NSAIDS have antipyretic activity and can be used to treat fever.   Fever is caused by elevated levels of prostaglandin E2 , which alters the firing rate of neurons within the hypothalamus that control thermoregulation.   Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis ( PGE2 ) within the hypothalamus .   PGE2 signals to the hypothalamus to increase the body's thermal set point.   Ibuprofen has been shown more effective as an antipyretic than paracetamol (acetaminophen).   Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D & E.
Although different NSAIDs have different structures, they all work by blocking cyclo-oxygenase (COX) enzymes. There are two main types of COX enzymes: COX-1 and COX-2. Both types produce prostaglandins; however, the main function of COX-1 enzymes is to produce baseline levels of prostaglandins that activate platelets and protect the lining of the gastrointestinal tract, whereas COX-2 enzymes are responsible for releasing prostaglandins after infection or injury. Prostaglandins have a number of different effects, one of which is to regulate inflammation.
Formulations of topical diclofenac, ibuprofen, ketoprofen, piroxicam, and indomethacin demonstrated significantly higher rates of clinical success (more participants with at least 50% pain relief) than matching topical placebo (moderate or high quality data ). Benzydamine did not. Three drug and formulation combinations had NNTs for clinical success below 4. For diclofenac, the Emulgel® formulation had the lowest NNT of (95% CI to ) in two studies using at least 50% pain intensity reduction as the outcome . Diclofenac plasters other than Flector® also had a low NNT of ( to ) based on good or excellent responses in some studies. Ketoprofen gel had an NNT of ( to ), from five studies in the 1980s, some with less well defined outcomes. Ibuprofen gel had an NNT of ( to ) from two studies with outcomes of marked improvement or complete remission. All other drug and formulation combinations had NNT values above 4, indicating lesser efficacy .