*1.4.3 Paracetamol (acetaminophen, N-acetyl-p-aminophenol; APAP)*

APAP are likely to be the most commonly used pharmaceutical worldwide [119, 120], are expected to reach a global market value of USD 999.4 million in 2020 [121] and is included in the 21st World Health Organisation Model List of Essential Medicines as updated in March 2017 [122]. However, recently there have been debates from the National Institute for Health and Care Excellence, about the relevance of APAP for some conditions [123]. The efficacy of paracetamol to treat chronic pain has been questioned with systematic reviews showing limited (sometimes null) effects on chronic pain in some conditions [120, 124, 125]. Nonetheless, APAP can be beneficial for acute pain, [126–128], similar to NSAIDs and opioids [129–131]. The precise mechanism of action remains unknown, however this is most likely due to the interwoven interactions that APAP have in multiple pain pathways. Our current knowledge suggests that APAPs are metabolised by the liver into p-aminophenol, then bound with arachidonic acid, primarily in the brain, to form AM404 (N- (4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide) through fatty acid amide hydrolase (FAAH) activity [132–134]. Like NSAIDs, APAP are analgesic and antipyretic, however APAP lacks peripheral anti-inflammatory properties, therefore act through the central nervous system and not peripheral tissues [135]. Current evidence suggests that there are four metabolic systems that interact to elicit the analgesic and antipyretic properties of APAP, the Eicosanoid, Opioidergic, Seretogentic and Endocannabinoid systems [136].

Briefly, like NSIADs, APAP can inhibit central cyclo-oxygenases (COX-1, COX-2) including a proposed third isoform COX-3 [137–142]. Although the results are controversial [143] it is thought that they are involved in prostaglandin (PGs) production thus the analgesic mechanism of action. Furthermore, APAP are more effective in environments with low peroxide tone and low arachidonic acid levels, such as in the central nerves system, mainly through local depletion of glutathione leading to decreased production of PGE2 [139]. Considering the antinociceptive effects of APAP, one of the main brain derived metabolites AM404 (N-arachidonoyl-phenolamine) is decrease in the presence of opioid receptor antagonist. AM404 inhibits the nociceptive activity of particular APAPs in part by modulating many neurotransmitters, including 5-HT, glutamate, and γ-aminobutyric acid [143–145]. Although the precise receptors have not been identified [146–149], serotonin antagonists block the analgesic effect of APAP through mainly indirect non-binding mechanisms [146, 150]. One possible interaction with the serotonergic pathway maybe though altering CNS monoamine neuron types in the brain that contain a major receptor for PGE2 (EP3 receptor [139]). Further to the above, AM404 can inhibit anandamide [151], with stimulation of (canobinoide 1) CB1 receptor activity (without binding) via FAAH [133], suggesting a reliance of APAP antinociceptive activity on interaction with the endocannabinoid system [134, 152]. Interestingly, AM404 is not identifiable in the blood after APAP administration [133] which might explain, to some degree, the absence of peripheral anti-inflammatory action [134]. This could help to explain why APAP may not have significant clinical effect on conditions such as osteoarthritis (further details below; [153, 154]). A recent study confirmed that APAPs act mainly on central analgesic pathways, showing that APAP modifies the activity and connectivity of analgesia via FAAH, activating a signalling cascade involving TRPV1 channels, mGlu5

receptors, PLC, DAGL and CB1 receptors, associated with the release of glutamate and GABA – through the endocannabinoid systems [155]. Though the molecular mechanisms that provide analgesia are beginning to come to light, there is also potential substantial detrimental side effects of APAPs.

APAPs are generally considered safe if administered at appropriate doses for short periods [156]. However, they remain one of the leading causes of liver disease in high-income countries [157, 158] which has led to legislative restrictions in many countries [159]. It is well accepted that APAPs cause liver injury, hepatotoxicity, mitochondrial toxicity [160, 161] and that this toxicity can be effected by interindividual variation [162]. Nonetheless, consuming APAP can increase the risks of hospitalisation for perforation, peptic ulceration and bleeding [163], relative rates of adverse cardiovascular events such as myocardial infarction, stroke, coronary heart disease and upper gastrointestinal disease such as gastroduodenal ulcers and haemorrhages [164], often in a dose response manor. However, observational studies show a favourable side effect profile for APAPs compared with NSAIDs when used in older people with chronic pain conditions [165]. Data from the most recent meta-analysis shows that APAPs are nearly four times more likely to have abnormal results on liver function tests than placebo [166].
