Paracetamol revisited

Paracetamol (recommended international nonproprietary name) (acetaminophen) was synthesized in 1878 by Morse (Morse HN: 1878.) and first used clinically by von Mering in 1887. But it was quickly discarded in favour of phenacetin. “Rediscovered” in 1948, following the studies of Brodie and Axelrod (Brodie BB 1948.) and marketed in the 1950s in the United States as an analgesic replacement for phenacetin, “condemned” for its nephrotoxicity. Unfounded concerns about paracetamol safety delayed its widespread acceptance until the 1970s. From then on, paracetamol is one of the most popular and widely used drugs in the world for the treatment of pain and fever; probably the most commonly prescribed medicine in children.
Paracetamol occupies a unique position among analgesic drugs, both for the type of pain relieved and for the side effects. So, for example, it is almost unanimously considered to be ineffective in inflammatory pain (unlike NSAIDs), as well as in intense pain or that arising from smooth muscle spasm in hollow viscera (unlike opiates); and it has no depressant effect on respiration (unlike opiates) and does not produce gastrointestinal damage or untoward cardiorenal effects (unlike NSAIDs).
The peculiarity of effects and side effects of paracetamol should have suggested a peculiar mechanism of action for this drug. On the contrary, and curiously, surprising efforts have repeatedly been made in order to demonstrate that paracetamol shares the mechanism(s) of action of NSAIDs.
Paracetamol would act as a pro-drug, the active metabolite (AM404) being formed in the brain through the conjugation of the de-acetylated derivative of paracetamol (p-aminophenol) with arachidonic acid, by the action of fatty acid amide hydrolase (FAAH).