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Introduction
Paracetamol (or acetaminophen - US English) is one of the most widely used in the
western world. In the UK alone approximately 4000 million tablets were consumed in
19931.
A more recent prediction made by IMS health is that 3500 million 500mg tablets were
consumed in the year 20002. US citizens purchased more than 28 billion doses of
acetaminophen-containing products such as Tylenol, various narcotics and the
hydrocodone/acetaminophen combination3.
Paracetamol is one of the primary antipyretic treatments. The current WHO guidelines
recommend paracetamol as treatment for children with a fever ≥39°C4. The NICE
guidelines suggest a use for paracetamol in pain management and the British Pain
Society suggest that paracetamol is a suitable treatment for mild to moderate pain5.
The recommended dose for adults and children older than 12 given by the NICE
guidelines is 0.5 grams to 1 gram every 4–6 hours (maximum 4 grams daily).
Aims and Objectives
Our SSC2a project focuses on whether use of paracetamol as an antipyretic produces
better or worse clinical outcomes than leaving the fever untreated. We considered
several areas where lowering fever using paracetamol may or may not necessarily
benefit the patient, and analysed literature to determine when it would and would not
be appropriate to prescribe paracetamol, namely: viral infections; mortality; febrile
convulsions; malaria; and vaccination. We also aim to look into the epidemiology of
paracetamol use and whether it is a actually effective as an antipyretic agent.
Paracetamol and Reducing Symptoms of Infection
Paracetamol is used for its antipyretic effects and analgesia for mild to moderate pain.
Prostaglandin synthesis and COX inhibition are suggested mechanisms of action but this
is still not clearly understood. It is often taken for common infections to control
associated fevers and body pains. Considering how commonly it is used, the costs and
the possibility of adverse effects it is important to know whether Paracetamol actually
works compared to a placebo6.
In a randomised double-blind placebo-controlled trial looking at respiratory tract
infections in 210 children, Gupta et al. found that Paracetamol reduced temperature
significantly faster than placebo. During the first 4 hours there was a mean rate of
temperature reduction of 0.33°C/h (standard deviation: 0.16) with Paracetamol and
0.07°C/h (SD: 0.13) with placebo (P<0.001). The mean percentage reduction in
temperature was 85.4% (SD: 22.4) with Paracetamol which was significantly higher
than 45.5% (SD: 34.1) with placebo (P<0.001). Other symptoms such as lack of activity,
poor alertness, mood and level of comfort also improved significantly (P<0.001). After 6
hours, children were sent home and parents recorded their temperature. It was
concluded from this that fever clearance times didn’t differ significantly between groups
but self-reporting bias, errors in recording and other confounding factors in the home
make this result unreliable. 7
Interestingly, Kofoed et al found no significant difference between the rate or the degree
of temperature reduction due to Paracetamol compared with placebo. 50mg of
Paracetamol per kg was used instead of Gupta’s 15mg per kg. 338 children with nonsevere malaria were involved in this randomised control trial. The large sample size
decreases the likelihood that this finding was due to chance. But the anti-malarial,
chloroquine, that children were taking in conjunction and the majority of Paracetamol
being administered by parents at home could have been confounding factors.8
Bachert et al found significant differences (P<0.001) between mean temperature
reduction with Paracetamol 1000mg, Paracetamol 500mg and placebo (1.71°C, 1.25°C
and 0.63°C respectively) concluding that there was a dose-related response to
Paracetamol and that Paracetamol was also effective at reducing fever in adults with
respiratory tract infections. Significant reductions in mean intensity of headaches,
achiness and feverish discomfort were observed (P<0.001) but not in intensity of sinus
sensitivity to percussion or sore throat. These results could still be due to chance
because the 78 participants per treatment group used in this study were inadequate; it
was calculated that 90 participants per group would be needed to give the results
sufficient power to produce reliable results therefore conclusions. However, the small Pvalue and the fact that a dose-dependent response was observed are quite persuasive of
the study’s validity. 9
A GSK funded study by Eccles et al. observed from the data that after a 1000mg dose of
Paracetamol nasal congestion worsened but after 3 doses per day (max. 4 hour
intervals) for 3 days nasal congestion improved. The primary focus of this paper was
Paracetamol in combination with pseudoephedrine, a decongestant, which is still
relevant as Paracetamol is often taken in combination with other drugs e.g. codeine. The
results showed that Pseudoephedrine-Paracetamol was 30% more effective in relieving
pain than pseudoephedrine alone. From this we could deduce that Paracetamol caused
this additional pain relieving effect, but this is extrapolated and not a reliable
conclusion. 10
Paracetamol seems to be effective at reducing fever and may be implicated for
treatment of lethargy, poor alertness, mood, discomfort, nasal congestion, pain,
headaches and achiness associated with respiratory tract infections in adults and
children but not children with malaria.
Conclusions are hard to draw because my search didn’t bring up many papers that were
fully relevant and among these papers the study populations were not comparable, for
example, the effects in adults may be different to the effects in children. Also, I only
address two out of many possible types of infection. Some symptoms of infection will
not have been covered so I don’t think I have fully answered my focused question.
Conclusions from the first two papers which administer Paracetamol to children in
weight-dependent doses should be treated with caution when advising parents on how
to control their child’s symptoms at home, because instructions supplied with over-thecounter Paracetamol for children give age-dependent doses. Weight-dependent doses
may be more effective but only practical in settings such as hospitals where staff are
trained. Trying to work doses out at home may cause confusion and lead to a child
receiving a higher or lower dose than is appropriate making the Paracetamol ineffective
or harmful.
