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Cited by 654Cannabis and Cannabinoid ResearchDrug-Induced Hepatotoxicity and ProtectionPharmacological Receptor Mechanisms and Effects

Paracetamol: New Vistas of an Old Drug

Open access
Bertolini, Alfio, Ferrari, Anna, Ottani, Alessandra, Guerzoni, Simona, Tacchi, Raffaella, Leone, Sheila·2006·CNS Drug Reviews
DOI 10.1111/j.1527-3458.2006.00250.xPMC PMC6506194
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Abstract

Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB(1) receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB(1) receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB(1) agonists are being introduced for pain treatment, it comes out that an indirect cannabino-mimetic had been extensively used (and sometimes overused) for more than a century.

Integrity signals

Registry

Crossref · 10.1111/j.1527-3458.2006.00250.x

Cites

250 of 250 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

35 of 163 cited sources checked · 14 supported · 3 flagged · accuracy not yet measured

  • Interpretationreasoning

    AM404's COX inhibition and prostaglandin reduction probably contribute little to paracetamol analgesia.

    “However, the actual contribution of these activities of AM404 to the analgesic effect of paracetamol seems negligible.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source

      The Results report that AM404 inhibits COX-1, COX-2, and prostaglandin E2 formation. The discussion accompanying Fig. 5 connects an analgesic dose of acetaminophen to likely local COX inhibition in the brain, rather than suggesting that this activity contributes negligibly to analgesia. The paper does not quantify that contribution. (LLM, conf=0.76)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Paracetamol should be considered a safe alternative to NSAIDs for mild-to-moderate pain in elderly patients and those with kidney disease, hypertension, or congestive heart failure.

    “Paracetamol must be considered as a safe alternative to NSAIDs for the relief of mildto-moderate pain in elderly patients, in patients with kidney disease (144), hypertension (56,93,104,110,166,184,185,225), congestive heart failure (81,85,98,139,157).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [144] 144. Mitic-Zlatkovic M, Stefanovic V. Acute effects of acetaminophen on renal function and urinary excretion of some proteins and enzymes in patients with kidney disease. Ren Fail 1999;21:525-532. source

      Citation (144) is attached specifically to the recommendation for patients with kidney disease. The Discussion (page unavailable) instead reports kidney-damage markers after a 2 g dose in such patients and urges caution in their use of acetaminophen. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [56] 56. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2. Short-term reductions in blood pressure: Overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827-838. source
    • cites [93] 93. Gurwitz JH, Avorn J, Bohn RL, et al. Initiation of antihypertensive treatment during nonsteroidal anti-in- flammatory drug therapy. JAMA 1994;272:781-786. source
  • Interpretationcitation

    Paracetamol produces analgesia by indirectly activating cannabinoid CB1 receptors.

    “the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB 1 receptors”
    • Also stated in: § INTRODUCTION · boosted
      “the analgesic activity of paracetamol involves a completely unforeseen mechanism, i.e., the potentiation of the cannabinoid/vanilloid tone in the brain and in dorsal root ganglia (102).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Zygmunt and colleagues

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Bertolini and colleagues

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source

      The Abstract reports that paracetamol is converted in the nervous system to AM404, which acts on the endocannabinoid system and is a ligand at CB1 receptors. The discussion following Fig. 5 suggests that AM404 may activate that system, but says its contribution to paracetamol’s effects can only be hypothesized; it does not establish that indirect CB1 activation causes the analgesic effect. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • Rests on an assumption: The cannabinoid mechanism of paracetamol analgesia observed in rats applies to humans.
  • Interpretationreasoning

    This peroxide dependence could account for paracetamol's lack of effect at inflamed sites, where peroxide levels are high, and its activity in brain, where they are low.

    “Such a peroxide-dependent inhibition of COX might explain why paracetamol is not active at sites of inflammation, where peroxides concentration is high, while being active in the brain, where peroxides concentration is very low.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [94] 94. Hanel AM, Lands WE. Modification of anti-inflammatory drug effectiveness by ambient lipid peroxides. Biochem Pharmacol 1982;31:3307-3311. source
    • cites [32] 32. Boutaud O, Aronoff DM, Richardson JH, et al. Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H 2 synthases. Proc Natl Acad Sci USA 2002;99:7130-7135. source

      The Discussion (page unavailable) proposes that hydroperoxides in inflammatory cells could attenuate paracetamol’s action and account for its lack of anti-inflammatory effect. It also links paracetamol’s activity in endothelial cells to brain pyrexia, but does not state that peroxide levels in the brain are very low or establish that contrast with inflammatory sites. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [155] 155. Ouellet M, Percival MD. Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. Arch Bio- chem Biophys 2001;387:273-280. source
  • Premisecitation

    In brain and spinal cord, paracetamol is deacetylated to p-aminophenol and then conjugated with arachidonic acid to form AM404.

    “In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine”
    • Also stated in: § CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL. · plain
      “paracetamol, following deacetylation to its primary amine (p-aminophenol) is conjugated with arachidonic acid in the brain and spinal cord to form AM404.”
    • Also stated in: § CNS Drug Reviews, Vol. 12, No. 3-4, 2006 PARACETAMOL REVISITED 257 · plain
      “in brain, spinal cord, and dorsal root ganglia of rats, paracetamol, following deacetylation (mainly in the liver) to p-aminophenol, is conjugated by enzyme fatty acid amide hydrolase (FAAH) with arachidonic acid to form N-arachidonoyl-phenolamine (AM404) (102).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation

    AM404 inhibits cyclooxygenases in the brain, but at concentrations probably not attainable with analgesic doses of paracetamol.

