An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact

Figures & data

Figure 1 Schematic representation of the central mechanism of action of paracetamol to its antinociceptive activity. Paracetamol is deacetylated in p-aminophenol in the liver, then metabolized in the brain by FAAH into AM404. AM404 activates the TRPV1 channel‐mGlu5 receptor‐PLC‐DAGL‐CB1 pathway and co-activates the Cav 3.2 T-type calcium channel, which in turn reinforces the activity of the descending serotonergic pathways.

Table 1 Selected Clinical Studies Using Paracetamol Plus Opioids for Acute Post-Operative Pain

Study, Year	Type of Surgery	Design	N	Treatment Groups, Doses (mg)	Doses/Timing	Outcome
Fricke et al, 2002^Citation130	Oral surgery	Double-blind RCT	200	Tramadol/Paracetamol 37.5 mg/325 mg Tramadol/ Paracetamol 75 mg/650 mg Hydrocodone/Paracetamol 10 mg/650 mg Placebo	Single dose, postoperative	Comparable analgesia, but better tolerability for tramadol/Paracetamol than hydrocodone/ Paracetamol
MacLeod et al, 2002^Citation131	Dental	Double-blind RCT	82	Codeine/Paracetamol 30 mg/1000 mg Paracetamol 1000 mg	3 doses over 8 hours	Better analgesia with combination, with a similar rate of adverse events
Smith et al, 2004^Citation132	Orthopedic and abdominal surgery	Double-blind RCT	305	Tramadol/Paracetamol 75 mg/650 mg Codeine/Paracetamol 60 mg/600 mg Placebo	1 to 2 tablets every 4 to 6 hours as needed for pain for 6 days.	Both active combinations provided significantly greater pain relief than placebo; scores were similar for tramadol/ Paracetamol and codeine/paracetamol.
Daniels et al, 2011^Citation122	Dental	Double-blind RCT	678	Ibuprofen/Paracetamol 400 mg/1000 mg Ibuprofen/Paracetamol 200 mg/500 mg Ibuprofen/Codeine 400 mg/25.6 mg Codeine/ Paracetamol 30 mg/1000 mg Placebo	Single dose, postoperative	Ibuprofen/Paracetamol groups were superior in pain reduction to ibuprofen/codeine; ibuprofen/Paracetamol, and noninferior to ibuprofen/codeine
Rawal et al 2011^Citation133	Ambulatory hand surgery	Double-blind RCT	462	Tramadol/Paracetamol 37.5 mg/325 mg Tramadol 50 mg	Before and immediately after surgery and every 6 hours thereafter	Comparable analgesic efficacy, fewer adverse events with tramadol/paracetamol, and reduced tramadol consumption by 24%
Sniezek et al, 2011^Citation123	Mohs surgery and cutaneous reconstruction	Double-blind RCT	210	Paracetamol 1000 mg Ibuprofen/Paracetamol 400 mg/1000 mg Codeine/Paracetamol 30 mg/ 325 mg	Immediately after surgery and every 4 hours for up to 4 doses	Ibuprofen/paracetamol is superior to other 2 treatments in pain control; Higher rate of AEs under codeine/Paracetamol compared with ibuprofen/Paracetamol and Paracetamol alone
Aweke et al, 2020^Citation134	Abdominal surgery	Single blind RCT	63	Paracetamol 1000 mg Diclofenac /Paracetamol 75 mg/1000 mg Tramadol/Paracetamol 100 mg/1000 mg	Single dose, postoperative	Paracetamol–tramadol and Paracetamol–diclofenac reduce cumulative postoperative analgesic consumption and prolongs the time to first rescue analgesic
Liu et al, 2021^Citation112	Arthroscopic knee surgery	Open-label RCT	232	Oxycodone/Paracetamol 10 mg/650 mg Celecoxib	Single dose, postoperative	Oxycodone–Paracetamol increased analgesic efficacy, with comparable safety profiles compared with celecoxib.
Singh et al, 2021^Citation135	Rotator cuff repair	Open-label RCT	57	Oxycodone/Paracetamol 5 mg/1000 mg Oxycodone 5 mg Paracetamol 1000 mg	Combinations every 6 hours postoperative as needed Paracetamol 1000 mg perioperative	Perioperative acetaminophen significantly decreased opioid consumption and improved overall pain control.

Abbreviation: RCT, randomized controlled trial.

Fricke JR, Karim R, Jordan D, Rosenthal N. A double-blind, single-dose comparison of the analgesic efficacy of tramadol/acetaminophen combination tablets, hydrocodone/acetaminophen combination tablets, and placebo after oral surgery. Clin Ther. 2002;24(6):953–968. doi:10.1016/S0149-2918(02)80010-8

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Smith AB, Ravikumar TS, Kamin M, Jordan D, Xiang J, Rosenthal N. Combination tramadol plus acetaminophen for postsurgical pain. Am J Surg. 2004;187(4):521–527. doi:10.1016/j.amjsurg.2003.12.038

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Daniels SE, Goulder MA, Aspley S, Reader S. A randomised, five-parallel-group, placebo-controlled trial comparing the efficacy and tolerability of analgesic combinations including a novel single-tablet combination of ibuprofen/paracetamol for postoperative dental pain. Pain. 2011;152(3):632–642. doi:10.1016/J.PAIN.2010.12.012

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Rawal N, Macquaire V, Catalá E, Berti M, Costa R, Wietlisbach M. Tramadol/paracetamol combination tablet for postoperative pain following ambulatory hand surgery: a double-blind, double-dummy, randomized, parallel-group trial. J Pain Res. 2011;4:103. doi:10.2147/JPR.S16760

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Sniezek PJ, Brodland DG, Zitelli JA. A randomized controlled trial comparing acetaminophen, acetaminophen and ibuprofen, and acetaminophen and codeine for postoperative pain relief after Mohs surgery and cutaneous reconstruction. Dermatol Surg. 2011;37(7):1007–1013. doi:10.1111/J.1524-4725.2011.02022.X

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Aweke Z, Seyoum F, Shitemaw T, Doba DN. Comparison of preemptive paracetamol, paracetamol-diclofenac & paracetamol-tramadol combination on postoperative pain after elective abdominal surgery under general anesthesia, Ethiopia: a randomized control trial study, 2018. BMC Anesthesiol. 2020;20(1). doi:10.1186/S12871-020-01115-6

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Liu J, Di J, Zhang Y, Xing E. Oxycodone–paracetamol tablet exhibits increased analgesic efficacy for acute postoperative pain, higher satisfaction and comparable safety profiles compared with celecoxib in patients underwent arthroscopic knee surgery. Inflammopharmacology. 2021;29(4):1091–1099. doi:10.1007/s10787-021-00828-5

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Singh AM, Kirsch JM, Patel MS, et al. Effect of perioperative acetaminophen on pain management in patients undergoing rotator cuff repair: a prospective randomized study. J Shoulder Elb Surg. 2021;30(9):2014–2021. doi:10.1016/J.JSE.2021.03.132

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