Mechanistic Insights into the Analgesic Action of Acetaminophen: Its Bioactive Metabolite Induces Peripheral Analgesia in Addition to Central Analgesia.

The molecular target and detailed mechanism of analgesic acetaminophen are still not fully understood despite being commonly used for many years. Through a literature search, the present study aimed to characterize the cyclooxygenase (COX) inhibitory properties of acetaminophen in comparison with nonsteroidal anti-inflammatory drugs (NSAIDs) and to gain novel mechanistic insights into its analgesic action, especially focusing on the peripheral mechanisms. Comparative characterization indicated that acetaminophen is relatively selective for COX-2 but less potent to inhibit COX than NSAIDs. This narrative review suggests that acetaminophen is very likely to be a prodrug, which is metabolically converted into bioactive N-arachidonoylphenolamine, AM404, by fatty acid amide hydrolase-mediated conjugation of acetaminophen metabolite 4-aminophenol with arachidonic acid not only in the central nervous system but also in the peripheral nervous system. It is considered that AM404 activates transient receptor potential vanilloid 1 and cannabinoid type 1 receptor distributed in the brain and spinal cord to induce analgesia centrally. In addition, it is speculated that AM404 produced in trigeminal ganglion neurons, dorsal root ganglion neurons, and primary sensory neurons inhibits nociceptive voltage-gated sodium channels through the local anesthetic binding site to suppress pain signaling and inhibits COX-2 to prevent the biosynthesis of prostaglandins responsible for nociception, thereby inducing peripheral analgesia. We propose the mechanistic hypothesis for the analgesic effects of acetaminophen to integrate central and peripheral action of its bioactive entity AM404, which should provide the pharmacological rationale for the use of acetaminophen to relieve postoperative and inflammatory pain and its application to multimodal analgesia.