Recent works has emphasized that the mechanism of action of paracetamol analgesic depend on
its metabolism in the body, since a breakdown product of paracetamol, the AM404 is now
considered the analgesic metabolite of paracetamol suggesting as paracetamol may be a
pro-drug.
Indeed, it has been shown that paracetamol may have a deleterious effect, especially in
vulnerable populations (hepatic insufficiency, elderly). First results showed a very
significant decrease in sulfatation and gluthatione and increased phase 1 metabolism of
acetaminophen, which involves enzymes such as cytochrome P450.
Multifactorial causes, combining nutrition (depletion of sulfur amino acids), increased
detoxification of toxic metabolites of paracetamol, stress or trauma are discussed to explain
the results.
Clinical studies showed a great variability of pain assessment by patients and variability in
the metabolic response of paracetamol. Genetic factors probably play a role remains largely
unknown.
The review of the literature on genetic polymorphism shows the involvement of a number of
enzymes that are well known, predominantly on the metabolism of acetaminophen liver, but
without connection with its analgesic effect. This is a critical missing link in the
understanding of the analgesic effect of paracetamol.