    “moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source

      The Results report that AM404 inhibits isolated COX-1 and COX-2, supporting the inhibition component. But the discussion following Fig. 5 says that, after an acetaminophen dose commonly used to induce analgesia in rodents, higher local brain concentrations of AM404 are likely and could inhibit COX. That is contrary to the claim that COX-inhibiting concentrations are probably unattainable at analgesic doses; the paper does not directly demonstrate COX inhibition in the brain. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    AM404 is an agonist at TRPV1 receptors and inhibits cellular anandamide uptake, increasing endogenous cannabinoid levels.

    “N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids”
    • Also stated in: § CNS Drug Reviews, Vol. 12, No. 3-4, 2006 254 A. BERTOLINI ET AL. · boosted
      “AM404 is a potent activator of vanilloid subtype 1 receptors (TRPV1) (235), and an inhibitor of the cellular anandamide uptake (anandamide membrane transporter, AMT), which leads to increased levels of endogenous cannabinoids”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [235] 235. Zygmunt PM, Chuang H, Movahed P, et al. The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol 2000;396:39-42. source
    • cites [19] 19. Beltramo M, Stella N, Calignano A, Lin SY, et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 1997;277:1094-1097. source
    • cites [66] 66. De Petrocellis, Bisogno T, Davis JB, et al. Overlap between the ligand recognition properties of the ananda- mide transporter and the VR1 vanilloid receptor: Inhibitors of anandamide uptake with negligible capsai- cin-like activity. FEBS Lett 2000;483:52-56. source

      The Abstract (page unavailable) reports that AM404 activates VR1/TRPV1 and inhibits cellular anandamide transport. The Introduction describes anandamide uptake as part of the process that terminates its activity, but the paper does not show that AM404 increases endogenous cannabinoid levels. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Pain and thermoregulatory pathways contain both TRPV1 and CB1 receptors.

    “TRPV1 (and also cannabinoid CB 1 ) receptors are present in pain and thermoregulatory pathways (66,111,165,209,210,216).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [66] 66. De Petrocellis, Bisogno T, Davis JB, et al. Overlap between the ligand recognition properties of the ananda- mide transporter and the VR1 vanilloid receptor: Inhibitors of anandamide uptake with negligible capsai- cin-like activity. FEBS Lett 2000;483:52-56. source

      The Introduction reports that VR1 (TRPV1) and CB1 occur in some of the same brain regions, including the hypothalamus, and that VR1 occurs in dorsal root sensory neurons. It does not establish that both receptors are present in pain and thermoregulatory pathways specifically. Page numbers were not available in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [111] source

      The Introduction (page not available) places TRPV1 in neurons that transmit noxious heat and pain signals. The paper does not establish that TRPV1 or CB1 is present in thermoregulatory pathways; CB1 appears only in the title of another work in the References. Thermal pain sensation is not the same as thermoregulation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [165] 165. Piomelli D, Giuffrida A, Calignano A, Rodriguez de Fonseca F. The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol Sci 2000;21:218-224. 166. 103. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med 1993;153:477-484. source

  • May combine two claims.

    Interpretationcitation

    Paracetamol behaves as a pro-drug; FAAH forms its active metabolite AM404 in the brain by conjugating p-aminophenol with arachidonic acid.

    “Thus, paracetamol would act as a pro-drug, with the active metabolite (AM404) being formed in the brain through conjugation of the deacetylated derivative of paracetamol (p-aminophenol) with arachidonic acid, by the action of fatty acid amide hydrolase (FAAH).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source
    • Rests on an assumption: The cannabinoid mechanism of paracetamol analgesia observed in rats applies to humans.

  • May combine two claims.

    Premisecitation

    Peak liver function disturbance occurs 2-4 days after paracetamol overdose, whereas renal impairment, if it develops, becomes more evident after 1 week and returns to normal about 2-3 weeks after ingestion.

    “While the peak disturbance in liver function occurs 2 to 4 days after a paracetamol overdose, renal impairment, if it develops, becomes more evident after 1 week and returns to normal about 2 to 3 weeks after ingestion (55,61).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [55] 55. Cobden I, Record CO, Ward MK, Kerr DNS. Paracetamol-induced acute renal failure in the absence of ful- minant liver damage. Br Med J 1982;284:21-22. source

      The Case reports section says renal failure was generally most evident one week after ingestion, compared with two to four days for liver damage. It does not say that renal function returned to normal about two to three weeks after ingestion; the table reports periods of oliguria, not a general time to normal renal function. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [61] 61. Curry RW, Robinson JD, Sughrue MJ. Acute renal failure after acetaminophen ingestion. JAMA 1982;247:1012-1014. source

  • May combine two claims.

    Premisecitation

    AM404 inhibits COX-1 and COX-2 in a concentration-dependent manner and also reduces LPS-induced prostaglandin E2 formation in macrophages.

    “Zygmunt and colleagues have shown that AM404 concentration-dependently inhibits both COX-1 and COX-2, as well as LPS-induced prostaglandin E 2 formation in macrophages.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source

  • May combine two claims.

    Interpretationcitation

    This fatty acid conjugation pathway matters functionally because it produces paracetamol's active metabolite, though it accounts for only a tiny fraction of the drug's overall metabolism.

