Acetaminophen (
APAP) in humans has robust effects with a high therapeutic index in altering postoperative and inflammatory
pain states in clinical and experimental
pain paradigms with no known abuse potential. This review considers the literature reflecting the preclinical actions of
acetaminophen in a variety of
pain models. Significant observations arising from this review are as follows: 1)
acetaminophen has little effect upon acute nociceptive thresholds; 2)
acetaminophen robustly reduces facilitated states as generated by mechanical and thermal hyperalgesic end points in mouse and rat models of
carrageenan and complete
Freund's adjuvant evoked
inflammation; 3) an antihyperalgesic effect is observed in models of facilitated processing with minimal
inflammation (eg, phase II intraplantar
formalin); and 4) potent anti-hyperpathic effects on the
thermal hyperalgesia, mechanical and cold
allodynia, allodynic thresholds in rat and mouse models of
polyneuropathy and
mononeuropathies and
bone cancer pain. These results reflect a surprisingly robust
drug effect upon a variety of facilitated states that clearly translate into a wide range of efficacy in preclinical models and to important end points in human
therapy. The specific systems upon which
acetaminophen may act based on targeted delivery suggest both a spinal and a supraspinal action. Review of current targets for this molecule excludes a role of
cyclooxygenase inhibitor but includes effects that may be mediated through metabolites acting on the TRPV1 channel, or by effect upon
cannabinoid and
serotonin signaling. These findings suggest that the mode of action of
acetaminophen, a
drug with a long therapeutic history of utilization, has surprisingly robust effects on a variety of
pain states in clinical patients and in preclinical models with a good therapeutic index, but in spite of its extensive use, its mechanisms of action are yet poorly understood.