney Erwin T. Manahan, MD, FPCP, FPRA
Fellowship Training Officer
EAMC Section of Rheumatology
Rational NSAID Use
What We Must Know Before Prescribing

2. Disclosures
• Previous module developer and speakers bureau for Celebrex (Pfizer)
• Previous module collaborator for Arcoxia (MSD)
• Previous speakers bureau for Ketesse (Menarini)

3. Objectives
At the end of the session, the participant should be able to:
• Appreciate the role of prostaglandins in health
• Describe the role of NSAIDs in managing pain and
inflammation
• Compare differences between traditional, COX-2 selective,
and COX-2 specific NSAIDs
• Implement a risk-based selection process when prescribing
NSAIDs for rheumatic and other painful conditions
• Observe risk mitigation strategies when prescribing NSAIDs
in high risk individuals

4. What medication did you
prescribe for the last
patient you saw
complaining of pain?

5. Analgesic Options to Treat CHRONIC Pain
PRIMARY ANALGESICS
Paracetamol
NSAIDs/ COXIBs
Opioids
ADJUNCT ANALGESICS
Tricyclic Antidepressants
Serotonin-Norepinephrine
Reuptake Inhibitors
Anti-convulsants
Muscle relaxants
Topical agents

6. Arachidonic Acid Pathway
Membrane Phospholipids
Arachidonic Acid
Prostaglandins
Thromboxane
Prostacyclin
Leukotrienes EETs
Epoxides
Phospholipase A2
Membrane perturbation
Tissue injury
Thrombin, Bradykinin
Epinephrine, Angiotensin II
Glucocorticoids
COX 1/2/3 5-LOX CYP2C/2J
NSAIDs
Paracetamol
Leukotriene
Antagonists
Broncho-constriction
Smooth muscle contraction
Asthma attacks

7. Products of the COX Pathway
What Do They Do?
Product Physiologic Roles
Thromboxane A2 (TXA2) Increase platelet aggregation, Vasoconstriction
Prostacyclin (PGI2)
Reduce platelet aggregation, Increase renal blood flow,
Vasodilation, Inhibit gastric acid production
Prostaglandin D2 (PGD2) Increase renal blood flow, Inhibit gastric acid production
Prostaglandin E2 (PGE2)
Increase renal blood flow, Vasodilation, Natriuresis, Inhibit
gastric acid production
Prostaglandin F2a (PGF2a)
Reduce progesterone, Increase uterine contractions,
Vasoconstriction, Bronchoconstriction

8. Physiologic Effects of Prostaglandins
Organ/ System Mediated by Functions
Female Reproduction PGE2, PGF2a Uterine contractions, oxytoxic action
Male Reproduction PGE2, PGF2a Fertility
Cardiovascular PGE2, PGI2, TXA2, PGF2a
Thrombosis, vascular permeability, platelet
aggregation, arterial vasodilation, venous
vasoconstriction, patency of ductus arteriosus
Respiratory PGE2, PGF2a, TXA2 Bronchodilation, Bronchoconstriction
Renal PGE2, PGI2 Regulation of blood flow/ GFR, renin release
Gastrointestinal PGE2, PGI2 Cytoprotection
Immune PGE2, PGI2 Inhibition of B and T cell activation and proliferation
Central Nervous PGE2, PGI2, PGD2 Fever, Sleep, Pain
Musculoskeletal Cartilage catabolism, bone homeostasis

9. Prostaglandin G/H Synthetase (PGHS)
More commonly known as cyclo-oxygenase (COX)
COX 1 COX 2 COX 3
Constitutive
Housekeeping function
Increases 2-4x with
humoral stimulation
Inducible
Immediate response to
inflammation, immunity
Increases 10-18x with
growth factor, cytokine,
LPS, etc stimulation
Variant of COX 1

10. Classification of NSAIDs
Based on Effects on COX 1 and COX 2
Non selective
COX 2
Selective
COX 2
Specific
Aspirin
Diclofenac
Indomethacin
Ibuprofen
Ketoprofen
Ketorolac
Naproxen
Piroxicam
Meloxicam
Nimesulide
Etodolac
Celecoxib
Etoricoxib
Valdecoxib
Lumiracoxib
Rofecoxib