    “This novel metabolic pathway (fatty acid conjugation) is of crucial functional importance because it generates the active metabolite of paracetamol.It is negligible, however, in the overall biotrasformation of the drug.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source

      The Abstract and Results identify AM404 as a bioactive metabolite formed from paracetamol by fatty acid conjugation in the nervous system. The Discussion reports AM404 in rat brain but not liver or blood; it does not quantify this pathway's share of overall drug metabolism. The paper also says AM404's contribution to paracetamol's effects in humans remains hypothetical, so calling it *the* active metabolite overstates the finding. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • Rests on an assumption: The cannabinoid mechanism of paracetamol analgesia observed in rats applies to humans.

  • May combine two claims.

    Interpretationcitation

    At pain-relieving doses, AM404 generated in rat brain areas rich in FAAH can activate CB1 receptors indirectly and TRPV1 receptors directly.

    “At analgesic doses of paracetamol, AM404 that is formed in rat brain regions expressing high levels of FAAH, can indirectly activate CB 1 receptors and directly activate TRPV1 receptors (66,102,235).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [66] 66. De Petrocellis, Bisogno T, Davis JB, et al. Overlap between the ligand recognition properties of the ananda- mide transporter and the VR1 vanilloid receptor: Inhibitors of anandamide uptake with negligible capsai- cin-like activity. FEBS Lett 2000;483:52-56. source

      The Results and discussion (page not available) show that AM404 inhibits anandamide uptake and directly activates the human VR1 receptor, now called TRPV1. The Introduction explains that anandamide is a CB1 agonist, which is consistent with an indirect CB1 mechanism. The paper does not establish that paracetamol produces AM404 in FAAH-rich rat brain regions, or that these receptor effects occur at analgesic doses. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source

      The discussion following Fig. 5 reports AM404 in rat brain after an analgesic acetaminophen dose and describes AM404 as a TRPV1 activator. The paper also links AM404’s inhibition of anandamide uptake to increased endocannabinoids, supporting indirect CB1 activation. But it says formation at higher concentrations in FAAH-rich brain regions is likely, rather than demonstrating formation in those specific regions. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [235] 235. Zygmunt PM, Chuang H, Movahed P, et al. The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol 2000;396:39-42. source

  • May combine two claims.

    Premisecitation

    At roughly 10 nM, AM404 activates rat and human TRPV1, whereas meaningful COX-1/COX-2 inhibition and prostaglandin E2 reduction need micromolar levels.

    “At this concentration AM404 activates both rat (102,235) and human (66) TRPV1 receptors, while significant COX-1 and COX-2 inhibition and prostaglandin E 2 formation reduction are obtained at micromolar concentrations (102).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [102] 102. Hogestatt ED, Jonsson BAG, Ermund A. Conversion of acetaminophen to the bioactive N-acylphenol- amine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280(36):31405-31412. source

      The discussion states that AM404 activates rat and human TRPV1 at concentrations above 10 nM. The Results and Fig. 5 caption report concentration-dependent COX-1/COX-2 inhibition and reduced PGE2 formation, but the available text does not establish that significant effects require micromolar AM404 concentrations. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [235] 235. Zygmunt PM, Chuang H, Movahed P, et al. The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol 2000;396:39-42. source
    • cites [66] 66. De Petrocellis, Bisogno T, Davis JB, et al. Overlap between the ligand recognition properties of the ananda- mide transporter and the VR1 vanilloid receptor: Inhibitors of anandamide uptake with negligible capsai- cin-like activity. FEBS Lett 2000;483:52-56. source

      The Results and discussion section reports that AM404 potently activates human VR1, supporting the human-receptor part of the claim. The passages do not establish activation of rat VR1 at roughly 10 nM, and a search of our copy found no COX-1, COX-2, or prostaglandin E2 result to support the micromolar comparison. Page numbers were not available in the indexed passages. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    NAC efficacy decreases stepwise with further delays, and there is no benefit if NAC is started more than 15 h after overdose.

    “Efficacy then decreases in a stepwise fashion with further delays, and there is no benefit if NAC administration is started more than 15 h after the overdose (167).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [167] 167. Prescott LF, Illingworth RN, Critchley JAH. Intravenous N-acetyl-cysteine: The treatment of choice for paracetamol poisoning. Br Med J 1979;2:1097-1100. source

  • May combine two claims.

    Premisecitation

    Several observations suggest NAC has other mechanisms effective even after NAPQI formation and binding, including enhancement of oxygen delivery and utilization.

    “However, several observations suggest that NAC has other mechanisms of action that are effective also after NAPQI formation and binding: enhancement of oxygen delivery and utilization (70,96,204).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [70] 70. Devlin J, Ellis AE, McPeake J, et al. N-Acetylcysteine improves indocyanine green extraction and oxygen transport during hepatic dysfunction. Crit Care Med 1997;25:236-242. source
    • cites [96] 96. Harrison PM, Wendon JA, Gimson AES, et al. Improvement by acetylcysteine of hemodynamics and oxy- gen transport in fulminant hepatic failure. N Engl J Med 1991;324:1852-1857. source
    • cites [204] 204. Spies CD, Reinhart K, Witt I, et al. Influence of N-acetylcysteine on indirect indicators of tissue oxygen- ation in septic shock patients. Crit Care Med 1994;22:1738-1746. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Depletion of glutathione in airway epithelial lining fluid by paracetamol metabolites has been suggested as a possible cause of asthma in chronic users.

    “Depletion of glutathione in airway epithelial lining fluid by paracetamol metabolites has been suggested as the possible cause (192).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [192] 192. Shaheen SO, Sterne JA, Songhurst CE, et al. Frequent paracetamol use and asthma in adults. Thorax 2000;55:266-270. source

      The Discussion proposes that frequent paracetamol use could contribute to asthma morbidity by depleting glutathione in airway epithelial lining fluid. However, the paper attributes depletion by a reactive paracetamol metabolite to the liver; it does not establish that metabolites deplete glutathione in airway lining fluid. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    NSAIDs can also antagonize the platelet inhibition induced by low-dose aspirin and lessen its cardioprotective effect.