Ultimately, larger studies which compare Paracetamol with a placebo for a range of
symptoms of infections in adults and children are needed to be able to come to a more
confident conclusion and reduce the effects of chance. More quality control is needed
including all signs and symptoms being recorded by trained staff in a hospital setting to
reduce confounding and self-reporting bias. Then we will be in a better position to give
advice to clinicians and the general public about the effectiveness of Paracetamol.
Adverse Events
It is important to understand the frequency and usage of paracetamol and to ascertain
whether the benefits of taking paracetamol outweigh its adverse effects.
Several studies have investigated whether paracetamol when taken at the
recommended doses has any clinically relevant adverse effects. When paracetamol is
taken at the recommended dose the incidence of adverse events appears trivial11. When
compared with a placebo, the incidence of adverse events were similar between
groups12.
One particular study13 investigated the link between paracetamol and acquiring cancer.
Paracetamol is a known metabolite of phenacetin which has been classified as a human
carcinogen14. They studied 39,946 individuals, after exclusions for bias reasons, in
Demark and studied them until cancer incidence, date of death or 31st December 1997,
which ever occurred first. Standardised incidence ratios were used to measure the
significance of the findings. The researchers found that their results did not support a
role of paracetamol in cancer development15.
There has also been research into liver function damage from paracetamol when used at
appropriate doses. Results show that there is no significant clinical link between
paracetamol and liver function damage16.
Paracetamol can be toxic to humans at doses greater than 7-10g in adults and more than
150mg/kg in children17. It has been well documented that liver failure is a clear
consequence of paracetamol overdose18. Research in the United States showed
paracetamol overdose to be the leading cause of acute liver failure from 1998-200319.
From 1900-1998, paracetamol was deemed to be the cause of 56,000 emergency room
visits and 458 deaths20.
Paracetamol overdose often results from attempted suicide. In the UK, paracetamol is
now the leading drug used in suicide attempts21. However, a significant proportion of
overdoses are unintentional, especially in children22. In the US, approximately 30%23 of
overdoses were accidental whereas in the UK only 8%24 were unintentional. Statistics
show however, that only 0.1% of all paracetamol overdoses resulted in death. Therefore,
paracetamol can hardly be considered to be an effective drug with which to commit
suicide25.
For regular consumers of paracetamol, the cost of paracetamol can become substantial.
Paracetamol can cost from between 15p for 16500mg tablets to £3.99 for 12 200mg
tablets26. UNICEF prices paracetamol at $0.50 per 100ml of liquid paracetamol 27.
The burden to healthcare services is significant both in terms of hospital admissions and
costs to health services. In 1995, it was conservatively estimated28 that the average cost
associated with intentional paracetamol poisoning involving adolescents and adults in
the US was $2172 per case and at $87 million annually.
The only significant adverse effects occur during overdose, so efforts should be made to
prevent these events. In one particular study29, patients who had overdosed on
paracetamol were questioned on what could have deterred them overdosing.
Only 35% of those questioned said that they would have continued to use it if they had
known that the harmful effects could be delayed for several days. Thus, more thorough
leaflets should be provided to educate consumers more of the details of the risks.
Another effective preventative measure could be to include an antidote such as
methionine to the paracetamol tablet. 64% of those interviewed claimed that they
would not have taken the overdose.
Warning labels such as ‘paracetamol can cause death’ would only have prevented 25%
from overdosing. Reducing the number of tablets in packages would have led to 37%
taking fewer tablets or not overdosing. If paracetamol was made prescription‐only, 35%
would not have taken an overdose, and 40% would have sought an alternative.
I have found that paracetamol is a very frequently used drug and is relatively cheap.
Research has found no significant adverse events when taken at the recommended dose.
However, serious events can occur during overdose, whether accidental or not. An effort
should be made to reduce the number of overdoses.
Mortality
Fever is a common symptom of patients admitted to intensive care units (ICU) especially
from infection.30,33,34 However, it is still under heavy debate, whether or not to
administer antipyretic therapy to patients without acute neurological
injury.33 Therefore it is important to find any implications antipyretic use of
acetaminophen has on the outcome, especially mortality, in critically ill patients.
Sepsis is a very common cause of admission to ICU and so it is important to consider the
effects of antipyretic acetaminophen on mortality. Lee et al. concluded that in septic
patients antipyretic therapy increased 28-day mortality (adjusted odds ratio: NSAIDs
2.61, p= 0.028; acetaminophen 2.05, p=0.01) while moderate fever decreased mortality
(37.5oC to 38.4oC: adjusted odds ratio 0.45, p=0.014).30 However, the opposite was found
in non-septic patients; antipyretic therapy was not independently associated with 28day mortality (adjusted odds ratio: NSAIDs 0.22, p=0.15; acetaminophen 0.58, p=0.63)
while fever increased 28-day mortality (adjusted odds ratio: 38.5oC to 39.4oC 7.49,
p=0.02; ≥39.5oC 11.77, p=0.02). These results are reliable large multi-centre prospective
observational study (n=1,425: with sepsis n = 606, without sepsis n= 819) justified by a
power analysis. This helped eliminate the effects of random variability and provides a
sample representative of the population. However there was no standardised method of
measuring treatment and so measurements varied depending on the site and external
environment. There was also a statistical significance in treatment preferences; the
proportion of non-septic patients treated with acetaminophen was less than septic
patients whilst the opposite was true for NSAIDs (P<0.001). The multimodal treatment
method and variation in preferences makes it difficult to identify the effect antipyretic
acetaminophen alone had on the results. However, it could be hypothesised that
antipyretic acetaminophenin use in critically ill septic patients with fever would
increase mortality.
