TeacherOfMedicine: Non-steroidal anti-inflammatory drugs

‘As needed’ treatment of mild-to-moderate pain (e.g. dysmenorrhoea, dental pain) as an alternative to or in addition to paracetamol. Analgesia from a single dose of a non-steroidal anti-inflammatory drug (NSAID) is similar to that from paracetamol, which is therefore preferred, particularly in those at risk of adverse effects.
Regular treatment for pain related to inflammation, particularly of the musculoskeletal system, e.g. in rheumatoid arthritis, severe osteoarthritis and acute gout.

NSAIDs inhibit synthesis of prostaglandins from arachidonic acid by inhibiting cyclooxygenase (COX). COX exists as two main isoforms. COX-1 is the constitutive form. It stimulates prostaglandin synthesis that is essential to preserve integrity of the gastric mucosa; maintain renal perfusion (by dilating afferent glomerular arterioles); and inhibit thrombus formation at the vascular endothelium.
COX-2 is the inducible form, expressed in response to inflammatory stimuli.
It stimulates production of prostaglandins that cause inflammation and pain. The therapeutic benefits of NSAIDs are principally mediated by COX-2 inhibition and adverse effects by COX-1 inhibition, although there is some overlap between the two. Selective COX-2 inhibitors (e.g. etoricoxib) were developed in an attempt to reduce the adverse effects of NSAIDs.

The main adverse effects of NSAIDs are gastrointestinal (GI) toxicity, renal impairment and increased risk of cardiovascular (CV) events (e.g. myocardial infarction and stroke). The likelihood of adverse effects differs between NSAIDs.
Of all the non-selective NSAIDs (>20 are available), ibuprofen is associated with the lowest risk of GI effects.
Naproxen and low-dose ibuprofen are associated with the lowest risk of CV events. COX-2 inhibitors cause fewer GI side effects than non-selective NSAIDs, but are associated with an increased risk of CV events.
All NSAIDs including COX-2 inhibitors can cause renal impairment.
Other adverse effects include hypersensitivity reactions, e.g. bronchospasm and angioedema, and fluid retention, which can worsen hypertension and heart failure.

Avoid NSAIDs in severe renal impairment, heart failure, liver failure and known NSAID hypersensitivity.
If NSAID use is unavoidable in patients at high risk of adverse effects (e.g. prior peptic ulcer disease or GI bleeding, cardiovascular disease, renal impairment), use the safest NSAID at the lowest effective dose for the shortest possible time.
Diclofenac appears to be associated with a significantly increased risk of cardiovascular events compared with other NSAIDs. Diclofenac is now contraindicated with any form of cardiovascular disease. Studies have shown that naproxen and low-dose ibuprofen have the best cardiovascular risk profiles of the NSAIDs.

Many drugs increase the risk of NSAID-related adverse effects including: GI ulceration: low-dose aspirin, corticosteroids; GI bleeding: anticoagulants, SSRIs, venlafaxine; renal impairment: ACE inhibitors, diuretics.
NSAIDs increase the risk of bleeding with warfarin and reduce the therapeutic effects of antihypertensives and diuretics.

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