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

Table 2.

Preclinical Analgesic Effect of Acetaminophen by PO, IT, IP/SC, IV, IT, ICV Administration in Tissue Injury and Inflammation

	Study	Test Model	Nociceptive State	Vehicle	Species Sex (M/F)	Effect of APAP	PO mg/kg	IP/SC/IPLT mg/kg	IV mg/kg	IT µg	ICV µg	Reference
1.	ATP-sensitive K⁺ channels and μ-opioid receptors in antinociceptive synergism of APAP-tapentadol	Formalin test	Formalin	Saline	Mice/M	Decreased behavior Dose dependent		56–562				Zapata-Morales et al 2018¹⁰⁶
2.	Synthesis and antinociceptive evaluation of bioisosteres and hybrids of naproxen, ibuprofen and APAP	Formalin test	Formalin	Saline	Rat/M	Decreased behavior Phase 2		0.6–3.2				González-Trujano et al 2018¹⁵⁷
4.	Enhanced analgesic effects of nefopam with APAP	Writhing test	Acetic acid	Saline	Mice/M	Decreased behavior Dose dependent		42–168				Li et al 2018¹⁰⁷
5.	APAP relieves inflammatory pain through CB1 in rostral ventromedial medulla	Von Frey	ITSP, extract IPLT zymosan	Saline	Mice/M	Increased threshold Dose dependent	30–300					Klinger-Gratz et al 2017⁶⁷
7.	Supraspinal TRPV1 desensitization induced by ICVT resiniferatoxin	Tail flick Formalin test	Resiniferatoxin agonist, hind paw)	Propylene glycol	Mice/M	Increased latency Decreased behavior		100 or 300				Fukushima et al 2017¹⁰⁸
8.	Imidazoline receptor and APAP schedule-controlled responses	Von Frey Thermal	Freund’s adjuvant	20% DMSO and saline	Rat/M	Increased threshold/latency Dose dependent		56–178				Siemian et al 2016¹⁰⁹
9.	Modulating 5-HT system on the analgesic action of APAP in mice	Formalin test	Formalin	N/A	Mice/M	Decreased behavior Phase 1/2		200				Karandikar et al 2016¹¹⁰
10.	Antinociceptive effects of sinomenine in postoperative pain	Von Frey	Incisional surgery model (Brennan)	N/A	Rat/M	Increased threshold Dose dependent	30–180					Zhu et al 2016⁶⁹
11.	Acetaminophen interacts with morphine and tramadol analgesia for the treatment of neuropathic pain	Von Frey	Carrag paw	Saline	Rat/M	Increased threshold Dose dependent	20–1000					Shinozaki et al 2015¹⁰⁴
12.	Supra-spinal FAAH required for APAP analgesia	Hot plate Von Frey	Carrag paw	Saline	Mice/M	Increased latency/threshold	200					Dalmann et al 2015⁹⁰
13.	Antinociception by MT(2) melatonin receptor partial agonists	Hot plate	MT(2) melatonin receptor partial agonists	70% dimethyl and 30% saline	Rat/M	Normalized threshold		200				López-Canul et al 2015¹⁵⁸
14.	Synergy of pregabalin-APAP in somatic/visceral pain	Writhing test	Acetic acid	Saline	Mice/M	Decreased behavior	200					Mititelu et al 2014¹⁰¹
15.	Adamantyl analogues of APAP as potent analgesic drugs via inhibition of TRPA1	Visceral pain	Acetic acid (IP, 2%)	N/A	Mice/M	Decreased behavior Dose dependent		100–200				Fresno et al 2014¹¹²
16.	Cav3.2 calcium channels in supra- spinal APAP effect	Formalin test	Formalin	Saline	Mice/M	Decreased behavior	200					Kerckhove et al 2014⁷⁰
17.	Arsenic decreases activity of APAP. Involvement of 5-HT and CB receptors	Formalin test	Formalin	Saline	Rat/M	Decreased behavior phase 1	400					Vijayakaran et al 2014⁷¹
18.	APAP involves spinal serotonin 5-HT7 and adenosine A1 receptors, and peripheral adenosine A1 receptors	Formalin test	Formalin	Saline	Mice/M	Decreased behavior Phase 2		300				Liu et al 2013¹²⁰
19.	Naltrexone did not change synergism between APAP and tramadol	Writhing test	Acetic acid	Saline	Mice/M	Decreased behavior Dose dependent				4.0		Miranda et al, 2012¹²¹
20.	APAP-induced analgesic and antihyperalgesic effects by 5-HT pathways and spinal 5-HT₇ receptors	Tail flick	Plantar incision	20:1:1:78 mixture of DMSO: ethanol: Tween saline	Mice/M	Increased latency Dose dependent	200–600					Dogrul et al 2012⁷²