    “It can also antagonize the platelet inhibition induced by low dose aspirin and lessens its cardioprotective effect (46).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [46] 46. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of as- pirin. N Engl J Med 2001;345:1809-1817. source

      The Discussion reports that multiple daily doses of ibuprofen competitively inhibit low-dose aspirin’s sustained antiplatelet effect. It says this may limit aspirin’s cardioprotection, but does not demonstrate a reduction in cardiovascular events; it also reports no such interaction for diclofenac or rofecoxib. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Paracetamol is indicated for mild-to-moderate pain, including headaches, cold, flu, muscle aches, sprains, backache (including low back pain), dysmenorrhea, minor arthritis pain, and toothaches.

    “Paracetamol is indicated for mild-to-moderate pain, such as that caused by headaches, cold, flu, muscle aches, sprains, backache (including low back pain) (4), dysmenorrhea, minor arthritis pain, toothaches.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] 4. Airaksinen O, Brox JI, Cedraschi C. European guidelines for the management of chronic non-specific low back pain. Eur Spine J 2006;15(Suppl 2):S192-S300. source

      Citation (4) is attached to backache, including low back pain, rather than to the other listed conditions. The Subjects (indications) section mentions paracetamol but says no trials compared it with NSAIDs in chronic low back pain; the Pharmacological approaches section calls for trials of its effectiveness. Neither passage establishes that paracetamol is indicated for backache or low back pain. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Chronic paracetamol use also causes renal damage; a case-control study of 1,077 frequent users found a dose-dependent relationship between heavier paracetamol use and increased risk of end-stage renal disease.

    “Renal damage is also produced by chronic use of paracetamol; in a case-control study involving 1,077 subjects who frequently took paracetamol, a dose-dependent relationship between heavier paracetamol use and an increased risk of end-stage renal disease was demonstrated (160).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [160] 160. Perneger TV, Whelton, Klag MJ. Risk of kidney failure associated with use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. N Engl J Med 1994;331:1675-1679. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisenone given

    Cannabinoid antinociception works through descending spinal inhibition and depends almost entirely on CB1 receptors.

    “Cannabinoids also produce their antinociceptive effect by descending spinal inhibition, CB 1 receptors being almost exclusively involved.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    In broken-cell preparations paracetamol weakly inhibits prostaglandin synthesis, but at therapeutic concentrations it inhibits prostaglandin production in intact cells in vitro when arachidonic acid is low.

    “while paracetamol is a weak inhibitor of prostaglandin synthesis in broken cell systems, therapeutic concentrations of paracetamol inhibit prostaglandin synthesis in intact cells in vitro when the levels of arachidonic acid are low.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Paracetamol's clinically important systemic actions are pain relief and fever reduction; its anti-inflammatory and antirheumatic effects are minimal.

    “It is generally accepted that the two systemic effects of paracetamol of therapeutic significance are analgesia and antipyresis, while its antiinflammatory and antirheumatic activities are negligible (39,54,177).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [39] 39. Bruton L, Lazo J, Parker K. Goodman & Gilman's the Pharmacological Basis of Therapeutics, 11 th Edition. New York: McGraw-Hill, 2006.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [54] 54. Clissold SP. Paracetamol and phenacetin. Drugs 1986;32(Suppl 4):46-59. source
    • cites [177] 177. Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology, 5 th Edition. Kidlington, Oxford: Elsevier Ltd, 2003.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In adults, 1,000 mg is the ceiling dose for paracetamol; raising the dose adds toxicity without more pain relief.

    “At 1,000 mg paracetamol reaches its ceiling effect in adults.Further increase in the dose does not increase analgesic activity (196,232), but does increase toxicity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [196] 196. Skoglund LA, Skjelbred P, Fyllingen G. Analgesic efficacy of acetaminophen 1000 mg, acetaminophen 2000 mg, and the combination of acetaminophen 1000 mg and codeine phosphate 60 mg versus placebo in acute postoperative pain. Pharmacotherapy 1991;11:364-369. source
    • cites [232] 232. Woodbury DM. Analgesics and Antipyretics. In: Goodman LS and Gilman A, Eds., The Pharmacological Basis of Therapeutics, 3 rd edition. New York: The Macmillan Company, 1965:312-344 233. 105. Young CR, Mazure CM. Fulminant hepatic failure from acetaminophen in an anorexic patient treated with carbamazepine [Letter]. J Clin Psychiatry 1998;59:622.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisenone given

    Unlike opiates, paracetamol provides little relief in severe pain and does not depress breathing.

    “Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration.”
    • Also stated in: § INTRODUCTION · plain
      “Unlike opiates, it is ineffective in pain arising from smooth muscle spasm in hollow viscera and has no depressant effect on respiration.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A COX-1 splice variant found in dog brain, called COX-3, is inhibited by paracetamol.

    “a splice variant of COX-1, derived from the same gene, was characterized in dog brain which was sensitive to inhibition with paracetamol (48); it was designated COX-3 (48)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] 48. Chandrasekharan NV, Dai H, Roos KL, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetamino- phen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proc Natl Acad Sci USA 2002;99:13926-13931. source

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Paracetamol's actions might result from selective inhibition of COX-2 pathways that are running slowly.