In contrast, Janz et al. suggest that in specific situations acetaminophen may reduce
mortality in sepsis. They found that cell-free haemoglobin increased mortality and that
acetaminophen may have a protective effect by reducing cell-free haemoglobin-induced
oxidative injury.31 They carried out multivariate analysis to limit the effects of
confounding but the study was limited by the small sample size for the analysis of
acetaminophen which reduces its reliability.
Other studies compared the mortalities from different methods of antipyresis. Schulman
et al. found that aggressive antipyretic strategy (acetaminophen every 6 hours enterally
for temperatures >38.5oC, cooling blanket for temperatures >39.5oC) had a trend of
higher mortality rate than the permissive antipyretic strategy (acetaminophen and
cooling blanket for temperatures >40oC until temperature was <40oC) group.32 However
all patients who passed away had sepsis and it was not accounted for as a confounding
factor which would therefore have led to inappropriate conclusions. Nevertheless, their
findings seems to support Lee et al.’s conclusion. However the study did not provide
data on sepsis for the surviving patients in the study so a comparison cannot be made
between survivors and non-survivors. Other flaws include a small population (n=82)
which makes the conclusion unreliable. Therefore a larger study with a better design is
needed to consider the differences between aggressive and permissive antipyretic
therapy.
Contrary to this, a pilot study by Niven et al. found that there was no increase in
mortality between aggressive or permissive antipyretic therapy.33 This study has a
reliable design with blinding and randomisation but since it is a pilot study a very small
sample size was used (n=26). However, it does show it is ethical and possible to conduct
a safe study analysing mortality and aggressive or permissive treatment types.
There was also a study looking the difference in mortality between early and late
antipyretic therapy. Mohr et al. found that in patients with severe sepsis or septic shock
there was no variation in mortality by early and late antipyretic therapy after
accounting for various confounders.34 However this study has several confounders
namely other medications as patients who were more ill received more interventions.
In conclusion, there is a wide range of results for the antipyretic use of acetaminophen
and mortality. It is difficult to draw conclusions on the associations between mortality
and antipyretic acetaminophen as all the studies, apart from Janz et al., adopted a
multimodal antipyretic strategy. The largest study proposes that antipyretic use of
acetaminophen does not increase mortality in critically ill non-septic patients but does
for critically ill septic patients.30 However one paper found that antipyretic
acetaminophen was protective against mortality in septic patients with high cell-free
haemoglobin.31 Other studies looked at differences in strategies of antipyresis. Schulman
et. al found that aggressive antipyresis increased mortality but this was contradicted by
Niven et al. Whilst another study found that there was no difference in outcomes in early
or late antipyresis.34 Therefore clearly, with the wide range ofconclusions, more studies
are needed to look at the effects of antipyretic acetaminophen use on mortality in
critically ill patients. However there is reason to believe that it would increase mortality
in critically ill patients with sepsis without high cell-free haemoglobin.
Paracetamol and Viral Infections
Paracetamol is commonly used in the treatment of viral fevers35. The use of paracetamol
in these circumstances is seen as status quo and is not often question. There are
concerns, however, that this practice could be relatively ineffective (compared to other
methods of antipyresis) or that it could potentially be harmful to patients.
It is seen as essential to treat these fevers – especially in the opinion of parents. This
reduces the number of parents who agree to studies involving paracetamol – they fear
that their child may be given the placebo35,36. Kramer et al. describes this as “parental
fever phobia”35. The worries about placebos demonstrates that paracetamol
administration is a paradigm of modern medicine.
This paradigm is based on the principle that paracetamol will reduce fever. This is
supported by evidence although the extent to which it reduces temperature is
debateable. Weisse et al found that paracetamol reduced temperatures by 1.16
Fahrenheit on average in virally induced fevers3. The evidence on this topic cannot all be
compared since the definition of a fever varies between papers: definitions of fever in
the literature varied between ≥38.0˚36 to ≥38.9˚35,36,37. The method was mostly
consistent although some papers included children with temperatures measured either
rectally or orally37. This makes the comparison of results problematic and introduces
error. A standard definition should be introduced. Despite these issues it is still clear
that paracetamol will reduce fevers of viral origin.
Whilst it is clear that paracetamol is an effective antipyretic, alternatives to
pharmacological interventions can be equally efficient if not more. Mahar et al found
that tepid sponging in addition to paracetamol was more efficacious than paracetamol
alone36. In their study of children with virally induced fevers, the mean rate of
temperature fall was faster in the group given manual antipyresis and paracetamol
compared to those just given paracetamol (P = 0.0004) and reached a lower
temperature (defined as < 38.5˚) faster (P < 0.0001)36. This demonstrates that manual
antipyresis has a role to play in the management of febrile children.
