Pain and Fever Handout: Paracetamol vs NSAIDs

Pain and Fever Handout

Paracetamol vs. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) — Clinical Pharmacology Overview

Section 1: Mechanism of Action

Aspect	Paracetamol (Acetaminophen)	NSAIDs (e.g., Ibuprofen)
Primary Mechanism	Weak central (CNS) inhibition of COX enzymes, mainly COX-3 (CNS isoform).	Peripheral and central inhibition of COX-1 and COX-2 → decreased prostaglandin (PG) synthesis.
Prostaglandin Effects	Reduces PGs mainly in CNS, not peripheral tissues.	Reduces PGs systemically (CNS and peripheral).
Site of Action	Brain and spinal cord → antipyretic and analgesic.	Inflamed tissues, kidney, gastric mucosa, platelets, brain.
Anti-inflammatory Action	Negligible (no peripheral COX inhibition).	Strong — main therapeutic use.

Section 2: Physiologic & COX Isoenzyme Overview

Feature	COX-1	COX-2	COX-3
Origin	Constitutive “housekeeping” gene	Inducible by cytokines and endotoxins	Splice variant of COX-1 mRNA (mainly CNS)
Physiologic Role	“Good PGs” — gastric protection, renal perfusion, platelet aggregation	“Bad PGs” — pain, swelling, fever	“Cerebral PGs” — pain and temperature regulation
Expression	Stomach, kidney, platelets, endothelium	Macrophages, fibroblasts, synovium, kidney, brain	Brain and spinal cord (especially hypothalamus)
Inhibited by	Nonselective NSAIDs, Aspirin (irreversible)	NSAIDs and COX-2 selective drugs (e.g., celecoxib)	Paracetamol (centrally)
Outcome of Inhibition	Decreased gastric protection, platelets, and renal perfusion	Decreased inflammation, pain, and fever (desired)	Decreased CNS pain and fever (desired, no GI effect)

Mnemonic Summary

COX-1: Constitutive — “good PGs” (protection, perfusion, platelets)
COX-2: Cytokine-induced — “bad PGs” (pain, swelling, fever)
COX-3: Cerebral — “central PGs” (pain and temperature regulation)

Section 3: Mechanistic Effects in Key Systems

A. Thermoregulation

Paracetamol: Inhibits hypothalamic COX → ↓ PGE₂ → resets set point → antipyretic.
NSAIDs: Same mechanism (↓ PGE₂) → effective antipyretics.
Both reduce fever, but paracetamol is gentler on stomach and kidneys.

B. Pain Modulation

Paracetamol: Acts centrally (COX-3 + serotonergic pathways). Minimal inflammatory pain effect.
NSAIDs: Peripheral COX-1/2 blockade → ↓ PGE₂ at nociceptors → ↓ sensitization → effective for inflammatory pain.

C. Gastrointestinal (GI) Mucosa

Paracetamol: No COX-1 inhibition → safe for stomach.
NSAIDs: ↓ COX-1 PGs → ↓ mucus/bicarbonate + ↑ acid → ulcer, gastritis, bleeding risk.
NSAIDs can cause ulcers; paracetamol does not.

D. Renal Blood Flow

Paracetamol: Minimal renal PG effect; safe at normal dose.
NSAIDs: ↓ renal PGE₂/PGI₂ → afferent constriction → ↓ GFR → risk of AKI (especially in CKD, CHF, elderly).
Paracetamol preferred in renal disease.

E. Platelet Aggregation

Paracetamol: No effect on platelets or bleeding.
NSAIDs: ↓ TXA₂ → ↓ aggregation (reversible except Aspirin = irreversible).
Paracetamol is safe with anticoagulants; NSAIDs increase bleeding risk.

F. Inflammation

Paracetamol: No anti-inflammatory effect.
NSAIDs: Potent anti-inflammatory (↓ PGE₂, ↓ vasodilation, ↓ edema).

Section 4: Summary Comparison Table

Feature	Paracetamol	NSAIDs
COX Inhibition	Central (mainly COX-3)	Peripheral and Central (COX-1, COX-2)
Antipyretic	Yes	Yes
Analgesic	Yes (mild–moderate)	Yes (moderate–severe, especially inflammatory)
Anti-inflammatory	No	Yes
Antiplatelet	No	Yes (especially Aspirin)
GI Safety	High	Low
Renal Safety	High (at normal dose)	Low
Cardiovascular Safety	Neutral	Variable
Ideal Use	Fever, headache, mild pain	Inflammation, arthritis, musculoskeletal pain

Section 5: Safety and Toxicity Profiles

A. Kidney Safety (↓ Renal Perfusion / AKI Risk)

Mechanism: NSAIDs ↓ renal PGs → ↓ afferent dilation → ↓ GFR. COX-2 selective ≠ kidney-safe.

Rank (Best → Worst)	Comment
1. Paracetamol	No renal PG inhibition → safest; only chronic abuse or hepatic failure causes indirect injury.
2. Low-dose Aspirin (≤100 mg/day)	Minimal renal impact.
3. Celecoxib / Etoricoxib	Still ↓ renal PGs → AKI risk in dehydration/CHF/CKD.
4. Ibuprofen	Lowest renal risk among NSAIDs.
5. Naproxen	Moderate risk; longer half-life.
6. Diclofenac / Ketoprofen	More nephrotoxic.
7. Indomethacin / Piroxicam	Highest nephrotoxicity.