21.	Caffeine inhibits APAP antinociception by spinal adenosine A₁ receptors	Formalin test	Formalin	20% DMSO	Mice/M	Decreased behavior phase 2 Dose dependent		100–300				Sawynok and Reid 2011¹²³
22.	Systematic evaluation of nefopam–APAP combination in rodent models of antinociception	Writhing test	Acetic acid	1% Tween 80 and saline	Mice/M	Decreased behavior Dose dependent		25–200				Girard et al 2011¹⁵⁹
		Formalin test	Formalin	1% Tween 80 and saline	Mice/M	Decreased behavior Dose dependent		100–600
		Hot plate	Carrag in hind paw	1% Tween 80 and saline	Rat/M	Normalized threshold		300–600
23.	Ondansetron does not block APAP-induced analgesia	Von Frey Hot plate	Fracture pain model	N/A	Mice/M	Increased threshold/Latency		300				Minville et al 2011¹¹³
24.	Synergy of APAP and oxcarbazepine	Paw pressure	Carrag hind paw	Tween 80 and saline	Rat/M	Increased threshold Dose dependent		50–200				Tomić et al 2010¹¹⁴
		Writhing test	Acetic acid	Tween 80 and saline	Rat/M	Decreased behavior Dose dependent		60–180
25.	Synergy between ibuprofen, APAP and codeine	Tail flick	Rat tail Ischaemia	DMSO and saline	Rat/M	Increased threshold Dose dependent		11–88				Mitchell et al 2010¹¹⁵
26.	TRPV1 in brain is involved in APAP- antinociception	Formalin test Hot plate Von Frey	FAAH and TRPV1 knockout mice	10% DMSO/2.5% Tween 80/Saline	Mice/M	Decreased behavior Increased latency/threshold	200					Mallet et al 2010⁷³
		Formalin test Hot plate Von Frey	FAAH and TRPV1 knockout mice	10% DMSO/2.5% Tween 80/Saline	Mice/M	Decreased behavior Increased latency/threshold		100
		Active movement	FAAH and TRPV1 knockout mice	10% DMSO/2.5% Tween 80/Saline	Mice/M	Decreased behavior Dose dependent		100–300
27.	Modulation of APAP and nefopam antinociception by 5-HT(3) receptor	Formalin test	Formalin	1% solution of Tween 80	Mice/M	Decreased behavior		400				Girard et al 2009¹⁶¹
28.	Synergy between rilmenidine/APAP	Writhing test	Acetic acid	Saline	Mice/M	Decreased behavior Dose dependent	127–445					Soukupová et al 2009⁹³
29.	Differential effects of APAP LPS induced hyperalgesia in various mouse pain models	Formalin test	Formalin	20% DMSO	Mice/M	Decreased behavior Phase 1/2 Dose dependent	25–300					Seo et al 2008¹⁴⁶
		Formalin test	Formalin	20% DMSO	Mice/M	Decreased behavior Dose dependent					25–100
		Formalin test	Formalin	20% DMSO	Mice/M	No effect				25–100
30.	Different mechanisms for APAP and dipyrone	Von Frey	Carrag hindpaw	Saline	Rat/M	Increased threshold		60–360				Rezende et al 2008¹²⁴
31.	CB and 5HT systems needed for APAP-analgesia	Formalin test	Formalin	DMSO and saline	Rat/M	Decreased behavior Phase 1/2.	300					Mallet et al 2008⁹⁵
35	APAP prevents hyperalgesia in central pain cascade	Hot plate	Spinal substance P	5% DMSO	Rat/M	Normalized threshold	300					Crawley et al 2008⁷⁴
		Hot plate	Spinal substance P	5% DMSO	Rat/M	Increased latency Dose dependent				10–200
32.	Morphine and ABT-594 (a nicotinic acetylcholine agonist) exert central analgesia	Abnormal postures and eye closure)	Cyclophosphamide to induce bladder inflammation	N/A	Rat/M	No change	44–480					Joshi et al 2008⁷⁵
33.	Different mechanisms underlie actions of APAP and dipyrone	Paw pressure	Carrag hindpaw	Saline	Mice/M	Increased threshold		60–360				Rezende et al 2008¹²⁴
34.	Isobolographic interactions between ketoprofen and APAP	Writhing test	Acetic acid	0.5% carboxymethylcellulose	Mice/M	Decreased behavior Dose dependent	ED 50 = 129 mg/kg					Qiu et al 2007⁹⁴
35.	Orofacial formalin test in the mouse: a behavioral model for studying physiology and modulation of trigeminal pain	Formalin test	Formalin	Saline	Rat/M	Decreased behavior Dose dependent		25–200				Luccarini et al 2006¹²⁵
