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PLoS ONE 14(12):e0226834

Furthermore, AM404 inhibits sodium channels such as anesthetics, lidocaine and procaine.[14] Either of these actions by themselves has been shown to reduce pain, and are a possible mechanism for paracetamol, though it has been demonstrated that, after blocking cannabinoid receptors and hence making any action of cannabinoid reuptake irrelevant, paracetamol no longer has any analgesic effect, suggesting its pain-relieving action is indeed mediated by the endogenous cannabinoid system.[15] A theory that held some sway, but has now largely been discarded, is that paracetamol inhibits the COX-3 isoform of the cyclooxygenase family of enzymes.[6][16] This enzyme, when expressed in dogs, shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol

Encyclopedia of Malaria