    “Thus, it has been suggested that the effects of paracetamol may be due to selective inhibition of COX-2 dependent pathways that are proceeding at low rates (90).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] 90. Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther 2005;12:46-55. source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Unlike NSAIDs, paracetamol lacks anti-inflammatory action and does not cause gastrointestinal or cardiorenal harm.

    “Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects.”
    • Also stated in: § INTRODUCTION · plain
      “unlike NSAIDs paracetamol does not produce gastrointestinal damage or untoward cardiorenal effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cannabinoids relieve pain in animal models of acute and tonic pain and in clinical pain states; endogenous cannabinoids are tonically released and help set basal nociceptive threshold.

    “cannabinoids produce analgesia either in animal models of pain (both acute pain and tonic pain) or in clinical painful conditions (for reviews see: 161,221), and endogenous cannabinoids are tonically released to participate in the control of basal nociceptive threshold (137).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [161] 161. Pertwee RG. Cannabinoid receptors and pain. Prog Neurobiol 2001;63:569-611. source
    • cites [221] 221. Walker JM, Huang SM. Cannabinoid analgesia. Pharmacol Ther 2002;95:127-135. source
    • cites [137] 137. Meng ID, Manning BH, Martin WJ, et al. An analgesia circuit activated by cannabinoids. Nature 1998;395: 381-383. 138. 101. Meredith TJ, Goulding R. Paracetamol. Postgrad Med J 1980;56:459-73. source

  • May combine two claims.

    Premisecitation

    In rats, paracetamol antinociception correlates with lower frontal cortex dynorphin A and is blocked by k-opioid receptor antagonists.

    “paracetamol-induced antinociception in rats is associated with a decrease of dynorphin A levels in the frontal cortex, and is prevented by blockade of k-opioid receptors (186).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [186] 186. Sandrini M, Romualdi P, Vitale G, et al. The effect of a paracetamol and morphine combination on dynor- phin A levels in the rat brain. Biochem Pharmacol 2001;61:1409-1416.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Paracetamol relieves pain as well as aspirin, but higher plasma concentrations are needed for analgesia than for fever reduction.

    “The analgesic efficacy of paracetamol is equivalent to that of aspirin, while its plasma levels required for the analgesic activity are higher than those needed for the antipyretic activity (18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] 18. Beck DH, Schenk MR, Hagemann K, et al. The pharmacokinetics and analgesic efficacy of larger dose rec- tal acetaminophen (40 mg/kg) in adults: A double-blinded, randomized study. Anesth Analg 2000;90: 431-436. source

  • May combine two claims.

    Premisecitation

    Subsequent work suggests COX-3 has little clinical relevance due to low expression and poor kinetics, and in rodents and humans it encodes proteins lacking COX activity.

    “while COX-3 might be active in canines, its low expression level and the unfavorable kinetics indicate unlikely clinical relevance.In rodents and humans COX-3 encodes proteins with completely different amino acid sequences than COX-1 or COX-2 and without COX activity”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] 112. Kis B, Snipes JA, Busija DW. Acetaminophen and the COX-3 puzzle: Sorting out facts, fictions and uncer- tainties. J Pharmacol Exp Ther 2005;315:1-7. source

  • May combine two claims.

    Premisecitation

    The kidney is the second target organ of paracetamol toxicity; renal dysfunction occurs in about 25% of cases with significant hepatotoxicity and in over 50% of those with hepatic failure.

    “Kidney is the second target organ of paracetamol toxicity: renal dysfunction occurs in about 25% of cases with significant hepatotoxicity (63,172) and in more than 50% of those with hepatic failure (128,230).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [63] 63. Davenport A, Finn R. Paracetamol (acetaminophen) poisoning resulting in acute renal failure without hepa- tic coma. Nephron 1988;50:55-56. source
    • cites [172] 172. Prescott LF. Analgesic nephropathy. Drugs 1982;23:75-149. source
    • cites [128] 128. Makin AJ, Williams R. The current management of paracetamol overdosage. Br J Clin Prac 1994;48: 144-148. source

  • May combine two claims.

    Premisereasoning

    The therapeutic dose of paracetamol is 10-15 mg/kg, giving a therapeutic index of about 10.

    “(the therapeutic paracetamol dose is 10-15 mg/kg, therefore the therapeutic index is ~10).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Overall mortality in alcohol-paracetamol syndrome is roughly 20%, and rises above 75% when acute liver failure occurs.

    “Overall mortality in alcohol-paracetamol syndrome is about 20%, and exceeds 75%, if acute liver failure develops (16,75,120,129).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] 16. Barker JD Jr, de Carle DJ, Anuras S. Chronic excessive acetaminophen use and liver damage. Ann Intern Med 1977;87:299-301. source
    • cites [75] 75. Draganov P, Durrence H, Cox C, et al. Alcohol-acetaminophen syndrome. Postgrad Med 2000;107: 189-195. source
    • cites [120] 120. Licht H, Seeff LB, Zimmerman HJ. Apparent potentiation of acetaminophen hepatotoxicity by alcohol [Letter]. Ann Intern Med 1980;92:511. source

  • May combine two claims.

    Premisecitation

    Taking paracetamol together with zidovudine can cause neutropenia or liver toxicity.

    “Coadministration of paracetamol with zidovudine may result in neutropenia or hepatotoxicity (180);”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [180] 180. Richman DD, Fischl MA, Grieco MH, et al. The toxicity of azidothymidine (AZT) in the treatment of pa- tients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 1987; 317:192-197. source

  • May combine two claims.

    Premisecitation

    Serious hepatotoxicity or death after acute paracetamol overdose has been reported in children but is extremely rare, especially in those under 5 years.

