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. 2021 Nov 12;14:3521–3552. doi: 10.2147/JPR.S308028

Table 1.

Preclinical Analgesic Effect of Acetaminophen by PO, IT, IP/SC, IV, IT, ICV Administration in Acute Nociception

Study Test Model Nociceptive State Vehicle Specie Sex (M/F) Effect of APAP PO mg/kg IP/SC/IPLT mg/kg IV mg/kg IT µg ICV µg Reference
1. Ginger rhizome enhances anti-inflammatory and anti-nociceptive effects of APAP in mouse fibromyalgia Paw pressure Hot plate Tail flick Fibromyalgia syndrome Saline Mice/F Increased threshold 400 Montserrat-de la Paz et al 201866
2. Enhanced analgesic effects of nefopam with APAP Tail flick Hot plate Normal Saline Mice/F, M No change 42–168 Li et al 2018107
Tail flick Hot plate Normal Saline Mice/F, M No change 60–240
3. Central dopaminergic system plays a role in analgesic action of APAP Hot plate Normal Saline Mice/M Increased escape latency 100 Bhagyashree et al 201868
4. Effect of modulating 5-HT on analgesic action of APAP Hot plate Normal N/A Albino mice/F, M Increased latency 200 Karandikar et al 2016110
5. Interactions with codeine and APAP in mice Hot plate Normal mice Saline Mice/F, M Increased latency 20 Raskovic et al 2015111
6. Synergic effects of pregabalin–APAP combination in somatic and visceral nociceptive reactivity Tail flick Normal mice Saline Mice/M Increased latency 200 Mititelu et al 2014101
7. APAP administration during neonatal brain development affects cognitive function and alters analgesic and anxiolytic response in adult Hot plate Normal mice Saline Mice/M Increased latency 30–60 Viberg et al 201491
8. Cav3.2 calcium channels in supraspinal effect of APAP Tail flick Von Frey Paw immersion tests Normal mice or Cav3.2 knockout mice Saline Mice/M Increased latency 200 Kerckhove et al 201470
9. TRPA1 mediates spinal antinociception induced by APAP and a cannabinoid. Hot plate Paw pressure Normal mice or Trpa1–/– mice Saline Mice/M Effects of spinal/systemic APAP lost in Trpa1–/– 300 Andersson et al 2011141
Hot plate Paw pressure Normal mice or Trpa1–/– mice Saline Mice/M Effects of spinal/systemic APAP lost in Trpa1–/– 50 or 100
10 Phenazopyridine on rat bladder primary afferent activity, and comparison with lidocaine and APAP Bladder primary afferent activity Normal Saline Rat/F Decreased activity 1–10 Aizawa et al 201092
11 Different mechanisms underlie analgesic actions of APAP and dipyrone in inflammatory pain Von Frey Normal Saline Rat/M Increased threshold
Dose dependent		 60–360 Rezende et al 2008124
12. Endocannabinoid and serotonergic systems needed for APAP-induced analgesia Von Frey Hot plate Normal DMSO and saline Rat/M Increased threshold 300 Mallet et al 200895
13. Differential involvement of opioid and 5-HT systems in the antinociceptive activity of AM404: comparison with APAP Hot plate Paw pressure Normal 12.5% 1,2-propanediol and saline Rat/M Increased threshold 400 Ruggieri et al 200876
14. Effect of acute and repeated administration of APAP on opioid and 5-HT systems Hot plate Normal Saline Rat/M Increased threshold 400 Sandrini et al 2007139
15. Modulation of APAP by caffeine and by adenosine A2 receptor antagonists.- Von Frey Hot plate Normal PO4 buffer saline Mice/N/A Increased threshold 10–200 Godfrey et al 2006116
16. The analgesic activity of APAP is prevented by CB1 receptor blockade Hot plate Normal Saline Rat/M Increased threshold
Dose dependent		 250–1000 Ottani et al 200677
17. Opioid receptor antagonists on action of APAP Paw pressure Normal Saline Rat/M Increased threshold 400 Bujalska 200481
18. APAP involves spinal tropisetron-sensitive, non–5-HT3 receptor Paw pressure Normal Saline Rat/M Increased threshold 400 Libert et al 2004173
19. Involvement of central 5-HT1B and 5-HT3 receptors in effect of APAP Hot plate Paw pressure Normal 1,2-propanediol/saline Rat/M Increased
latency/threshold		 400 Sandrini et al 2003117
20. Role of 5-HT1A/B autoreceptors in antinociceptive effect of APAP Hot plate Normal Propylene glycol/water Mice/M Increased latency
Dose dependent		 300–800 Roca-Vinardell et al 2003140
21. NCX-701 (nitroAPAP) is an effective antinociceptive agent in rat withdrawal reflexes and wind-up Electrical stimulation Von Frey Normal DMSO/polyethylene glycol Rat/M Increased threshold 22–724 Romero-Sandoval et al 2002150
22. COX and NOS inhibitors on action of APAP Paw pressure Normal Saline Rat/M Increased threshold
Dose dependent		 100–800 Bujalska and Gumulka 200184
23. 5-HT receptor subtypes involved in spinal antinociceptive effect of APAP Paw pressure test Normal Trisodic citrate, 0.02 g/mL Rat/M Increased threshold 200 Courade et al 2001151
24. APAP-induced antinociception via central 5-HT2A receptors Tail flick Normal rat 12.5% of 1,2-propanediol in saline Rat/M Increased latency 300 or 400 Srikiatkhachorn et al 1999127
25. APAP exerts spinal antinociceptive effect involving interaction with 5-HT3 receptors Paw pressure Normal Solvent trisodic citrate, 0.02 g/mL Rat/M Increased threshold 200–800 Pelissier et al 199687
Paw pressure Normal Solvent trisodic citrate, 0.02 g/mL Rat/M Increased threshold 50–300
Paw pressure Normal Solvent trisodic citrate, 0.02 g/mL Rat/M Increased threshold 100–200
26. Antinociceptive action of APAP associated with changes in 5-HT system in brain Hot plate Normal 1,2-propanediol in saline Rat/M Increased latency
Dose dependent		 200–400 Pini et al 1996128
27. Central APAP effect involving spinal 5-HT3 receptors C fiber-evoked reflex Normal N/A Rat/M Increased threshold 200–400 Pelissier et al 1995153
28. Increasing-temperature hot plate test Hot plate Normal Propanediol in NaCl Rat or mice/M Increased latency 200–400 Tjølsen et al 1990119
29. Depression by morphine, metamizol (dipyrone), lysine acetylsalicylate and APAP, of thalamus neurons evoked by electrical stimulation Behavioral response and evoked activity in thalamus Normal Saline Rat/M Increased threshold
Dose dependent		 5–25 Carlsson et al 1988174
30. Central effect of APAP depresses nociceptive activity in thalamic neurons Behavioral response Normal Saline Rat/M and F Increased threshold 50–150 Carlsson and Jurna 1987134
31. Acute toxicity and analgesic action of a combination of buclizine, codeine and APAP in tablet/suppository form Tail flick Normal Saline Mice/M and F Increased latency
Dose dependent		 97–772 Behrendt et al 198598
32. Blood levels and analgesic effects of APAP Paw pressure Normal Water Mice/M Increased threshold
Dose dependent		 149–360 Shibasaki et al 1979152
Paw pressure Normal Water Mice/M Increased threshold
Dose dependent		 111–360
33. Inhibition of prostaglandin synthetase in the brain by APAP N/R N/R N/R Rabbit/NR Increased threshold ID50 14 μg/mL Flower and Vane 1972105