There have been various papers linking use of paracetamol to a reduced molecular
immunological response in-vitro. The suppression of serum neutralising antibody was
by paracetamol was noted by Graham et al38. This was demonstrated in a group of
healthy individuals inoculated with rhinovirus. The clinical effects of this were likely to
be minimal in healthy adults especially since other immunological defences – e.g.
interferon production – were unaffected38 – and it is interferons, not antibodies that
play make the greatest difference in the primary response to viruses. There is, however,
some evidence of paracetamol increasing disease duration in non-immunocompromised
individuals. One study found that paracetamol use increased the time taken for varicella
zoster lesions to scab by 1.1 days. It is worth noting the exact P value was 0.04839, a
value close to the border of statistical significance. Since scabbing is a good measure of
varicella shedding this is possibly indirect evidence of mild immunosuppression.
Alternatively there is also evidence that paracetamol does not affect the immune
response – fevers of viral aetiology were not prolonged by the administration of
paracetamol35. That said given the extent of the evidence suggested from various papers
it would be reasonable to suggest that there is some immunomodulation by
paracetamol.
There is also the suggestion that paracetamol may increase the incidence of secondary
bacterial complications from some case reports. This prompted a study from Lesko et
al40 which concluded that there was a weak association between ibuprofen coadministered with paracetamol and group A streptococcus infection40 but no evidence
of increased risk with just paracetamol. More research is clearly needed to establish if
this association is merely correlation or causation. This could relate to the previously
mentioned immunosuppression, especially antibody suppression.
Future research into this area should include larger more clinically based studies. These
could provide evidence to decide whether or not the immunomodulation shown by
paracetamol in vitro is clinically significant or not. For further research there should be
a standard definition of fever to allow different studies to be more easily compared.
The current perception that fever from viral illnesses should automatically warrant
antipyretic treatment is wrong. Whilst the evidence is not by any means conclusive
there is some reason for concern notably surrounding the possible immunosuppressing
effects of paracetamol. In patients who are not experiencing great distress or discomfort
from their fever it may be best to avoid paracetamol treatment thus avoiding any
potential unwanted immunosuppressing effects.
Febrile Convulsions
Paracetamol is widely used in the treatment of childhood fevers but its effectivness for
preventing the occurrence febrile convulsions is generally disputed. It is important
that paracetamol is only used where it is indicated; thus exploring the question on
‘Paracetamol vs Fever?’.
Febrile convulsions are experienced in 3-5% of infants and children aged 6 months to 6
years41. This type of seizure is normally associated with fever and not with any other
specific cause, such as intra-cranial infection or epilepsy. There are a number of risk
factors associated with developing febrile seizures, namely age of child, previous family
history of febrile seizures and number of previous febrile seizure episodes. Young age at
the time of the first febrile seizure increases the risk of recurrence41.
In a randomised, placebo-controlled, double-blind trial investigating the effectiveness of
3 antipyretic agents – Paracetamol, Ibuprofen and Diclofenac – the effectiveness of each
was tested in preventing the recurrence of febrile seizures. All the antipyretic agents
were efficient in lowering the temperature during a febrile episode without a seizure.
However, the study showed that antipyretic agents are ineffective at preventing febrile
seizures and in the lowering of the raised temperature during a febrile episode that led
to a recurrent febrile seizure41. In this trial random sampling was not possible as the
inclusion criteria only permitted children between the ages of 4 months-4 years having
their first febrile seizure. The lack of control over the sample size may indicate reduced
statistical power to produce meaningful results.
Another study found that paracetamol effectively reduces temperature in children with
a history of febrile seizures, but did not look into the effectiveness of febrile seizure
prevention42. The two remaining relevant papers also came to similar conclusions. The
penultimate paper established that paracetamol had no effect on the recurrence rate of
febrile seizures43. This paper went on to discuss the mechanism of action of paracetamol
compared to other antipyretic agents; paracetamol acts on the CNS by lowering the
thermoregulation set point. In contrast, most modem antipyretic and analgesic agents
are recognised as prostaglandin inhibitors43. Perhaps the effect of prostaglandin
inhibitors on reduction of febrile seizures deserves further study.
The final paper looked into antipyretic effects in febrile seizures by ongoing prophylaxis
versus sporadic usage. It concluded that paracetamol administration to children with
febrile seizures is not effective in preventing the early recurrence of febrile seizures,
prevention of fever, or the reduction of its degree44. Rigorous prophylactic antipyretic
therapy was not superior, when judged by febrile episodes and degrees of temperature,
to the conventional approach based on sporadic usage of paracetamol44.
Fever is often treated quite aggressively in febrile children; an approach that is largely
based on the assumption that fever and convulsions are causally related. Recently, it has
been suggested that convulsions occurring during a febrile disease may be due to
various viral or bacterial antigens affecting the CNS, and that convulsions may be
independent from increases in temperature44. Consequently, the prescription of
antipyretic agents – and paracetamol in particular – should be monitored and perhaps
reduced where prescription is unnecessary.
Although Paracetamol has been found to be an effective antipyretic for childhood fevers,
evidence of it’s effectiveness in preventing the occurrence of febrile seizures is lacking.
The effects of alternative antipyretic agents (Ibuprofen, Diclofenac etc) on febrile
seizures reduction should be studied further. These findings tie in with the overall
question ‘Paracetamol vs Fevers'; indicating that there are certain situations (i.e.
reducing the recurrence of febrile seizures) when paracetamol is contraindicated.