11. NSAIDs Quick Check
Drug Preparation Max Daily Dose Precaution
ASA 80, 325 mg 3000 mg Decrease by 50% in renal/ liver failure
Diclofenac 25, 50, 75, 100 225 mg Higher rates of transaminitis vs other NSAIDs
Indomethacin 25, 50 200 mg
Ketorolac 15, 30 120 mg Decrease by 50% in renal failure, elderly
Ibuprofen 200, 400 3200 mg Avoid with severe liver disease
Naproxen 250, 500 1375 mg Decrease in renal/ liver disease, elderly
Ketoprofen 25, 50 300 mg Decrease in renal/ liver disease, elderly
Piroxicam 10, 20 20 mg Decrease in liver disease, elderly
Meloxicam 7.5, 15 15 mg
Celecoxib 100, 200, 400 400 mg Contraindicated in sulfonamide allergy
Etoricoxib 60, 90, 120 120 mg Contraindicated in severe liver/ renal disease

12. NSAID doses by Indication
There are differences!
Drug OA Gout Rheum Arthritis
Naproxen 250-500 mg BID 250 mg every 8h 250 - 500 mg BID
Ibuprofen 300-800 mg TID-QID 600 mg QID 300 - 800 mg TID-QID
Indomethacin 25 mg BID-TID 50 mg TID 25 mg BID-TID
Diclofenac 50 mg BID-TID 50 mg TID-QID
Meloxicam 7.5 mg OD 7.5 - 15 mg OD
Celecoxib 100 mg BID 200-400 mg BID 200 mg BID
Etoricoxib 30-60 mg OD 120 mg OD x 7-8 days 90 mg OD
DO NOT INCREASE DOSES UNTIL PAIN-FREE!

13. Is there a less effective NSAID?

14. What’s an important difference between NSAIDs?

15. What are the safety concerns with NSAIDs
System Problems
Gastrointestinal Dyspepsia, Esophagitis, GI bleeding, perforation, obstruction, colitis
Renal
Sodium retention, water retention/ edema, hypertension, Type IV RTA, AKI, papillary
necrosis, Acute interstitial nephritis, Accelerated chronic kidney disease
Cardiovascular Heart failure, myocardial infarction, stroke, CV death
Hepatic Elevated liver function tests, Reye’s syndrome (ASA)
Allergy NSAID induced respiratory disease, Rash
Hematologic Cytopenias
Neurologic Dizziness, confusion, drowsiness, seizures, aseptic meningitis
Bone Delayed healing

16. Risk Factors for Upper GI Bleeding
Associated with NSAID Use
• Previous complicated ulcer (OR 13.5)
• Multiple NSAIDs / Concomitant ASA use (OR 8.9)
• High dose NSAIDs (OR 7.0)
• Anti-coagulant treatment (OR 6.4)
• Previous uncomplicated ulcer (OR 6.1)
• Age >70 (OR 5.6)
• H. pylori infection (OR 3.5)
• Oral corticosteroids (OR 2.2)
Modified from Gutthann SP, et al. Individual NSAID and other risk factors for upper GI bleeding and perforation. Epidemiology 1997; 8: 18-24.

17. GI Risk Mitigation Strategies
GI RISK FACTORS
Age > 65 years
High Dose NSAIDs
Previous history of
uncomplicated ulcer
Concurrent use of ASA, GC, or
anticoagulants
GI Risk Potential Strategies
Low (No Risk Factors)
Intermittent NSAID use
Low-dose NSAID
Moderate
(1-2 Risk Factors)
COX-2 selective/ specific NSAID
Intermittent NSAID use
NSAID + PPI/ H2RA/ misoprostol
High (>2 Risk Factors) OR
History of previous
complicated ulcer
Alternative treatment
COX-2 specific inhibitor + PPI/misoprostol
H. pylori positivity
Consider eradication
in moderate-high risk patients

18. Paracetamol, ASA, tramadol, opioid analgesics
Non-acetylated salicylates
Stepped Care Approach for MS symptoms
In Patients with Risk Factors or Known to have CV Disease
Non-selective NSAIDs
COX-2 selective NSAIDs
COXIBs
Patients at low risk for
thrombotic events
Prescribe lowest dose to
control symptoms
Consider ASA + PPI in
patients at increased risk for
thrombotic events
Regular monitoring for sustained
hypertension (or worsening BP control),
edema, OR worsening renal function. If
these occur, consider reducing or
stopping the drug
Antman EM, et al. Use of NSAIDs: A Scientific Statement from the American Heart Association. Circulation 2007; 115: 1632-34.