    “Serious hepatotoxicity or death after acute paracetamol overdose has been reported in children, but is extremely rare (11,122,181), particularly in children under 5 years of age.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [11] 11. Arena JM, Rourk MHJ, Sibrack CD. Acetaminophen: Report of an unusual poisoning. Pediatrics 1978;61:68-72. source
    • cites [122] 122. Lieh-Lai MW, Sarnaik AP, Newton JF, et al. Metabolism and pharmacokinetics of acetaminophen in a se- verely poisoned young child. J Pediatr 1984;105:125-128. source
    • cites [181] 181. Rumack BH, Peterson RG. Acetaminophen overdose: Incidence, diagnosis and management in 416 pa- tients. Pediatrics 1978;62(Suppl):898-903. source

  • May combine two claims.

    Interpretationcitation

    The new findings account for paracetamol's mechanism and may explain why it inhibits brain prostaglandin production.

    “These novel findings explain the mechanism of action of paracetamol and may provide an explanation of the observation that paracetamol inhibits prostaglandin production in the brain (84).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] 84. Flower RJ, Vane JR. Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of pa- racetamol (4-acetamidophenol). Nature 1972;240:410-411. source
    • Rests on an assumption: The cannabinoid mechanism of paracetamol analgesia observed in rats applies to humans.

  • May combine two claims.

    Premisecitation

    No acute toxicity has been reported in healthy adults taking a single paracetamol dose below 125 mg/kg, and historical data indicate toxicity usually appears only above 150 mg/kg.

    “There have been no reports of acute toxicity in healthy adults ingesting a single dose of paracetamol below 125 mg/kg; historical data suggest that toxicity generally occurs only above 150 mg/kg (176)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [176] 176. Prescott LF. Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs 1983;25:290-314. source

  • May combine two claims.

    Premisecitation

    Chronic ethanol raises the risk from acute paracetamol dosing through induced P450 metabolism, increased NAPQI formation, or reduced glutathione supply or hepatic regeneration, whereas acute ethanol coadministration may be somewhat hepatoprotective, likely by competitively inhibiting P450 metabolism of paracetamol to NAPQI.

    “While chronic ethanol increases risk from acute paracetamol dosing (121,189,214) on the basis of induced P450 paracetamol metabolism, and consequent increased formation of NAPQI, or decreased glutathione supply or hepatic regeneration power (118), acute ethanol coadministration with paracetamol may be somewhat hepatoprotective (212,214) presumably by competitive inhibition of P450 paracetamol”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [121] 121. Lieber CS, Lasker JM, Alderman J, et al. The microsomal ethanol oxidizing system and its interaction with other drugs, carcinogens, and vitamins. Ann NY Acad Sci 1987;492:11-24. source
    • cites [189] 189. Seeff LB, Cuccherini BA, Zimmerman HJ, et al. Acetaminophen hepatotoxicity in alcoholics. A thera- peutic misadventure. Ann Intern Med 1986;104:309-404. source
    • cites [214] 214. Tredger JM, Smith HM, Read RB, Williams R. Effects of ethanol ingestion on the metabolism of a hepato- toxic dose of paracetamol in mice. Xenobiotica 1986;16:661-670. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In most countries, paracetamol is the most used analgesic-antipyretic drug in children.

    “In most countries, paracetamol is the most used analgesic-antipyretic drug in children (21,158,179).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] 21. Bentley E, Mackie IC. Trends in prescriptions of paracetamol for children. Br Med J 1995;311:362. source
    • cites [158] 158. Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr 2005;164: 552-558. source
    • cites [179] 179. Riano-Galan I, Gonzalez M, Sanchez SG, et al. Opinion de los pediatras sobre el dolor infantil. An Esp Pediatr 1998;49:587-593.

  • May combine two claims.

    Premisecitation

    The first symptoms after paracetamol overdose may be those of hepatic injury, which develops many hours after ingestion, when antidotal therapy is already less effective.

    “The first symptoms after paracetamol overdose may be those of hepatic injury, which develops many hours after the ingestion, when antidotal therapy is already less effective (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] 26. Bizovi KE, Smilkstein MJ. Acetaminophen. In: Golfrank LR, Howland MA, Flomenbaum NE, Hoffman RS, Lewin NA, Nelson RS, Eds. Goldfrank's Toxicologic Emergencies, 7 th Edition. New York: McGraw- Hill, 2002;480-501.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In these patients, NSAIDs may worsen renal and cardiovascular function and cause gastrointestinal damage due to their mechanism of action.

    “In such patients, NSAIDs, for their mechanism of action, may worsen the renal and cardiovascular function, besides causing gastrointestinal damage (23,85,227,228,229).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] 23. Bertolini A, Ottani A, Sandrini M. Selective COX-2 inhibitors and dual acting anti-inflammatory drugs: Critical remarks. Curr Med Chem 2002;9:1033-1043. source
    • cites [85] 85. Gaziano JM, Gibson CM. Potential for drug-drug interactions in patients taking analgesics for mild-to- moderate pain and low-dose aspirin for cardioprotection. Am J Cardiol 2006;97(Suppl 9A):23E-29E. source
    • cites [227] 227. Whelton A. Clinical implications of nonopioid analgesia for relief of mild-to-moderate pain in patients with or at risk for cardiovascular disease. Am J Cardiol 2006;97(Suppl 9A):3E-9E. source

  • May combine two claims.