Malaria
Malaria is a real challenge to medicine; it causes huge mortality in parts of the world,
and has a significant case fatality. Pyrexia is part of its clinical course8, 45, 46, 47 and
paracetamol is commonly given as an antipyretic to patients with malaria who are
experiencing pyrexia8, 47. WHO recommends paracetamol’s use in people with malaria
experiencing high fever45, even though there isn’t a huge amount of evidence on its
benefit. In addition, there is always the possibility of adverse effects which should be
taken into account.
In order to establish the best treatment strategy possible, we should address two points:
whether reducing malarial fever improves outcomes and whether paracetamol is the
best pharmacological agent for reducing fever.
If we find that fever is beneficial, or at least indifferent, to clinical outcome in malaria,
then it would be important to reassess the benefits of health care workers routinely
being giving paracetamol to patients suffering from malaria. It is also obvious that if
another drug is found to have a pharmacology which is better than paracetamol in
treating malaria, then it should be considered as a replacement.
We have looked at 6 articles which compare different treatments for malaria. None of
the articles had results which showed paracetamol to be clearly more effective than
other methods of antipyresis (e.g. chloroquine, NSAID or mechanical).
All suggested that there should be concern that paracetamol impinges on the body’s
natural immunological methods of removing parasitaemia; with the suggested
explanation being that Tumour Necrosis Factor (TNF) and fever itself are effective in
removing an infection, and that paracetamol reduces TNF levels, causing the longer
Parasite Clearance Time (PCT) that has been seen. 8, 46, 47, 48, 49 The clearest example47
showed that mean PCT was 16 hours longer in children receiving paracetamol (as well
as mechanical antipyresis), it had a 95% confidence interval that the increase was 8-24
hours, and a power of 0.004. This shows that the result was significant. A major issue
with this study, however, is that the control group (receiving only mechanical
antipyresis) didn’t receive a placebo. I feel the result is still significant, although a future
experiment to rule out a ‘nocebo’ effect would be helpful.
One of the studies’ results didn’t show an increased PCT; the authors suggested that this
may be due to a combination therapy, so the results of that trial were not sufficiently
conclusive to dismiss concerns about paracetamol’s effect on PCT48.
As mechanical antipyresis has been shown to be as effective as paracetamol at lowering
body temperature,47, 49 and it does not have an adverse effect on TNF levels (meaning
that the PCT isn’t affected) it has been suggested that the use of sponging, cooling
blankets etc may be preferable. Evidence against this hypothesis could be suggested47 as
fever clearance time was 11 hours faster in children receiving paracetamol (rather than
mechanical antipyresis), but p=0.176 and a wide confidence interval made this result
inconclusive.
An issue we have considered is that it may not be very practical to recommend cooling
physical items when the areas with high incidence of malaria are so hot, and storage
could be difficult. We haven’t looked any further into this question, however, so its an
area that could benefit from further investigation.
Two trials looked at ibuprofen.49, 50 One referred to another article stating that ibuprofen
is a better antipyretic than paracetamol (this was supported in other literature45, 50 but
in the article’s trial ibuprofen had the same adverse effect: patients treated with the
NSAID also had delayed parasite clearance, the median PCT being 13.4 hours longer
than the placebo group (p=0.0024, which is strong). 49 Perhaps the well documented
other adverse effects of NSAIDs mean it is better that paracetamol is used more often
than ibuprofen in this context.
Another reason to question the necessity of antipyresis is given in one paper which
made reference to the fact that in malaria, fever (measured as rectal temperature)
doesn’t have any effect on the incidence of seizures.8 The paper used this evidence to
hypothesize that perhaps the pathogenesis of malaria is independent of pyrexia/body
temperature. There may of course be other areas where temperature is very important
in the clinical course of malaria, so this is a hypothesis that requires more research.
This trial specifically measured hospitalisation with high fever and convulsions as a
clinical outcome; here paracetamol seemed to protect the children from being
hospitalised, but it was much too small a trial to draw any conclusion from, other than
that more information is needed. It mentioned that in animal studies fever is associated
with consistently improved outcomes, and, conversely, that antipyresis increases
mortality. It also mentioned that there is no clear evidence that antipyretic treatment
reduced febrile convulsion, questioning whether or not antipyretic treatment was
something of benefit.
Another of the papers made similar comments; highlighting that there is the suggestion
that paracetamol only alleviates patient suffering through analgesia, rather than through
antipyretic means. 47
It has been difficult to draw conclusions from some of the reports, as they rely heavily
on PCT, which isn’t actually a clinical outcome, evidence on mortality or morbidity could
be more useful in future, and due to other weaknesses of the trials. However they
offered some insight.
These papers haven’t convinced me that the current treatment guidelines are beneficial:
Paracetamol seems to impinge on the human body’s immunological capabilities, and we
don’t know that antipyrexia improves the clinical course of malaria. Until there is strong
evidence that paracetamol does improve outcomes, it may be prudent to put less effort
into antipyrexia. There is no doubt, however, that larger trials could offer more
definitive information on these important aspects of the discussion.
Paracetamol use with Vaccinations
Paracetamol may be sensible to give as a prophylactic drug to prevent induction of fever
in patients (particularly children) who are receiving a vaccination. Normally,
vaccinations work by inducing an immune response within the body – mimicking that of
a true infection – involving the release of inflammatory mediators, which have pyretic
effects (i.e. fever). As previously discussed in this website, paracetamol’s impact on the
immune response may have an in turn reduce the effectiveness of vaccination. This
could be because the body is not producing the same volume of inflammatory
mediators, which may in turn prevent adequate production of antibodies against the
vaccine. If paracetamol does reduce the effectiveness of vaccines, this could leave people
who think they are immunized to certain diseases much more susceptible than they
realise. This would not only have an impact on individuals’ health, but could also have
public health consequences if vaccines were rendered less effective in even a minority of
the population as it would increase the carriage of many infectious diseases.
