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Anaesthesia
Originally published in Update in Anaesthesia, edition 23 (2007)
MECHANISM OF ACTION Side-effects after paracetamol use are rare, and usually
Summary mild and transient. At therapeutic doses paracetamol
The disproportionate cost, Although paracetamol was found to be an effective
use is associated with an extremely low rate of liver
slow onset time and wide analgesic more than a century ago, its mechanism of
dysfunction (less than 1 in 500000)6 and there are only
variation in bioavailability action remains unclear and is the subject of continuing
make rectal paracetamol less
two contra-indications; paracetamol hypersensitivity
research. Unlike non-steroidal anti-inflammatory drugs
attractive in the presence of and severe hepatocellular insufficiency. There are few
(NSAIDs), whose analgesic and anti-inflammatory
the intravenous formulation. known drug interactions and breast-feeding women
effects are thought to relate to their inhibition of
Given the similar cost, may use paracetamol. Paracetamol has been shown to
the cyclooxygenase enzymes (COX-1 and COX-2),
intravenous paracetamol have a comparable benefit to ibuprofen and diclofenac
should be considered as a
paracetamol is a weak anti-inflammatory agent with an
in general and orthopaedic surgery7 and can significantly
more effective alternative abscence of COX-related adverse effects. Experimental
reduce the opiate requirement postoperatively – it has
to suppositories, when oral studies show that paracetamol can inhibit both
an opioid-sparing effect.8
dosing is not possible. It may COX-1 and COX-2 in an environment where the
also have a role to play when ambient concentrations of arachidonic acid and Number-needed-to-treat (NNT) – This gives the
prompt analgesia is required peroxides are kept low. However, where extracellular clinician an indication of the size of the treatment
and oral administration concentrations of these two chemicals are high in effect described by a clinical trial of a treatment. It
is not appropriate. Oral inflammatory conditions such as rheumatoid arthritis, tells the reader the number of patients that they
paracetamol is a simple would need to treat in order to see an effect in one
paracetamol shows limited in vivo suppression of
well-tolerated analgesic; patient.
however a more generous
inflammation and platelet activity.1
loading dose is needed if It has been demonstrated that paracetamol may 95% confidence intervals – These give the reader
meaningful early plasma of a study an indication of the reliability of the result
exert its analgesic effect via molecular targets distinct
concentrations are to be of the study. If you repeated the study 100 times, 95
from COX. In the brain and spinal cord paracetamol of the studies would give a result within these two
achieved. Intravenous
is conjugated with arachidonic acid to form N- confidence intervals. Larger studies tend to give
paracetamol provides a
method of achieving rapid arachidonoylphenolamine (AM404).2 AM404 is a narrower confidence intervals (i.e. results that more
therapeutic concentrations known activator of the capsaicin receptor (TRPV1) accurately represent reality). 95% (rather than a higher
of paracetamol that can and the cannabinoid CB1 receptor system both of or lower figure) is a generally agreed acceptable
subsequently be maintained which confer analgesia in the central nervous system. level of certainty that a study result reflects a true
This pathway may also account for the antipyretic effect
by oral absorption. treatment effect.
of paracetamol, known to be related to inhibition of A placebo is a pharmacologically inert substance
prostaglandin production in the brain.3 Cerebrospinal that may have a medical effect based solely on
fluid levels of prostaglandin are shown to be high in the power of suggestion. This is known as the
rats during pyrogen induced fever, and these levels placebo effect. By comparing drugs to a placebo,
are reduced along with the fever after paracetamol the pharmacological effects of the study drug are
Chris Oscier administration.4 At this time, however, such a link identified.
Specialist Trainee remains speculative.
ROUTE OF ADMINISTRATION
Nicki Bosley ANALGESIC EFFICACY Plasma concentrations of paracetamol between 10-
Specialist Trainee There is good evidence to show paracetamol as an 20mcg.ml-1 are known to produce an antipyretic effect
analgesic is effective and safe. A Cochrane systematic but the concentrations required to provide analgesia are
Quentin Milner review of oral paracetamol use in acute postoperative not well defined.9 One study, in which 120 children
Consultant pain analysing 47 studies, including 4186 patients, were given oral or rectal paracetamol post tonsillectomy,
Department of Anaesthesia found the number-needed-to-treat (NNT) - see box concluded an effect site concentration of 10mcg.ml-1
Royal Devon and Exeter NHS - for at least 50% pain relief, over 4-6 hours was 3.8 was needed to achieve pain scores of less than 4/10.10
Foundation Trust (95% confidence intervals: 3.4-4.4).5 There was no However, both higher and lower values than this have
Exeter EX2 5DW significant difference in the frequency of reported been suggested.11,12 There are significant differences
UK adverse effects between paracetamol and placebo. in the absorption of paracetamol, and therefore in the