B. Gastrointestinal / Peptic Ulcer Safety

Mechanism: COX-1 inhibition ↓ PGE₂/PGI₂ → ↓ mucus and bicarbonate → ulcers.

Rank (Best → Worst)	Comment
1. Paracetamol	No COX-1 inhibition → ulcer-safe.
2. Celecoxib / Etoricoxib	Spare COX-1 → much lower GI risk.
3. Ibuprofen	Short half-life, weak COX-1 inhibition → safer NSAID.
4. Naproxen	Moderate risk.
5. Diclofenac / Ketoprofen	High ulcerogenic potential.
6. Indomethacin / Piroxicam	Most ulcerogenic.
Aspirin (≥300 mg/day)	Very high ulcer and bleeding risk.

C. Cardiovascular (CV) Safety

Mechanism: COX-2 inhibitors ↓ PGI₂ but not TXA₂ → prothrombotic imbalance → ↑ CV risk.

Rank (Best → Worst)	Comment
1. Paracetamol	Neutral (no platelet or vascular PG effect).
2. Low-dose Aspirin	Cardioprotective (↓ TXA₂).
3. Naproxen	Neutral to slightly protective CV profile.
4. Ibuprofen	Slight ↑ CV risk; may blunt aspirin’s effect.
5. Diclofenac	High CV risk.
6. Celecoxib / Etoricoxib	↑ MI/stroke risk (dose and duration dependent).
7. Piroxicam / Indomethacin	Substantial CV and CNS side effects.

D. Medication-Overuse Headache (MOH)

Mechanism: Chronic exposure → central sensitization → rebound headache.

Rank (Least → Most Likely)	Comment
1. Paracetamol	Lowest MOH risk if ≤15 days/month.
2. Naproxen / Ibuprofen	Moderate risk (>15 days/month).
3. COX-2 inhibitors	Similar moderate risk.
4. Diclofenac / Indomethacin	Higher risk.
5. Combination analgesics	Highest MOH risk.

Section 6: Safe-Use Summary by Risk Category

Drug	Typical Max Daily Dose	Safe Frequency per Month	Key Limiting Risk
Paracetamol	3–4 g/day	≤20–25 days	Hepatotoxicity (chronic)
Ibuprofen	1200–2400 mg/day	≤15 days	GI and renal risk
Naproxen	500–1000 mg/day	≤15 days	GI irritation; mild CV risk
Diclofenac	75–150 mg/day	≤10–12 days	CV and renal toxicity
Celecoxib	100–200 mg/day	≤15 days	CV risk (chronic use)
Etoricoxib	60–90 mg/day	≤10 days	CV risk
Aspirin (analgesic)	2–3 g/day	≤10 days	GI/bleeding risk
Low-dose Aspirin	75–100 mg/day	Daily (CV prevention)	Minor GI irritation

Section 7: Analgesic Potency and Clinical Use

Rank	Drug/Class	Analgesic Strength	Key Notes
1.	Ketorolac	Very high	Comparable to parenteral opioids; limit ≤5 days; high GI/renal risk.
2.	Diclofenac	High	Excellent for visceral/musculoskeletal pain; high CV risk.
3.	Indomethacin / Piroxicam	High	Potent but toxic; rarely first-line.
4.	Naproxen	Moderate–Strong	Balanced analgesia and long half-life.
5.	Ibuprofen	Moderate	Short-acting, good safety balance.
6.	Celecoxib / Etoricoxib	Moderate	Useful in chronic arthritis; less acute power.
7.	Aspirin (≥300 mg)	Mild–Moderate	Limited by GI irritation.
8.	Paracetamol	Mild	Excellent for fever, headache, mild pain.

Section 8: “Power vs. Safety” Matrix

Drug	Analgesic Potency	Renal Safety	GI Safety	CV Safety
Ketorolac	Very High	Low	Low	Moderate
Diclofenac	High	Moderate	Moderate	Low
Indomethacin / Piroxicam	High	Low	Low	Moderate
Naproxen	Moderate–High	Moderate	Moderate	High
Ibuprofen	Moderate	High	High	Moderate
Celecoxib / Etoricoxib	Moderate	Moderate	High	Moderate–Low
Aspirin (high dose)	Mild–Moderate	Moderate	Low	High (low dose)
Paracetamol	Mild	High	High	High

Section 9: Clinical Pearls and Takeaways

First-line for pain or fever: Paracetamol (especially in PUD, CKD, cirrhosis, elderly, anticoagulated).
When inflammation predominates: NSAIDs (e.g., gout, arthritis, trauma).
Avoid chronic combinations — increased renal and hepatic toxicity.
Long-term NSAID users: use PPI and monitor renal/CV risk.
Ibuprofen offers the best OTC balance between efficacy and safety.
Safest sequence: Paracetamol → Ibuprofen (short-term) → Celecoxib (arthritis with GI protection).

Key Takeaway Summary

Risk Domain	Safest Choice	Most Toxic
Kidney	Paracetamol	Indomethacin / Piroxicam
Gastrointestinal (Ulcer)	Paracetamol	Aspirin (high dose), Piroxicam
Cardiovascular	Paracetamol / Naproxen	Diclofenac / Etoricoxib
Medication-Overuse Headache	Paracetamol (≤15 days/month)	Combination analgesics, chronic NSAIDs

Paracetamol remains the safest broad-use analgesic and antipyretic for most patient populations.

NSAIDs are superior for inflammatory conditions but require individualized risk assessment (GI, renal, CV).

Rational use: employ the lowest effective dose, for the shortest necessary duration, tailored to comorbidity profile.