36.	Analgesic effects of nonsteroidal anti-inflammatory drugs, APAP, and morphine	Von Frey	Bone cancer pain model	Methylcellulose 0.5% solution	Mice/M	Increased threshold	300					Saito et al 2005⁷⁸
37.	Spinal 5-HT1A influence nociceptive processing and effects of APAP, venlafaxine	Formalin test Paw pressure	IT administration of substance P	Saline containing 0.02 g/mL trisodium citrate	Rat/M	Decreased behavior Normalized threshold			50–300			Bonnefont et al 2005¹⁴⁹
38.	Effect of aspirin and APAP on proinfl ammatory cytokine-induced pain	Scratch biting episodes	IT TNF-α, IL-β or IFN-γ	20% DMSO	Mice/M	Decreased behavior Dose dependent	100–300					Kwon et al 2005⁷⁹
39.	IPLT APAP does not act locally	Formalin test	Formalin	Saline	Rat/M	Decreased behavior phase 1		10–20 (IPLT)				Bonnefont et al 2003⁸²
		Formalin test	Formalin	Saline	Rat/M	Decreased behavior phase 1/2 Dose dependent	100–400
		Formalin test	Formalin	Saline	Rat/M	Decreased behavior Phase 1/2 Dose dependent		100–300
		Formalin test	Formalin	Saline	Rat/M	Decreased behavior Phase 2					200
40.	Time course of progression of allodynia and efficacy of analgesics	Von Frey Hot plate Vocal	Freund’s adjuvant	Suspended in 0.5% methylcellulose	Rat/M	No change	100–600					Nagakura et al 2003⁸³
41.	APAP exerts a spinal, tropisetron-reversible effect	Von Frey	Carrag treated	Trisodic citrate, propacetamol	Rat/M	Normalized threshold Dose -dependent			100–300			Alloui et al 2002¹⁴³
		Von Frey	Carrag treated	Trisodic citrate, propacetamol	Rat/M	Normalized threshold Dose dependent				50–200
42.	Antinociceptive profiles of aspirin and APAP in formalin, substance P and glutamate pain models	Formalin test	Formalin	20% DMSO	Mice/M	Decreased behavior Dose dependent	10–300					Choi et al 2001⁸⁵
		Licking/biting	Intrathecal Substance P Glutamate pain	20% DMSO	Mice/M	Decreased behavior Dose dependent	10–300
43.	Antinociceptive synergy between spinal APAP and phentolamine	Abdominal irritant test	IP acetylcholine bromide	5% ethanol/water	Mice/M	Decreased behavior				137		Raffa et al 2001¹⁴⁴
44.	“Self-synergistic” spinal/supraspinal antinociception produced by APAP	Abdominal irritant test	Injected IP with acetylcholine bromide	5% ethanol/water	Mice/M	Decreased behavior				137		Raffa et al 2000¹⁵⁴
		Abdominal irritant test	Injected IP with acetylcholine bromide	5% ethanol/water	Mice/M	Decreased behavior					45–150
45.	Phenacetin, APAP and dipyrone: analgesic and rewarding effects	Formalin test	Formalin	Ethanol/water/10% Tween	Rat/M	Decreased behavior Phase 2 Dose dependent		25–400,				Abbott and Hellemans 2000¹²⁶
		Formalin test	Formalin	Ethanol/water/10% Tween	Rat/M	Decreased behavior, low > high dose		5–100 µg (IPLT)
		Formalin test	Formalin	Ethanol/water/10% Tween	Rat/M	Decreased behavior, phase 2 No dose dependency					3–50
46.	NitroAPAP exhibits anti-inflammatory and anti-nociceptive activity	Von Frey	Carrag hind paw	Saline	Mice/M	Normalized threshold Dose -dependent		25–100				Al-Swayeh et al 2000⁸⁶
		Abdominal irritant test	Acetic acid induced abdominal constrict	Saline	Mice/M	Normalized behavior Dose dependent	25–100
47.	Potentiation of APAP plus morphine involves 5-HT system	Formalin test	Formalin	12.5% of 1,2-propanediol in saline	Rat/M	Decreased behavior Phase 1/2		100				Sandrini et al 1999¹¹⁸
48.	APAP is associated with changes in the serotonergic system in the rat brain	Formalin test	Formalin	12.5% of 1,2-propanediol in saline	Rat/M	Decreased behavior		200–400				Pini et al 1996¹²⁸
49.	The dose-related effects of APAP on hyperalgesia and nociception in the rat	Von Frey Paw pressure	IPLT Brewer’s yeast	0.25% methocel in 0.9% NaCl	Rat/M	Normalized threshold Dose dependent	25–100					Bianchi et al 1996⁹⁶
