Overview

• NSAIDs are commonly used for pain, inflammation and fever.
• Common agents:
  • Ibuprofen, naproxen, diclofenac, meloxicam, celecoxib, aspirin
• Mechanism: Inhibit COX-1 and COX-2 → ↓ prostaglandins
• Clinical challenge:
  • Balance analgesic benefit vs multi-system toxicity
• Pharmacology (key principles)
  • COX-1:
    • Gastric protection
    • Platelet aggregation
    • Renal perfusion
  • COX-2:
    • Inflammation, pain, fever
    • COX-2 selective drugs: Less GI toxicity (relative)
    • More cardiovascular risk (relative)
• Most NSAIDs have similar analgesic efficacy → drug choice driven by risk profile

Comparison of nonsteroidal anti-inflammatory drugs (NSAIDs)

https://australianprescriber.tg.org.au/articles/choosing-a-nonsteroidal-anti-inflammatory-drug-for-pain.html

NSAID	COX selectivity	Route of administration	Dose frequency
Aspirin	nonselective	oral	every 4 to 6 hours (when used as an anti-inflammatory)
Celecoxib	COX-2 selective	oral	1 to 2 times daily
Diclofenac	COX-2 preferential	oral, topical, rectal	2 to 3 times daily
Etoricoxib	COX-2 selective	oral	once daily
Ibuprofen	nonselective	oral, topical	every 4 to 6 hours
Indometacin	nonselective	oral, rectal	2 to 3 times daily
Ketorolac	nonselective	intramuscular, intravenous, oral	every 4 to 6 hours
Mefenamic acid	nonselective	oral	3 times daily
Meloxicam	COX-2 selective	oral	once daily
Naproxen	nonselective	oral	2 times daily
Parecoxib	COX-2 selective	intravenous, intramuscular	every 6 to 12 hours
Piroxicam	nonselective	oral	once daily

from :

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1. Gastrointestinal toxicity

https://australianprescriber.tg.org.au/articles/peptic-ulcer-disease-and-non-steroidal-anti-inflammatory-drugs.html

Mechanism

• COX-1 inhibition → ↓ prostaglandins → ↓ mucosal protection → ulceration
• NSAIDs reduce protective gastric prostaglandins.
• This leads to:
  • ↓ mucus protection
  • ↓ bicarbonate secretion
  • ↓ mucosal blood flow
  • impaired mucosal repair
• Result:
  • gastritis
  • erosions
  • peptic ulcer disease
  • upper GI bleeding
  • perforation

NSAID use and H. pylori are two major risk factors for peptic ulcer disease.

GI risk factors

• Age >65 years
• Previous peptic ulcer disease
• Previous GI bleed
• High-dose NSAID use
• Long-term NSAID use
• Concurrent:
  • aspirin
  • antiplatelets
  • anticoagulants
  • corticosteroids
• Cardiovascular disease
• H. pylori infection
• Post-Roux-en-Y gastric bypass

Patients with multiple GI risk factors have substantially higher serious adverse event risk than chronic NSAID users without risk factors.

Relative GI risk by NSAID

• Lower GI risk:
  • ibuprofen
  • celecoxib
• Intermediate:
  • diclofenac
  • meloxicam
  • parecoxib
  • parecoxib
• Higher:
  • naproxen
  • indomethacin
  • mefenamic acid
• Highest:
  • piroxicam
  • ketorolac

Low-dose aspirin

• ↑ GI bleeding risk (RR ~2; higher in high-risk patients)
• In patients with prior ulcer bleeding, consider secondary ulcer prevention with a PPI.
• Switching aspirin to another antiplatelet solely for ulcer prevention is not recommended.

GI risk reduction

• Avoid NSAIDs where possible in high-risk patients.
• Use:
  • lowest effective dose
  • shortest duration
• Ask about OTC NSAIDs and aspirin.
• Consider non-NSAID alternatives.
• Co-prescribe PPI where indicated.

PPI protection

• PPI therapy is the most effective common strategy for reducing NSAID-induced ulcer risk.
• Consider PPI if:
  • previous PUD
  • previous GI bleed
  • dual antiplatelet therapy
  • anticoagulant therapy
  • older patient with multiple risk factors
  • long-term NSAID required
  • post-RYGB and NSAID unavoidable

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2. Renal toxicity: acute kidney injury

https://www.medsafe.govt.nz/profs/PUArticles/June2013NSAIDS.htm

Key concept

• All NSAIDs, including COX-2 inhibitors, can cause AKI.