A study by Prymula, R. et al51 shows that antibody response is in fact lowered by the
administration of prophylactic paracetamol when giving a vaccine. The study was a
phase III open label clinical trial and studied the effects after children were vaccinated
with a ten-valent pneumococcal non-typeable Haemophilus influenzae protein Dconjugate vaccine and hexavalent diphtheria-tetanus-3-component acellular pertussishepatitis B-inactivated poliovirus types 1, 2, and 3-H influenzae type band oral human
rotavirus vaccines. It showed that six months after receiving the vaccine, the children
that were given prophylactic paracetamol had a significantly lower antibody response
than those who were not given the prophylactic paracetamol. As it was the participants’
parents recording adverse effects could mean this aspect of the study was susceptible to
observational bias as they may not have noticed certain side effects if it had not been
suggested that they should have been recording them, and additionally different parents
may have a different perception of the severity of any side effects.
However, a follow-up study, also by Prymula52 showed that although there was a
reduction in antibody response in the initial 6 months following the vaccination, when
such cases were followed up 2 years later, the prophylactic paracetamol group and the
control group showed no difference in antibody levels. This suggests that there are no
long-term reductions in immunogenicity. Again in this trial, there was no statistical
analysis of the significance of the results.
Dhingra, B. and Mishra, D. 53 studied differences between children receiving the
Diphtheria-Tetanus-Pertussis vaccine between a group of children who were and were
not given prophylactic paracetamol, there was no difference in the quantity of additional
paracetamol given as required by parents. This study suggested that this indicated the
paracetamol did not cause any significant alleviation of symptoms. One concern about
this study is that the parents are told that they may give additional paracetamol as and
when required, and this may prompt parents to do so when they ordinarily may not
think it necessary to give their child paracetamol after a vaccine.
Similarly, a study on elderly patients receiving the influenza vaccine either with or
without prophylactic paracetamol shows that paracetamol neither alleviated side effects
of the influenza vaccine nor impaired the antibody response in this patient group54. A
major flaw in the design of this study is that these elderly patients are likely to have had
similar vaccinations before, and the vaccinations in this study may have acted more like
a “booster”, merely improving any immunity they already had.
One key issue with these studies is that many side-effects are reported by either the
patient or their parents, which could lead to subjectivity and observer bias as opposed
to clinical staff taking objective measures, such as ‘irritability scales’, and so on. Due
to the amount of observation bias, flaws in the study designs and overall lack of
evidence, it is difficult to make a full conclusion. There needs to be more clinical trials
conducted over this subject, preferably comparing antibody levels over a set period of
time, analyzing both sort and long term effects. As there is evidence showing there may
be reduced vaccine efficacy in the short term for children who are given prophylactic
paracetamol, it may be counter intuitive to do so when vaccinating against seasonal flu
and vaccines which may be needed for increased immunity in the near-future.
Nevertheless, I conclude that this evidence appears to show there are no long-term
reduction of efficacy or, and conflicting evidence on whether PP actually reduces
vaccine-related pyrexia, it may be reasonable to give patients who are at higher risk of
adverse effects associated with fever a dose of prophylactic paracetamol in order to
avoid such occurrences, and that paracetamol may be taken as and when needed in
patients who are not at high risk to alleviate side effects if and when they arise.
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REFERENCES
Introduction
1. Spooner JB, Harvey JG. The history and usage of paracetamol.J Int Med Res1976; 4:1–
6.
2. IMS Health, Sheen unpublished data
3. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of
medication use in the ambulatory adult population of the United States: the Slone
survey. JAMA, 2002 Jan 16; 287(3) 337-44
4. World Health Organization. Integrated Management of Childhood Illness. Geneva:
World Health Organization; 2000. WHO document WHO/FCH/CAH/00.12.
5.MHRA (2004) Advice from the CSM Expert Working Group on analgesic options in
treatment of mild to moderate pain. Medicines and Healthcare products Regulatory
Agency. mhra.gov.uk
Is Paracetamol effective?
6. Ward B, Alexander-Williams JM. Paracetamol revisited: a review of the
pharmacokinetics and pharmacodynamics. Acute Pain 1999 Sept;2(3):139-149.
7. Gupta H, Shah D, Gupta P, Sharma KK. Role of Paracetamol in treatment of childhood
fever: a double-blind randomised placebo controlled trial. Indian Paediatrics2007 Dec
17;44:903-911.
8. Kofoed PE, Ursing J, Rodrigues A, Rombo L. Paracetamol versus placebo in treatment
of non-severe malaria in Children in Guinea-Bissau: a randomised control trial. Malaria
Journal 2010;10:148
9. Bachert C, Chuchalin AG, Eisebitt R, Netayzhenko VZ, Voelker M. Aspirin compared
with acetaminophen in the treatment of fever and other symptoms of upper respiratory
tract infection in adults: a multicentre, randomised, double blind, double dummy,
placebo controlled parallel group, single dose, 6 hour dose ranging study. Clinical
Theraeutics 2005;27(7):994-1003.
