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MKT 049
MKT 049
Key points Paracetamol was first synthesized in 1878 by acts by inhibition of cyclooxygenase (COX)-
a COX-like action; in humans, however, the expressed protein has AM404 appears to be a key player in a number of pain pathways.
no role in the physiology of prostaglandins.1, 4, 5 Apart from endocannabinoid reuptake inhibition, it has also been
shown to activate transient receptor potential vanilloid type 1
Serotoninergic pathway activation (TRPV1) and inhibit cyclooxygenase, NO and tumour necrosis
factor-alpha (TNF-a), all involved in acute and chronic pain states.
Serotonergic pathways are part of the descending pain system, ori- The central production of AM404 would also account for the anti-
ginating in the brainstem nuclei, hypothalamus, and cortex, and pyretic effect of paracetamol, known to be related to inhibition of
interact with pain afferents in the dorsal horn. Serotonin receptors prostaglandin production in the brain, whilst still without peripheral
are present throughout the central nervous system, involved in a actions (Fig. 2).
number of functions, including consciousness, mood, memory, and
nausea and vomiting, the latter of which are mediated via the
Efficacy
5-HT3-receptor subtype. It has become widely accepted that the acti-
vation of descending serotonergic pathways plays a key role in the Paracetamol demonstrates efficacy comparable with that of standard
action of paracetamol, and it has been demonstrated that the anti- equivalent doses of many NSAIDs (including ibuprofen, diclofenac,
nociceptive effects of paracetamol can be partially inhibited by ketorolac, and parecoxib), tramadol, and 10 mg i.v. morphine, with
co-administration of 5-HT3-receptor antagonists, interestingly using fewer side-effects.6 This applies across a variety of surgical proce-
anti-emetic drugs which are indeed frequently given together with dures, as well as for other sources of acute and chronic pain such as
paracetamol in the perioperative period.5 musculoskeletal pain and headaches, including tension-type head-
ache and migraine. As a component of a multimodal analgesic
regime, it is generally considered to have useful opioid-sparing
Endocannabinoid enhancement
effects; a reduction in opioid consumption is mostly if not universally
In the presence of fatty acid amide hydrolase (FAAH), an enzyme borne out with the statistical significance in clinical studies, but
found predominantly in the central nervous system, paracetamol the addition of regular paracetamol invariably reduced pain scores
(via an intermediary, p-aminophenol, formed in the liver) is con- and the incidence of nausea and vomiting, and improved patient
jugated with arachidonic acid to form the active metabolite, satisfaction.7
N-arachidonoylphenolamine (AM404). Analogous to the action of It is a useful first-line drug, and works in synergy when combined
serotonin or norepinephrine reuptake inhibitors, AM404 inhibits the with a number of other agents including ibuprofen, codeine, trama-
reuptake of the endocannabinoid, anandamide, from synaptic clefts, dol, and caffeine, improving analgesic efficacy whilst minimizing
increasing cannabinoid receptor activation on the post-synaptic side-effects of the adjunct agent.
membrane. This would explain the experiences of relaxation, tran- Although the onset of action of i.v. paracetamol is much faster
quility, and euphoria reported by many paracetamol users, apparent- compared with oral, a recent study showed no significant difference
ly independent of analgesia. in overall efficacy between the two routes, as measured using pain
154 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 14 Number 4 2014
Paracetamol: mechanisms and updates
scores at 1 h after administration in patients having third molar Table 1 MHRA guidelines for i.v. paracetamol dosing in children
extractions. This was, however in healthy, fasted individuals with Dose per administration Max. daily dose
presumed normal gastric emptying, undergoing daycase surgery,
and results may not be readily extrapolated to other patient groups.8 Term newborn infants, 7.5 mg kg21 30 mg kg21
up to children ,10 kg
Weight 10 –33 kg 15 mg kg21 60 mg kg21 up to max. 2 g
Dose Weight 33 –50 kg 15 mg kg21 60 mg kg21 (max. 3 g)
Weight .50 kg 1g 4g
The Medicines and Healthcare products Regulatory Agency
Continuing Education in Anaesthesia, Critical Care & Pain j Volume 14 Number 4 2014 155
Paracetamol: mechanisms and updates
Table 2 Drug interactions with paracetamol There has been equivocal data regarding whether moderate to
† Paracetamol absorption is increased by substances that increase gastric emptying long-term use may increase the risk of end-stage renal disease. The
(e.g. metoclopramide) mechanism of damage is thought, yet again, to involve the depletion
† Paracetamol absorption is decreased by substances that decrease gastric emptying of glutathione—a known anti-oxidant, rendering renal cells particu-
(e.g. anticholinergic agents, and opioids)
† Cholestyramine (ion-exchange resin) reduces the absorption of paracetamol if given larly sensitive to oxidative damage. Optimizing hydration and nutri-
within 1 h of paracetamol tion status is therefore of specific relevance in those receiving
† Caution with concomitant intake of enzyme-inducing substances, such as regular paracetamol.
carbamazepine, phenytoin, or barbiturates, or isoniazid, may increase the risk of
paracetamol toxicity
156 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 14 Number 4 2014
Paracetamol: mechanisms and updates
preparations of paracetamol itself include in their list of possible The mechanisms of these proposed effects are unknown, and the
adverse effects, difficulty breathing, and bronchospasm in patients role of any number of confounding factors cannot be excluded.
having a tendency of analgesic asthma.
Aside from its role in detoxifiying paracetamol in the liver, gluta-
Dermatological effects
thione is a pulmonary antioxidant, which may limit airway inflam-
mation in asthma. Consistent with findings in animal and in vitro Pain or a burning sensation may be experienced at the injection site
studies that paracetamol may deplete the lung of glutathione, a pleth- after i.v. administration and 100 ml volume should be infused over
ora of, largely epidemiological, data are strongly suggestive that fre- 15 min, but whilst uncomfortable, this is short-lived, and does not
Continuing Education in Anaesthesia, Critical Care & Pain j Volume 14 Number 4 2014 157
Paracetamol: mechanisms and updates
References 10. Boyle M, Nicholson L, O’Brien M et al. Paracetamol induced skin blood
flow and blood pressure changes in febrile intensive care patients: an
1. Mattia C, Coluzzi F. What anesthesiologists should know about paraceta- observational study. Aust Crit Care 2010; 23: 208– 14
mol (acetaminophen). Minerva Anestesiol 2009; 75: 644– 53 11. Eneli I, Sadri K, Camargo C, Jr, Barr RG. Acetaminophen and the risk of
2. Jahr JS, Filocamo P, Singh S. Intravenous acetaminophen: a review of phar- asthma: the epidemiologic and pathophysiologic evidence. Chest 2005;
macoeconomic science for perioperative use. Am J Ther 2013; 20: 189–99 127: 604– 12
3. Moller PL, Sindet-Pedersen S, Petersen CT, Juhl GI, Dillenschneider A, 12. Ishida T, Sato T, Irifune M, Tanaka K, Nakamura N, Nishikawa T. Effect of
Skoglund LA. Onset of acetaminophen analgesia: comparison of oral and acetaminophen, a cyclooxygenase inhibitor, on Morris water maze task
intravenous routes after third molar surgery. Br J Anaesth 2005; 94: 642 –8 performance in mice. J Psychopharmacol 2007; 21: 757– 67
158 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 14 Number 4 2014