Mechanism

• ↓ prostaglandins → afferent arteriole constriction → ↓ GFR
• Renal prostaglandins dilate the afferent arteriole.
• This maintains GFR when renal perfusion is reduced.
• NSAIDs inhibit renal prostaglandins.
• Result:
  • afferent arteriole constriction
  • ↓ renal blood flow
  • ↓ GFR
  • AKI

Types of NSAID-related AKI

• Haemodynamic AKI:
  • pre-renal injury
  • acute tubular necrosis
• Immune-mediated:
  • acute interstitial nephritis

Risk factors

• Age >65 years
• CKD or pre-existing renal impairment
• Hypertension/atherosclerosis
• Dehydration
• Vomiting/diarrhoea
• Blood loss
• Diuretic use
• Heart failure
• Cirrhosis
• ACE inhibitor or ARB use
• “Triple whammy”:
  • ACEi/ARB + diuretic + NSAID

: Risk factors for NSAID induced acute kidney injury^1, 2

Risk factor	Effect
Increasing age (particularly age >65), chronic hypertension and atherosclerosis	Narrowing of renal arterioles which may reduce their capacity for renal afferent dilatation
Pre-existing glomerular disease or renal insufficiency	Renal afferent dilatation is likely to be required to maintain GFR
Volume depletionTrue volume depletion (ie, GI or renal salt and water losses, blood loss, diuretic use)Effective volume depletion (ie, cirrhosis or heart failure)	Lowers afferent glomerular arteriolar pressure and stimulates secretion of angiotensin II
Use of ACE inhibitors or ARBs	ACE inhibitors and ARBs prevent efferent arteriole vasoconstriction which is also important in maintenance of GFR
Use of the ‘triple whammy’ (ACE inhibitor or ARB plus diuretic plus NSAID)	Diuretic may cause volume depletion. See above for ACE inhibitor/ARB effects.

ACE=Angiotensin Converting Enzyme; ARB=Angiotensin II Receptor Blocker

Triple whammy mechanism

• ACEi/ARB:
  • efferent arteriole dilation
• Diuretic:
  • volume depletion
• NSAID:
  • afferent arteriole constriction
• Combined effect:
  • marked reduction in intraglomerular pressure and GFR

Triple therapy is associated with increased AKI risk, especially in the first 30 days.

New Zealand- The Centre for Adverse Reactions Monitoring (CARM) received 119 reports of renal adverse reactions associated with NSAID (including COX-2 inhibitor) use from 1 January 2000.

Approximately 70% of reports were serious, including four deaths and 12 that were considered to be life-threatening. The majority of reports (74%) occurred in patients aged 50 years and over.

Diclofenac was the most commonly implicated NSAID (53 reports). In two thirds of the reports, other medicines were also considered suspect, including four reports that described the ‘triple whammy’. Reports included acute renal failure (33 reports), renal tubular necrosis and interstitial nephritis

Presentation

• May be asymptomatic.
• Non-specific symptoms:
  • fatigue
  • nausea
  • confusion
  • dyspnoea
  • reduced urine output
  • ankle/leg swelling
• Pre-renal features:
  • tachycardia
  • postural hypotension
  • low JVP
  • dry mucous membranes
• Acute interstitial nephritis features:
  • fever
  • rash
  • arthralgia
  • eosinophilia

Monitoring

• Consider baseline and repeat:
  • creatinine
  • eGFR
  • urea
  • electrolytes, especially potassium
  • BP and fluid status

Management

• Stop NSAID if AKI occurs.
• Rehydrate/correct volume depletion.
• Review other nephrotoxic or renal-risk medications.
• Repeat renal function.
• Avoid future NSAIDs in patients with NSAID-induced interstitial nephritis.

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3. Respiratory toxicity: NSAID-induced bronchospasm

Key concept

• Aspirin and NSAIDs can trigger bronchospasm in susceptible asthmatics.
• Also known as:
  • aspirin-induced asthma
  • NSAID-exacerbated respiratory disease
  • aspirin-exacerbated respiratory disease

Frequency

• Occurs in approximately 8–20% of adult asthmatics.
• Rare in children.

High-risk patients

• Asthma
• Chronic rhinitis
• Nasal polyps
• Known aspirin/NSAID sensitivity
• Adult-onset asthma with upper airway disease

Classic triad

• Asthma
• Nasal polyps/chronic rhinosinusitis
• NSAID/aspirin sensitivity

Mechanism

• COX inhibition shifts arachidonic acid metabolism toward leukotrienes.
• Leukotrienes cause:
  • bronchoconstriction
  • rhinorrhoea
  • nasal congestion
  • airway inflammation

Clinical presentation

• Onset usually 20 minutes to 3 hours after NSAID exposure.
• Symptoms:
  • acute bronchospasm
  • wheeze
  • dyspnoea
  • rhinorrhoea
  • conjunctival irritation
  • flushing
  • urticaria/angioedema
• Severe cases:
  • respiratory arrest
  • circulatory collapse

Important prescribing points

• Prior tolerance does not exclude future reaction.
• Cross-sensitivity occurs between many NSAIDs.
• Reactions can occur with systemic or topical NSAIDs.
• NSAIDs should be avoided in asthmatics with nasal polyps and used cautiously in other asthmatics.