    Premisecitation

    A 1,000 mg dose was effective for up to 5 h after oral surgery, with maximal pain relief at 1-2 h, and was effective for impacted third molar extraction and various other oral surgeries including difficult extractions, alveolectomy, multiple extractions, apicoectomy, biopsy, and deep gingival curettage.

    “The dose of 1,000 mg was effective for up to 5 h after oral surgery (134), although pain relief was maximal at 1 to 2 h after administration (22), and was shown to be an effective treatment for extraction of impacted third molars and for various other oral surgeries, including difficult extractions, alveolectomy, multiple extractions, apicoectomy, biopsy, and deep gingival curettage (135,196).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [134] 134. Mehlisch DR, Frakes LA. A controlled comparative evaluation of acetaminophen and aspirin in the treatment of postoperative pain. Clin Ther 1984;7(1):89-97.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [22] 22. Bentley KC, Head TW. The additive analgesic efficacy of acetaminophen, 1000 mg, and codeine, 60 mg, in dental pain. Clin Pharmacol Ther 1987;42:634-640. source
    • cites [135] 135. Mehlisch DR. The efficacy of combination analgesic therapy in relieving dental pain. Jada 2002;133: 861-871. source

  • May combine two claims.

    Premisecitation

    In a mouse model, NAC reversed NAPQI oxidation, but there is no evidence of this process in humans.

    “In a mouse model, NAC actually reversed NAPQI oxidation (58), but there is no evidence of such a process in humans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] 58. Corcoran GB, Mitchell JR, Vaishnav YN, et al. Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyl-p-benzoquinoneimine. Mol Pharmacol 1980;18:536-542. source

  • Probably not a substantial claim: may not pass S1 (asserted), S2 (checkable), S3 (load-bearing), S4 (based).

    Premisecitation

    The treatment line is one of the most sensitive screening tools used in medicine.

    “The”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] 26. Bizovi KE, Smilkstein MJ. Acetaminophen. In: Golfrank LR, Howland MA, Flomenbaum NE, Hoffman RS, Lewin NA, Nelson RS, Eds. Goldfrank's Toxicologic Emergencies, 7 th Edition. New York: McGraw- Hill, 2002;480-501.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Oral paracetamol at 15-20 mg/kg up to every 4 h is the mainstay for childhood headache; because rectal absorption is variable, doses up to 45 mg/kg may be needed rectally.

    “Paracetamol, at oral doses of 15-20 mg/kg up to every 4 h, is the mainstay of treatment in childhood headache; since rectal absorption is variable, doses up to 45 mg/kg may be required for this route of administration (89,131,223).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [89] 89. Graf WD, Riback PS. Pharmacologic treatment of recurrent pediatric headache. Pediatr Ann 1995;24: 477-484. source
    • cites [131] 131. McGrath PA, Hillier LM, Eds. The Child With Headache: Diagnosis and Treatment. Seattle: IASP Press, 2001;12.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [223] 223. Welborn CA. Pediatric migraine. Emerg Med Clin N Am 1997;15:625-636. source

  • May combine two claims.

    Premisecitation

    NAC can increase the substrate for non-toxic sulfation, enhancing metabolism by this route and reducing oxidation to NAPQI.

    “NAC can also increase the substrate for non-toxic sulfation, allowing increased metabolism by this route and less metabolism by oxidation to NAPQI (198).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [198] 198. Slattery JT, Wilson JM, Kalhorn TF, et al. Dose-dependent pharmacokinetics of acetaminophen: Evidence for glutathione depletion in humans. Clin Pharmacol Ther 1987;41:413-418. source

  • May combine two claims.

    Premisecitation

    Large clinical trials indicate that NAC efficacy is nearly complete when started within 8-10 h of paracetamol overdose, with no deaths in cases treated within that window.

    “Based on large clinical trials, it appears that NAC efficacy is nearly complete as long as it is initiated within 8-10 h of paracetamol overdose (200): there have been no deaths in cases so treated (182).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [200] 200. Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral N-acetylcysteine in the treatment of acetami- nophen overdose: Analysis of the national multicenter study (1976-1985). N Engl J Med 1988;3190: 1557-1562. source
    • cites [182] 182. Rumack BH, Peterson RC, Koch GG, et al. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med 1981;414:380-385. source

  • May combine two claims.

    Premisecitation

    These effects include non-specific antioxidant actions and preservation of cerebral blood flow and perfusion in cerebral edema after liver failure.

    “These effects include non-specific antioxidant effects, preservation of cerebral blood flow and perfusion in cerebral edema after liver failure (224).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [224] 224. Wendon JA, Harrison PM, Keays R, et al. Cerebral blood flow and metabolism in fulminant liver failure. Hepatology 1994;19:1407-1413. source

  • May combine two claims.

    Premisecitation

    The implications are that cannabinoids and similarly acting drugs may regulate cognitive functions, modulate food intake, affect female and male reproduction, provide neuroprotection, be involved in neurodegenerative diseases and shock pathophysiology, inhibit fertilized oocyte implantation, and inhibit cancer growth, angiogenesis, and metastasis.

    “The obvious implications are that cannabinoids and similarly acting drugs may regulate cognitive functions, modulate food intake, affect both female and male reproduction, provide neuroprotection and be involved in neurodegenerative diseases; pathophysiology of shock; inhibition of fertilized oocyte implantation; inhibition of cancer growth, angiogenesis and metastasis (for a review see ref. 71).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] 71. Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 2004;3:771-84. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The paracetamol nomogram plots serum paracetamol concentration against time after ingestion.