10. Eccles R, Jawad M, Jawad S, Ridge D, North M, Jones E, Burnett I. Efficacy of a
Paracetamol-Pseudoephedrine combination for treatment of nasal congestion and painrelated symptoms in upper respiratory tract infection. Current Medical Research and
Opinion2006;22(12):2411-2418
Adverse events
11. MATHIESEN O, WETTERSLEV J, KONTINEN V, POMMERGAARD H, NIKOLAJSEN L,
ROSENBERG J et al. Adverse effects of perioperative paracetamol, NSAIDs,
glucocorticoids, gabapentinoids and their combinations: a topical review. Acta
Anaesthesiologica Scandinavica. 2014;58(10):1182-1198.
12. Williams C, Maher C, Latimer J, McLachlan A, Hancock M, Day R et al. Efficacy of
paracetamol for acute low-back pain: a double-blind, randomised controlled trial. The
Lancet. 2014;384(9954):1586-1596.
13. Eken C, Serinken M, Elicabuk H, Uyanik E, Erdal M. Intravenous paracetamol versus
dexketoprofen versus morphine in acute mechanical low back pain in the emergency
department: a randomised double-blind controlled trial. Emergency Medicine Journal.
2013;31(3):177-181.
14. Friis S, Nielsen G, Mellemkjr L, McLaughlin J, Thulstrup A, Blot W et al. Cancer risk in
persons receiving prescriptions for paracetamol: A Danish cohort study. International
Journal of Cancer. 2001;97(1):96-101.
15. IARC Monographs on the evaluation of carcinogenic risks to humans, suppl. 7.
Overall evaluations of carcinogenicity: an updating of IARC monographs 1 to 42. Lyon:
IARC, 1987. 310–2
16. Dippel D, van Breda E, van Gemert H, van der Worp H, Meijer R, Kappelle L et al.
Effect of Paracetamol (Acetaminophen) on Body Temperature in Acute Ischemic Stroke :
A Double-Blind, Randomized Phase II Clinical Trial. Stroke. 2001;32(7):1607-1612.
17.SHEEN C. Paracetamol toxicity: epidemiology, prevention and costs to the health-care
system. QJM. 2002;95(9):609-619.
18. Kearns G, Leeder J, Wasserman G. Acetaminophen overdose with therapeutic intent.
The Journal of Pediatrics. 1998;132(1):5-8.
19. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Lee WM et al. Acute Liver
Failure Study Group (ALFSG). Acetaminophen-induced acute liver failure: results of a
United States multicenter, prospective study. Hepatology, 2005 Dec; 42(6):1364-72.
20. Nourjah et al. Estimates of Acetaminophen (Paracetomil)-associated overdoses in
the United States, Pharmacoepidemiol Drug Safety 2006 Jun, 15(6).
21. Hawton K, Ware C, Mistry H, Hewitt J, Kingsbury S, Roberts D, Weitzel H.
Paracetamol self‐poisoning: characteristics, prevention and harm reduction. Br J Psych
1996; 168:43–
22. Alander SW, Dowd MD, Bratton SL, Kearns GL. Pediatric acetaminophen overdose:
risk factors associated with hepatocellular injury. Arch Pediat Adolesc Med 2000;
154:346–50.
23. Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban
county hospital. N Engl J Med 1997; 337:1112–17
24. Makin AJ, Wendon J, Williams R. A 7‐year experience of severe acetaminophen‐
induced hepatotoxicity (1987–1993). Gastroenterology 1995; 109:1907–16
25. Zed PJ, Krenzelok EP. Treatment of acetaminophen overdose. Am J Health Syst
Pharm 1999; 56:1081–93.
26. Mail Online. Own-brand paracetamol that cost 11 times less are as effective as big
name rivals at pain relief [Internet]. 2012 [cited 29 November 2014]. Available from:
http://www.dailymail.co.uk/news/article-2175696/Own-brand-paracetamol-cost-11times-effective-big-rivals-pain-relief.html
27. Management service for health. International drug price guide. Arlington 1999.
28. Bond GR, Novak JE. The human and economic cost of paracetamol (acetaminophen)
overdose. Pharmacoeconomics 1995; 8:177–81.
29. Hawton K, Ware C, Mistry H, Hewitt J, Kingsbury S, Roberts D, Weitzel H.
Paracetamol self‐poisoning: characteristics, prevention and harm reduction. Br J Psych
1996; 168:43–
Mortality
30. Lee, B. H., Inui, D., Suh, G. Y., Kim, J. Y., Kwon, J. Y., Park, J., … & Koh, Y. (2012).
Association of body temperature and antipyretic treatments with mortality of critically
ill patients with and without sepsis: multi-centered prospective observational
study.Critical Care, 16(1), R33.
31. Janz, D. R., Bastarache, J. A., Peterson, J. F., Sills, G., Wickersham, N., May, A. K., &
Roberts, L. J. (2013). Association between cell-free hemoglobin, acetaminophen, and
mortality in patients with sepsis: an observational study.Critical care medicine,41(3),
784.
32. Schulman, C. I., Namias, N., Doherty, J., Manning, R. J., Li, P., Elhaddad, A., … & Cohn, S.
M. (2005). The effect of antipyretic therapy upon outcomes in critically ill patients: a
randomized, prospective study.Surgical infections, 6(4), 369-375.
33. Niven, D. J., Stelfox, H. T., Léger, C., Kubes, P., & Laupland, K. B. (2013). Assessment of
the safety and feasibility of administering antipyretic therapy in critically ill adults: a
pilot randomized clinical trial.Journal of critical care, 28(3), 296-302.