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5. Cardiovascular risk

https://assets.primaryhealthtas.com.au/uploads/2023/03/A-guide-to-deprescribing-non-steroidal-anti-inflammatory-drugs.pdf

• Non-aspirin NSAIDs increase cardiovascular risk
• Risk is:
  • Dose-dependent
  • Can occur early, even within the first week
  • Greater in patients with higher baseline CV risk
• Low-dose aspirin is the exception because it is antiplatelet and cardioprotective.

1. Myocardial infarction / major coronary events

Mechanism

• NSAIDs affect prostaglandin pathways:
  • ↓ prostacyclin → less platelet inhibition
  • Ongoing thromboxane effect → platelet aggregation
  • Sodium/water retention and endothelial effects may also contribute

Evidence

• CNT Collaboration RCT meta-analysis:
  • Coxibs: ~75% increase in major coronary events
  • Diclofenac: ~70% increase
  • High-dose ibuprofen: ~120% increase
  • Naproxen: no significant increase in RCT data

Absolute risk

• In low CV-risk patients:
  • Around 0–2 extra vascular events per 1000 patient-years
• In high CV-risk patients:
  • Around -1 to 9 extra vascular events per 1000 patient-years

2. NSAID-specific CV risk

NSAID	Estimated excess CV events/year in low CV risk	Estimated excess CV events/year in high CV risk	NNH/year in high CV risk
Coxib	2 per 1000	7 per 1000	143
Diclofenac	2 per 1000	8 per 1000	125
Ibuprofen	2 per 1000	9 per 1000	111
Naproxen	0 per 1000	-1 per 1000	Not increased in this analysis

3. Early MI risk

Evidence

• 2017 Bayesian meta-analysis:
  • Increased MI risk seen with all NSAIDs within 7 days
  • Odds ratios:
    • Celecoxib: 1.24
    • Ibuprofen: 1.48
    • Diclofenac: 1.50
    • Naproxen: 1.53
    • Rofecoxib: 1.58

Clinical meaning

• Short courses are not automatically CV-safe
• Higher doses increase risk regardless of NSAID choice.

4. Heart failure

Mechanism

• NSAIDs can cause:
  • Sodium and water retention
  • Reduced renal perfusion
  • Increased BP
  • Worsening fluid overload

Evidence

• RCT meta-analysis:
  • NSAIDs increased heart failure risk: OR 2.31
  • Placebo HF incidence: 0.18%
  • NSAID HF incidence: 0.47%
  • Absolute risk increase: 0.29%
  • NNH: 348

Higher risk groups

• Older patients
• Pre-existing heart failure
• CKD
• Patients on ACEi/ARB + diuretic

5. Atrial fibrillation

Evidence

• Meta-analysis:
  • NSAIDs increased AF risk by 12% overall
  • New NSAID users: 53% increased risk

Applies to

• Both COX-2 selective and non-selective NSAIDs.

6. Aspirin exception

• Low-dose aspirin
  • Antiplatelet
  • Reduces MI/stroke risk in appropriate patients
• High-dose aspirin
  • Acts more like other NSAIDs
  • More GI toxicity
• Ibuprofen interaction
  • May reduce aspirin’s antiplatelet effect if taken together.

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6. Hepatic and bleeding risks

Hepatic

• Avoid NSAIDs in cirrhosis
• Risks:
  • hepatotoxicity (notably diclofenac)
  • hepatorenal syndrome
  • worsening ascites/oedema

Bleeding

• NSAIDs:
  • increase GI bleeding risk
  • double bleeding risk when combined with anticoagulants
• Platelet effects vary (aspirin strongest COX-1 inhibition)

Thrombosis

• NSAIDs associated with ↑ thrombotic risk (e.g. VTE)
• Likely due to prostacyclin–thromboxane imbalance

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7. Hypersensitivity reactions

• Non-allergic:
  • urticaria, angioedema (COX-1 mediated)
• Allergic:
  • anaphylaxis
  • Stevens–Johnson syndrome
• Cross-reactivity:
  • common in non-allergic reactions
  • less with COX-2 selective agents

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8. Pregnancy and breastfeeding

• short-acting NSAIDs generally safe (except high-dose aspirin)
• 1st trimester:
  • avoid if possible (miscarriage risk)
• 3rd trimester:
  • contraindicated (>30 weeks)
    • risk:
      • ductus arteriosus closure
      • oligohydramnios
• Breastfeeding:
  • short-acting NSAIDs generally safe (except high-dose aspirin)

