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Non-steroidal anti-inflammatory drugs (NSAIDs)

Created: 5/5/2017
Updated: 16/6/2017
This group includes a number of different drugs which share a common mechanism of action. In general, they are administered orally, with some available as rectal, topical or intravenous formulations


Mechanism of action for analgesia

The generation and modulation of pain is multi-faceted and dependent on multiple chemical mediators. Prostaglandins (such as PGE2 and PGI2) are one group of mediators particularly implicated in acute pain and inflammation. NSAIDs block the production of prostaglandins by inhibiting the cyclo-oxygenase (COX) enzymes needed for their synthesis (see Figure 1). Aspirin is the only NSAID that binds irreversibly to COX enzymes; the others are reversible inhibitors.

There are two common forms of COX: COX-1 and COX-2. Most NSAIDs are not selective in their COX inhibition and therefore block both forms. COX-1 produces prostaglandins that are often described as maintaining a “housekeeping role” within the body. This role includes:

  • • Control of smooth muscle tone in blood vessels, the lungs, the gastrointestinal tract and the uterus.
  • • Modulation of gastric acid (¯) and mucus (­­­­­) secretion.
  • • Effects on platelet aggregation (inhibition: PGD2/PGI2; promotion: thromboxane A2).
  • • Renal renin release (PGs released via macula densa cells).

COX-2 is the inducible form of the enzyme, produced secondary to tissue damage and inflammation. It causes activation of PGE2 and PGI2 which are implicated in hyperalgesia and further inflammation (predominantly through vasodilatation and increasing the effects of bradykinin and histamine). Selective COX-2 inhibitors exist which provide some gastric protection; however, they are associated with an increased risk of major coronary events.


Absorption: rapid via the small intestine
Distribution: high protein binding, low volume of distribution
Metabolism: hepatic
Excretion: inactive metabolites via urine and bile

Side effects of NSAIDs

  • Damage to the gastric mucosa
  • Irritation, erosion and ulceration within the GI tract. The systemic reduction of prostaglandins leads to reduction of gastric mucus, lack of inhibition of gastric acid production and mucosal wall vasoconstriction which may all contribute to mucosal damage. 
  • BNF risk profiles:
    • o Ketorolac, ketoprofen and piroxicam are associated with the highest risk of gastrointestinal erosion.
    • o Naproxen, diclofenac and indomethacin are associated with an intermediate risk.
    • o Ibuprofen is associated with the lowest risk.
    • o Selective COX-2 inhibitors (celecoxib, etoricoxib, parecoxib) are associated with a lower risk than non-selective NSAIDs.
  • The risk is higher in the elderly.

Cardiovascular events

• All NSAIDs may be associated with a slightly elevated risk of thrombotic events (e.g. myocardial infarction and stroke). Increased incidence of major coronary events was originally associated with COX-2 inhibitors but has now been noted with diclofenac (150 mg/day) and high-dose (2.4 g/day) ibuprofen.
• Naproxen and ibuprofen (<1.2 g/day) have the lowest thrombotic risk.
• NSAIDs increase blood pressure and should be used with caution in patients with hypertension. They are contraindicated in severe heart failure.

Renal impairment

• PGI2 and PGE2 are vital to renal vasculature smooth muscle tone, and thus renal perfusion. Analgesic nephropathy (renal papillary necrosis and chronic interstitial nephritis) can occur due to these effects.
• Caution should be used in patients with pre-existing renal disease (and avoidance where possible). If required, renal function should be monitored and the lowest dose used, for the shortest duration.
• NSAIDs also cause electrolyte and fluid retention, which may worsen renal and cardiac failure as well as hypertension.

NSAID-induced asthma

• Prevalence thought to be 7–14% in the USA.
• Samter’s triad: asthma, aspirin sensitivity and nasal polyps.
• Thought to be due to increased leukotrienes (causing bronchospasm) and reduced PGE2-mediated bronchodilation.

Altered platelet function

• Aspirin irreversibly affects platelets, reducing aggregation and preventing vasoconstriction to allow stable clot formation. Its effects remain for the duration of the platelet’s lifespan (7–14 days). This is advantageous in the prevention and treatment of coronary and cerebrovascular disease.
• COX-2 inhibitors do not inhibit platelet function.


• NSAIDs should be avoided or used with caution with concurrent highly protein-bound medications (e.g. warfarin and phenytoin) as their effects may be increased.
• They may increase bleeding risk if taken with anticoagulants, selective serotonin release inhibitors or other NSAIDs.
• Increased risk of toxicity with certain drugs (e.g. lithium, methotrexate).


• More commonly seen with long-term use and initially may see rise in transaminase levels. Caution in hepatic impairment (increased risk of gastrointestinal bleeding and fluid retention); avoid in severe liver disease.

Specific NSAIDs

Table 1. Pharmacological information for specific NSAIDs.
(Adapted from T. E. Peck & S. A. Hill. Pharmacology for Anaesthesia and Intensive Care 2014 (4th edition). Cambridge University Press)

 COX selectivity
 Max. dose/d
 Elim t1/2
   Side effect profile
 Protein binding  GI  ACS  CVA
 Aspirin  Salicylates  NS  PO/PR  4 g  *  85%  +++  –  –
 Paracetamol  Para-aminophenol  N/A  PO/IV/PR  4 g  2 h  10%  0  0  0
 Ibuprofen  Propionic acid  NS  PO/TOP  1.2/2.4 g  2–3 h  99%  ++/ ++++  +/ +++  0
 Naproxen  Propionic acid  NS  PO  1 g  12–17 h  99%  ++++  0  0
 Ketorolac  Acetic acid derivative  NS  PO/IV/eye  40 mg  5 h  99%  ++++  ?  0
 Diclofenac  Acetic acid derivative  NS  PO/PR/ IV/TOP  150 mg  1–2 h  99%  ++  +++  0
 Tenoxicam  Oxicam  NS  PO/IV  20 mg  72 h  99%  +  ?  0
 Meloxicam  Oxicam  COX-2> COX-1  PO/PR  15 mg  20 h  99%  +  ?  0
 Celicoxib  Pyrazole  COX-2  PO  400 mg  11 h  97%  +  +++  0
 Etoricoxib  Methyl sulfone  COX-2  PO  120 mg  22 h  90%  +  +++  0
 Parecoxib  Pyrazole  COX-2  IV  80 mg  22 m  98%  +  +++  0

Max. dose/d: maximum daily dose; Elim t1/2: elimination half life (hours); Side effect profile – GI: gastrointestinal erosions, ACS: acute coronary events, CVA: cerebrovascular events; GI, gastrointestinal; NS: not selective; *initial first-order kinetics 15–30 minutes followed by zero-order kinetics when saturated enzyme system.

Author: Dr Sarah Hudson

Further reading

Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care 2014 (4th edition). Cambridge University Press. pp 141–53.

E-Learning for healthcare. E-Pain module: Non-steroidal Anti-inflammatory Drugs Available at (last accessed 10 September 2016).

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. Available at (last accessed 10 September 2016).

Laidlaw T, Israel E. Aspirin-exacerbated respiratory disease. In: UpToDate, Bochner B (Ed). Available at URL: (last accessed 10 September 2016).

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