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Review
. 2020 Nov 30:11:580289.
doi: 10.3389/fphar.2020.580289. eCollection 2020.

Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action

Nobuko Ohashi  1 , Tatsuro Kohno  2
Affiliations
Review

Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action

Nobuko Ohashi et al. Front Pharmacol. .

Abstract

Acetaminophen is one of the most commonly used analgesic agents for treating acute and chronic pain. However, its metabolism is complex, and its analgesic mechanisms have not been completely understood. Previously, it was believed that acetaminophen induces analgesia by inhibiting cyclooxygenase enzymes; however, it has been considered recently that the main analgesic mechanism of acetaminophen is its metabolization to N-acylphenolamine (AM404), which then acts on the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid 1 receptors in the brain. We also recently revealed that the acetaminophen metabolite AM404 directly induces analgesia via TRPV1 receptors on terminals of C-fibers in the spinal dorsal horn. It is known that, similar to the brain, the spinal dorsal horn is critical to pain pathways and modulates nociceptive transmission. Therefore, acetaminophen induces analgesia by acting not only on the brain but also the spinal cord. In addition, acetaminophen is not considered to possess any anti-inflammatory activity because of its weak inhibition of cyclooxygenase (COX). However, we also revealed that AM404 induces analgesia via TRPV1 receptors on the spinal dorsal horn in an inflammatory pain rat model, and these analgesic effects were stronger in the model than in naïve rats. The purpose of this review was to summarize the previous and new issues related to the analgesic mechanisms of acetaminophen. We believe that it will allow clinicians to consider new pain management techniques involving acetaminophen.

Keywords: N-acylphenolamine; acetaminophen; analgesia; brain; spinal dorsal horn.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Analgesic mechanism of acetaminophen. Acetaminophen is metabolized to p-aminophenol, which easily crosses the blood-brain barrier and is converted to AM404 by FAAH. AM404 mainly acts on both the brain and spinal cord via COX, anandamide, CB1, TRPV1, opioid, and 5-HT3 receptors. AM404, N-acylphenolamine; FAAH, fatty acid amide hydrolase; COX, cyclooxygenase; CB1, cannabinoid 1; TRPV1, transient receptor potential vanilloid 1.
See this image and copyright information in PMC

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