50.	Central antinociceptive effects of non-steroidal anti-inflammatory drugs and APAP	Biting, scratch licking	Intrathecal SP, NMDA, AMPA	Saline	Rat/M	Decreased behavior		0.01–10				Björkman 1995¹²⁹
51.	APAP blocks spinal hyperalgesia induced by NMDA and substance P	Biting, scratch licking	Intrathecal SP, NMDA, AMPA	Saline	Rat/M	Decreased behavior		200				Björkman et al 1994¹³⁰
52.	Morphine, nefopam and APAP	Formalin test	Formalin	12.5% of 1,2-propane- diol in 0.9% sterile saline	Rat/N/A (Naked mole rat)	Decreased behavior Phase 2, not phase 1		200–400				Kanui et al 1993¹³¹
53.	Intrathecal APAP on visceral noxious stimulation in rabbits	Visceral	Colonic distension Cutaneous electrical	N/R	Rabbit/M	Colonic: increased thresholds Electrical increased threshold Dose dependent				0.5–5 mg		Jensen et al 1992¹⁴⁵
		Visceral	Colonic distension	N/R	Rabbit/M	Colonic No change Electrical No change			10–50
54.	APAP plasma levels and analgesic effect	Impairment	Joint uric acid	Saline	Rat/M	Increased threshold Dose dependent	178–562					Granados-sato et al 1992⁸⁸
55.	Spinal nonsteroidal anti-inflammatory agents	Formalin test	Formalin	5% ethanol/distilled water	Rat/M	Decreased behavior (phase 2) Dose dependent				163–405		Malmberg and Yaksh 1992¹³²
56.	Anti-inflammatory effects of a low dose of APAP following surgery	Applied pressure	Postoperative pain	NA	Dog/M and M	Normalized threshold	500					Mburu 1991⁹⁷
57.	APAP effect is partly dependent on spinal 5-HT systems	Formalin test	Formalin	5% ethanol/distilled water	Rat/M	Normalized behavior		400				Tjølsen et al 1991¹³³
58.	Acetylsalicylic acid, APAP and morphine inhibit behavioural responses to substance P or capsaicin	Biting, licking and scratch	Intrathecal SubsP/Capsaicin	12.5% 1,2-propanediol/saline	Mice/M	Decreased behavior Dose dependent		300–400				Hunskaar et al 1985¹³⁶
59.	Aspirin, mefenamic acid, dihydrocodeine, dextropropoxyphene and APAP on respiration and prostaglandin biosynthesis	Writhing test	Acetic acid	1% tragacanth and saline	Rat/M	Decreased behavior	213					Sewell et al 1984⁹⁹
60.	Analgesic drugs in chronic inflammatory pain: possible central analgesic action of NSAIDs	Electrical stimulus Vocalize	Heat-killed adjuvant	Saline	Rat/M	Increased threshold Dose dependent	50–400				25–400	Okuyama and Aihara 1984⁸⁹
		Electrical stimulus Vocalize	Heat-killed adjuvant	Saline	Rat/M	Increased threshold Dose dependent					25–400
61.	Aspirin/APAP on naloxone potency induced by morphine	Writhing test	Acetic acid	Saline	Mice/M	Decreased behavior		10 or 20				Wong et al 1980¹⁶⁰
62.	Butorphanol and APAP combination	Writhing test	Acetic acid	Saline	Mice/M	Decreased behavior Dose dependent	137–171					Pircio et al 1978¹⁰⁰
63.	Central/peripheral action of aspirin-like drugs	Paw pressure	Carrag Hind paw	Saline	Mice/M	Increased threshold Dose dependent		100–400				Ferreira et al 1978¹³⁵
		Paw pressure	Carrag Hind paw	Saline	Mice/M	Increased threshold Dose dependent		50–400 μg (IPLT)
		Paw pressure	Carrag Hind paw	Saline	Mice/M	Increased threshold Dose dependent					50–400 µg
64.	Comparison of analgesic and anti-inflammatory activities of aspirin, phenacetin and APAP in rodents	Paw pressure	IPLT Trypsin Hind paw	N/A	Rat/NA	No change	ED 50 > 360 mg/kg					Vinegar et al 1976¹⁰²
		Paw pressure	IPLT Kaolin Hind paw	N/A	Rat/NA	Increased threshold Dose dependent	ED 50 = 305 mg/kg
		Paw pressure	IPLT Carrag Hind paw	N/A	Rat/NA	Increased threshold Dose dependent	ED 50 = 110 mg/kg
		Paw pressure	Acetic acid	N/A	Rat/NA	Increased threshold Dose dependent		ED 50: = 305 mg/kg