    “The so-called”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [168] 168. Prescott LF, Matthew H. Cysteamine for paracetamol overdosage. Lancet 1974;1:998. source
    • cites [182] 182. Rumack BH, Peterson RC, Koch GG, et al. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med 1981;414:380-385. source
    • cites [183] 183. Rumack BH, Peterson RG. Acetaminophen poisoning and toxicity. Pediatrics 1975;55:871-876. source
47 of 47

  • The authors state this as an assumption.

    AM404 is evenly distributed throughout the brain.

    “Assuming an even distribution of AM404 in brain”

  • The paper relies on this without support.

    The cannabinoid mechanism of paracetamol analgesia observed in rats applies to humans.

    “The blockade of cannabinoid CB 1 receptors has been shown to completely prevent the analgesic activity of paracetamol in rats (154).”
    “At analgesic doses of paracetamol, AM404 that is formed in rat brain regions expressing high levels of FAAH, can indirectly activate CB 1 receptors and directly activate TRPV1 receptors (66,102,235).”

  • The paper relies on this without support.

    Paracetamol is safe when taken at appropriate dosage.

    “Paracetamol is a safe drug at appropriate dosage.”

  • The paper relies on this without support.

    The mechanism of action of paracetamol had been a mystery of pharmacology for well over a century.

    “For well more than a century the mechanism of action of paracetamol (acetaminophen), one of the most commonly used drugs in the world, has been one of the mysteries of pharmacology.”

  • The paper relies on this without support.

    Drinking alcohol while taking paracetamol can enhance CYP2E1-mediated conversion of paracetamol to the hepatotoxic metabolite NAPQI.

    “Concurrent use of alcohol and paracetamol may increase the CYP2E1-mediated metabolism of paracetamol to the highly hepatotoxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI).”

  • The paper relies on this without support.

    In people who do not drink alcohol, NAPQI is detoxified by conjugation with glutathione.

    “In non-alcoholics, NAPQI is detoxified by conjugation with glutathione.”

  • The paper relies on this without support.

    Paracetamol is the drug of choice for minor-to-moderate non-inflammatory conditions in patients prone to gastric damage, and is preferable to aspirin in patients on anticoagulants or with coagulation disorders.

    “Paracetamol is the drug of choice for treating minor-moderate, non-inflammatory conditions in patients who are prone to gastric damage, and is preferable to aspirin in patients receiving anticoagulants or in patients with coagulation disorders.”
7 of 7

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Metabolism discussion points to the wrong figure

    Minor

    The metabolism discussion cites Fig. 2, but the paper labels Fig. 2 as an analgesia experiment and Fig. 3 as the metabolism diagram.

  • Therapeutic concentration range conflicts with reported peak levels

    Minor

    The stated therapeutic range is 5,000-20,000 μg/mL after unit conversion, far above the 8-32 μg/mL peak concentrations reported after recommended doses.

2 of 2

Cites

Flagged first, then by citations

1 of the 251 references couldn’t be matched to a known paper.

Research works printed but not linked: 11

  1. Anderson BJ, 1998, Variability of concentrations after rectal paracetamol [Letter], Paediatr Anaesth, 8, 324
  2. Chan A, 1886, Das Antifebrin, einneues Fiebermittel, Centralbl Klein Med, 7, 561
  3. Chao TC, 1993, Adverse drug reactions: Tales of aforensic pathologist, Ann Acad Med Singapore, 22, 86
  4. 10.1006/taap.1994.1116 · DOI · Paper page
  5. McCrae TA, 1989, Evaluation of 3‐(cys‐tein‐S‐yl) acetaminophen in the nephrotoxicity of acetaminophen in rats, Toxicologist, 9, 47
  6. Prescott LF, 1996, Paracetamol (acetaminophen). A Critical Bibliographic Review, 103
  7. Prescott LF, 1996, Paracetamol (acetaminophen). A critical Bibliographic Review
  8. Rang HP, 2003, Pharmacology
  9. Skjelbred P, 1984, Postoperative administration of acetaminophen to reduce swelling and other inflammatory events, Curr Ther Res, 35, 377
  10. Speight TM, 1997, Avery's Drug Treatment
  11. Von Mering J, 1893, Beitrage zur Kenntniss der Antipyretica, Ther Monatsch, 7, 577

Cited by

Sorted by citations

Related

Authors
Bertolini, A., Ferrari, A., Ottani, A., Guerzoni, S., Tacchi, R., & Leone, S.
Affiliations
  • University of Modena and Reggio Emilia (IT)
  • University of Chieti-Pescara (IT)
Corresponding author
Bertolini, Alfio
ORCID
Venue
CNS Drug Reviews
Publisher
Wiley
Published
2006-09
Volume
12
Issue
3-4
Pages
250-275
ISSN
  • 1080-563X (ISSN-L)
  • 1527-3458
DOI
10.1111/j.1527-3458.2006.00250.x
PMC
PMC6506194
OpenAlex
W1971079627
Cited by
654
References
251
Citations by year
2026: 15 · 2025: 33 · 2024: 33 · 2023: 46 · 2022: 34 · 2021: 48 · 2020: 42 · 2019: 44 · 2018: 42 · 2017: 34 · 2016: 42 · 2015: 44 · 2014: 31 · 2013: 36 · 2012: 35
FWCI
8.58
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 132 d)
Locations
  • CNS Drug Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
Keywords
paracetamol, analgesic mechanism, CB1 receptor, fatty acid amide hydrolase, TRPV1 receptor, endocannabinoids, cyclooxygenase inhibition, prodrugs
MeSH terms
Acetaminophen, Animals, Humans, Pain, Analgesics, Non-Narcotic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-29.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-29.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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