NSAIDs Summary

Mechanism of Action

  • Inhibit COX enzymes → ↓ prostaglandin synthesis
  • COX-1: Gastric protection, platelet function
  • COX-2: Inflammation, pain mediation

NSAID Classification

  • Non-selective: Ibuprofen, naproxen, diclofenac
  • COX-2 selective: Celecoxib, etoricoxib
  • 60% patients respond to any given NSAID

Absolute Contraindications

  • Active GI bleeding/ulcer
  • NSAID hypersensitivity
  • Severe heart failure
  • Severe hepatic/renal impairment
  • CV disease (COX-2 inhibitors)

Major Adverse Effects

  • GI: Ulcers, bleeding, perforation
  • CV: MI, stroke, heart failure
  • Renal: Failure, hypertension
  • Bronchospasm, skin reactions

High Risk Groups

  • Age >65 years
  • Previous GI events
  • CV/renal disease
  • Concomitant anticoagulants/steroids

GI Protection

  • High risk: COX-2 + PPI
  • Moderate risk: COX-2 or NSAID + PPI
  • Low risk: Non-selective NSAID

CV Risk Management

  • Avoid COX-2 inhibitors in CV disease
  • Lowest effective dose, shortest duration
  • Monitor BP and renal function

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Comprehensive guide to mechanism, selection, and risk management

Mechanism of Action

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis, which normally potentiates the pain caused by other inflammatory mediators (such as histamine and bradykinin).

COX Enzyme Inhibition

COX-1 Enzyme

  • Present in most tissues
  • Produces prostaglandins that help maintain gastric mucosal integrity
  • Facilitates platelet-initiated blood clotting
  • Inhibition: Causes gastrointestinal toxicity

COX-2 Enzyme

  • Usually undetected in tissues
  • Produced in response to inflammatory cytokines
  • Produces prostaglandins that mediate pain and inflammation
  • Inhibition: Provides anti-inflammatory effect

NSAID Classification

Type Examples Characteristics
Standard NSAIDs Ibuprofen, indometacin, mefenamic acid, naproxen Non-selective COX inhibition
Coxibs Celecoxib, etoricoxib COX-2 specific inhibitors

Important: There is no absolute selectivity for one COX enzyme — even highly selective COX-2 inhibitors will also inhibit COX-1 at high enough concentrations.

Therapeutic Effects

Single Doses

  • Analgesic activity comparable to paracetamol
  • Paracetamol preferred due to better side effect profile
  • Particularly in elderly patients

Regular Full Dosage

  • Lasting analgesic and anti-inflammatory effects
  • Useful for continuous or regular pain with inflammation
  • Indicated for inflammatory arthritides

Choice of NSAID

About 60% of patients will respond to any NSAID; of the others, those who do not respond to one may well respond to another. Pain relief starts soon after taking the first dose and a full analgesic effect should normally be obtained within a week.

Common NSAIDs Comparison

Ibuprofen

  • Fewer side effects than other non-selective NSAIDs
  • Weaker anti-inflammatory properties
  • Unsuitable for conditions with prominent inflammation
  • Not recommended for acute gout

Naproxen

  • Good efficacy with relatively low incidence of side effects
  • More side effects than ibuprofen
  • Recommended first-line treatment in acute gout

Diclofenac

  • Similar efficacy to naproxen
  • Higher incidence of cardiovascular adverse events
  • Contraindicated: Ischemic heart disease, cerebrovascular disease, peripheral arterial disease, congestive heart failure

Mefenamic Acid

  • Minor anti-inflammatory properties
  • Typically used for painful dysmenorrhea
  • Associated with diarrhea and hemolytic anemia
  • Requires discontinuation if adverse effects occur

Contraindications

Do not prescribe NSAIDs to people with the following conditions:

Absolute Contraindications

  • Active gastrointestinal bleeding or active GI ulcer
  • History of GI bleeding related to previous NSAID therapy
  • History of GI perforation related to previous NSAID therapy
  • History of recurrent GI hemorrhage (≥2 episodes)
  • History of recurrent GI ulceration (≥2 episodes)
  • Hypersensitivity/severe allergic reaction to NSAIDs
  • Severe heart failure
  • Severe hepatic impairment (albumin <25 g/l or Child-Pugh ≥10)
  • Severe renal impairment (eGFR <30 mL/min/1.73 m²)

Specific Drug Contraindications

Do not prescribe COX-2 inhibitors, diclofenac, aceclofenac or high-dose ibuprofen (>2400 mg daily) to people with:

  • Ischemic heart disease
  • Peripheral arterial disease
  • Cerebrovascular disease
  • Congestive heart failure (NYHA II-IV)
  • Inflammatory bowel disease (COX-2 inhibitors only)
  • Uncontrolled hypertension (>140/90 mmHg) (etoricoxib or high-dose ibuprofen only)

Cautions

Prescribe NSAIDs with caution to people with the following conditions:

Gastrointestinal

  • History of peptic ulceration
  • High risk of GI adverse effects
  • Inflammatory bowel disease

Cardiovascular/Renal

  • Cardiac impairment
  • Heart failure
  • Hypertension
  • Renal impairment
  • Coagulation disorders

Other Considerations

  • Allergic disorders and asthma
  • Elderly patients
  • Women trying to conceive
  • Connective-tissue disorders
  • CV risk factors

Adverse Effects

General Principle: The lowest effective dose of NSAID should be prescribed for the shortest period of time to control symptoms and the need for long-term treatment should be reviewed periodically.

Common Adverse Effects

Gastrointestinal

  • Dyspepsia (most common)
  • Ulcer, perforation, obstruction
  • GI bleeding

Cardiovascular/Renal

  • Myocardial infarction
  • Stroke
  • Cardiac failure
  • Hypertension
  • Renal failure

Other Effects

  • Prolonged bleeding (platelet inhibition)
  • Bronchospasm (asthma exacerbation)
  • Severe skin reactions
  • Angioedema
  • Kounis syndrome
  • Hepatic reactions (rare)

NSAIDs and Cardiovascular/Renal Effects

System Mechanism Risk Factors
Cardiovascular COX-2 inhibition → ↓ prostacyclin → prothrombotic state CV disease, age >65, risk factors
Renal ↓ PGE2/PGI2 → sodium retention, ↓ renal blood flow Renal impairment, heart failure, elderly

Gastrointestinal Risk Management

Risk Stratification for GI Adverse Events

Lowest Risk NSAIDs

  • Ibuprofen

Intermediate Risk NSAIDs

  • Naproxen
  • Diclofenac
  • Indometacin

Highest Risk NSAIDs

  • Piroxicam
  • Ketoprofen
  • Ketorolac

Risk Factors for GI Adverse Events

Patient Factors

  • Age >65 years
  • History of gastroduodenal ulcer/bleeding
  • Serious comorbidities
  • Heavy smoking
  • Excessive alcohol consumption

Medication Factors

  • High NSAID dose
  • Concomitant anticoagulants
  • Concomitant corticosteroids
  • Concomitant SSRIs
  • Prolonged NSAID use

Prevention Strategies

General Measures
  1. Consider alternative analgesics (paracetamol, topical NSAIDs)
  2. Use lowest effective dose for shortest duration
  3. Avoid concomitant use of multiple NSAIDs
  4. Prefer short-acting NSAIDs over long-acting

GI Protection Based on Risk Level

Risk Level Definition Recommended Strategy
Low Risk No risk factors Non-selective NSAID
Moderate Risk 1-2 risk factors COX-2 inhibitor alone OR NSAID + PPI
High Risk History of complicated ulcer OR >2 risk factors COX-2 selective NSAID + PPI