19. Cardiovascular Risk Mitigation Strategies
10-year risk of FATAL
CARDIOVASCULAR EVENT
GI RISK <10% >10%
Low
Intermittent or low
dose NSAID
Naproxen + PPI
Moderate
NS-NSAID + PPI
COXIB
Naproxen + PPI
High COXIB + PPI
Alternative tx
COXIB + PPI
Burmester G, et.al. Appropriate Use of NSAIDs in rheumatic disease: opinions of a multi-disciplinary European expert panel. Ann Rheum Dis 2010.
OTHER MITIGATION STRATEGIES
• Do not use NSAIDs within 3-6 months of
an acute CV event or procedure
• Use low dose, short-half life NSAIDs and
avoid extended-release preparations
• If using ASA, take ASA >2 hours before
the NSAID dose
• Carefully monitor and control BP.
• Avoid using ibuprofen and naproxen with
ASA.

20. Renal Risk Mitigation Strategies
RENAL RISK FACTORS
Serum creatinine > 2 mg/dl (177 umol/l)
Age > 65 years
Hypertension
Heart Failure
Concurrent use of ACEi/ ARB/ diuretics
AVOID
if eGFR < 30 ml/min
MONITOR
if with risk factors

21. Rational NSAID Use
How do we do it?
• Make a correct diagnosis
• Identify the type of pain being managed.
• Know what drugs works, at what dose, and for how long.
• Profile the patient - CV, GI, Renal, etc.
• Choose the appropriate drug given the patient’s profile.
• Properly appraise the patient.
• Monitor for adverse events.

22. What will you give?
• 45M was admitted for UGIB. He
underwent EGD on the 4th hospital
day with findings of erosive gastritis
and (+) H. pylori. He was started on
H. pylori eradication therapy. On the
6th HD, he developed inflammatory
monoarthritis, left knee. No other
co-morbid conditions.
• Assessment
• Acute Gout
• UGIB 2 to Erosive Gastritis
• H. pylori infection
CV Risk Low
GI Risk High
Renal Risk None
OPTIONS
(1) COXIB + PPI
(2) Systemic steroids (IV or IM)
(3) Intra-articular steroids

23. What will you give?
• 65F complaining of chronic
oligoarthralgia affecting both knees.
Pains worse with activity, improves
with rest, and with AM stiffness 20
mins. PE reveals crepitations of both
knees, limited flexion/ extension on
both active, passive ROM, (-) warmth/
tenderness. Normal blood tests.
• AMI 3 mos ago; Type 2 DM x 10
years.
• Assessment
• Osteoarthritis
• Previous MI
• Type 2 DM
CV Risk High
GI Risk Moderate
Renal Risk Age
OPTIONS
(1) Naproxen + PPI
(2) Analgesics (Paracetamol)
(3) Opioids (Tramadol)

24. What will you give?
• 55M admitted for uremia. Developed UGIB
on 2nd hospital day. Underwent EGD on
the 6th hospital day with findings of
erosive gastritis. Patient has co-morbid
HPN and Type 2 DM.
• 14th hospital day, developed warmth,
tenderness of left knee with significant
effusion.
• Assessment
• Acute Gout
• CKD 2 to DKD/ HKD
• Type 2 DM
• Hypertension
• UGIB 2 to Uremic Gastritis
CV Risk High
GI Risk High
Renal Risk CKD
OPTIONS
(1) Systemic steroids (IV or IM)
(2) Intra-articular steroids

25. SUMMARY
What we learned
• Prostaglandins have physiologic roles in body functions
• NSAIDs, as inhibitors of PG synthesis, have effects other
than pain relief
• All NSAIDs are effective against pain but with differences
in safety profile
• In prescribing NSAIDs, patients should be profiled for
their CV, GI, and renal risks.
• The decision of what to give depends on the indications
and patient risk profile. There are strategies to minimize
adverse events.