34. Mohr, N., Skrupky, L., Fuller, B., Moy, H., Alunday, R., Wallendorf, M., … & Fagley, R.
(2012). Early antipyretic exposure does not increase mortality in patients with gramnegative severe sepsis: a retrospective cohort study. Internal and emergency medicine,
7(5), 463-470.
Viral Infection
35. Kramer M.S., Naimark L.E., Roberts-Brauer R., McDougall A., Leduc D.G.Risks and
benefits of paracetamol antipyresis in young children with fever of presumed viral
origin. Lancet 1991; 337(8741): 591-4. DOI: 10.1016/0140-6736(91)91648-E
36. Mahar AF. Allen SJ. Milligan P. Suthumnirund S. Chotpitayasunondh T. Sabchareon A.
Coulter JB. Tepid sponging to reduce temperature in febrile children in a tropical
climate. Clinical Paediatrics 1994; 33(4): 227-31.
37. Weisse ME. Miller G. Brien JH. Fever response to acetaminophen in viral vs. bacterial
infections. Paediatric Infectious Disease Journal 1987; 6(12):1091-4
38. Graham NM. Burrell CJ. Douglas RM. Debelle P. Davies L. Adverse effects of aspirin,
acetaminophen, and ibuprofen on immune function, viral shedding, and clinical status in
rhinovirus-infected volunteers. Journal of Infectious Disease 1990; 162(6):1277-82.
39. Doran TF. De Angelis C. Baumgardner RA. Mellits ED. Acetaminophen: more harm
than good for chickenpox? Journal of Paediatrics 1989; 114(6):1045-8
40. Lesko SM. O’Brien KL. Schwartz B. Vezina R. Mitchell AA. Invasive group A
streptococcal infection and nonsteroidal antiinflammatory drug use among children
with primary varicella. Pediatrics 2001; 107(5):1108-15.
Febrile convulsions
41. Strengell T et al. Antipyretic Agents for Preventing Recurrences of Febrile Seizures:
A randomised controlled trial. Archives of Paediatrics and Adolescent Medicine. 2009.
163(9).
42. Van Esch A et al. Antipyretic efficacy of ibuprofen and acetaminophen in children
with febrile seizures. Archives of Paediatrics and Adolescent Medicine. 1995. 149:632637.
43. Uhari M et al. Effect of acetaminophen and of low intermittent doses of diazepam on
prevention of recurrences of febrile seizures. Paediatric Pharmacology and
Therapeutics. 1995. 126(6):991-995.
44. Schnaiderman D et al. Antipyretic effectiveness of acetaminophen in febrile seizures:
ongoing prophylaxis versus sporadic usage. European Journal of Paediatrics. 1993.
152:747-749.
Malaria
45. Russell, FM. Shann, F. et al, Evidence on the use of paracetamol in febrile children, B
WORLD HEALTH ORGAN, 2003 January; 81(5): 367-372
46. Matslegul, P. Missinou, MA. et al, Antipyretic effect of ibuprofen in Gabonese children
with uncomplicated falciparum malaria: a randomized, double-blind, placebo-controlled
trial, Malaria Journal 2008 May 26; 7(91)
47. Brandts, CH. Ndjave, M. et al, Effect of paracetamol on parasite clearance time in
Plasmodium falciparum malaria, Lancet 1997 Sept. 6; 350 (9079): 704-709
48. Hugosson, E. Tarimo, D. et al, antipyretic, parasitologic, and immunological effects of
combining sulfadoxine/pyrimethamine with chloroquine or paracetamol for treating
uncomplicated Plasmodium Falciparum malaria, AM J TROP MED HYG 2003 October;
69(4): 366-371
49. Krudsood, S. Tangpukdee, N. et al, Intravenous Ibuprofen (IV-ibuprofen) Controls
Fever Effectively in Adults with Acute Uncomplicated Plasmodium falciparum Malaria
but Prolongs Parasitemia, AM J TROP MED HYG 2010 July; 83(1): 51-557.
50. Krishna, S. Pukrittayakamee, S. et al. Fever in uncomplicated Plasmodium falciparum
malaria: randomised double blind comparison of ibuprofen and paracetamol treatment,
Trans R Soc Trop Med Hyg 1995 Sep; 89(5): 507-9
Vaccines
51. Prymula R, Siegrist C, Chlibek R, Zemlickova H, Vackova M, Smetana J et al. Effect of
prophylactic paracetamol administration at time of vaccination on febrile reactions and
antibody responses in children: two open-label, randomised controlled trials. The
Lancet. 2009;374(9698):1339-1350.
52. Prymula R, Habib A, François N, Borys D, Schuerman L. Immunological memory and
nasopharyngeal carriage in 4-year-old children previously primed and boosted with 10valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine
(PHiD-CV) with or without concomitant prophylactic paracetamol. Vaccine.
2013;31(16):2080-2088.
53. Dhingra B, Mishra D. Immediate versus as-needed acetaminophen for postimmunisation pyrexia. Annals of Tropical Paediatrics. 2011;31(4):339-344.
54. Chernesky M, O’Neill D, Pickard L, Castriciano S, Kraftcheck D, Sellors J et al.
Immunogenicity and adverse reactions of influenza vaccination in elderly patients given
acetaminophen or placebo. Clinical and Diagnostic Virology. 1993;1(2):129-136.