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Practical checklist – Before prescribing

Assess:

• GI risk (ulcer, bleeding, RYGB)
• Renal risk (CKD, dehydration, triple whammy)
• CV risk (IHD, HF, stroke)
• Respiratory risk (asthma, nasal polyps)
• Hepatic disease

Safer prescribing principles

• Lowest dose, shortest duration
• Avoid duplication (OTC NSAIDs)
• Avoid in dehydration/acute illness
• Use PPI in GI risk
• Monitor renal function in at-risk patients
• Avoid in:
  • CKD stage 4–5
  • HFrEF (moderate–severe)
  • RYGB (chronic use)
  • NSAID-sensitive asthma

Alternatives

• Paracetamol
• Topical NSAIDs (lower systemic risk)
• Physiotherapy
• Injections (e.g. intra-articular steroid)

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Patient counselling

Advise patients to stop NSAID and seek medical review if:

GI symptoms

• melaena
• haematemesis
• severe epigastric pain
• persistent dyspepsia
• dizziness/syncope

Renal symptoms

• reduced urine output
• new ankle swelling
• shortness of breath
• severe fatigue
• confusion
• vomiting/diarrhoea with poor intake

Respiratory symptoms

• wheeze
• chest tightness
• shortness of breath
• worsening asthma
• facial swelling
• urticaria

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other:

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Topical NSAIDs (point form)

General

• Topical NSAIDs widely used in Australia
• Most common: diclofenac gel
• Indications:
  • Osteoarthritis (especially knee, hand)
  • Localised musculoskeletal pain

Efficacy

• Meta-analysis (da Costa et al.):
  • Topical diclofenac (plaster form) highly effective in knee OA
  • Probability of clinically meaningful pain relief:
    • Topical diclofenac: ~92.3%
    • Oral diclofenac (150 mg/day): ~99.9%
• Conclusion:
  • Slightly less effective than oral NSAIDs
  • Still clinically significant benefit

Safety

• Lower systemic absorption → reduced adverse effects
• Compared to oral NSAIDs:
  • ↓ GI risk
  • ↓ cardiovascular risk (theoretical + supported by real-world data)
  • ↓ dropout due to adverse effects

Comparative effectiveness

• OARSI 2020:
  • Topical NSAIDs:
    • More effective than paracetamol
    • Less effective than oral NSAIDs (for function)
    • Safer than both paracetamol and oral NSAIDs

Guideline recommendations

• Osteoarthritis Research Society International:
  • Supports use in knee OA
• American College of Rheumatology / Arthritis Foundation (2019):
  • Strong recommendation:
    • Knee OA
  • Conditional recommendation:
    • Hand OA (practical limitations with application)
  • Key principle:
    • Use topical NSAIDs before oral NSAIDs where appropriate

Formulation evidence

• Limited head-to-head comparisons
• 2017 Cochrane review:
  • Diclofenac gel:
    • Likely most effective for acute pain
    • Similar efficacy to other topical diclofenac formulations in chronic pain

Practical clinical points

• First-line for:
  • Mild–moderate OA (especially knee)
  • Patients with ↑ GI/CV risk
• Application:
  • Regular application required (e.g. 2–4 times daily depending on product)
• Limitations:
  • Less useful for:
    • Deep joints (e.g. hip OA)
    • Widespread pain

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Bariatric surgery: RYGB and sleeve gastrectomy

• NSAIDs are generally avoided after Roux-en-Y gastric bypass (RYGB) due to risk of marginal/peptic ulceration.
• Risk appears less clear after sleeve gastrectomy (SG).

Evidence: Skogar & Sundbom 2022

• Retrospective Swedish population-based cohort.
• Included 41,380 patients:
  • 37,913 RYGB
  • 3,467 SG
• Overall peptic ulcer diagnosis after surgery:
  • 1.8% overall
  • 1.9% after RYGB
  • 0.2% after SG
• NSAID exposure:
  • 60% had NSAID prescription during median 4.1 years follow-up.
• Risk increased with cumulative exposure:
  • 0–30 DDD: OR 1.10
  • 30–100 DDD: OR 1.43
  • 100 DDD: OR 1.52
• Conclusion:
  • continuous NSAID use ≥30 days significantly increased ulcer risk after RYGB
  • temporary use <30 days was not clearly associated
  • no association found after sleeve gastrectomy

Practical implications

• After RYGB:
  • avoid NSAIDs where possible
  • if unavoidable, use very short course only
  • use PPI cover
  • counsel strongly about ulcer/bleeding symptoms
• After sleeve gastrectomy:
  • NSAIDs may be lower risk than RYGB
  • still assess standard GI, renal and cardiovascular risk factors
  • consider PPI if additional risk factors