Disclaimer: This website was made by a group of University of Edinburgh medical students who studied this as part of the   Student Selected Component (SSC) . This website has not been peer reviewed. We certify that this website is our own work and that we have authorisation to use all the   content in this website.

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 ObjectivesOur 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 InfectionParacetamol 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 non-severe 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 P-value 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-the-counter 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 EventsIt 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.MortalityFever 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 28-day 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 co-administered 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 ConvulsionsParacetamol 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.

MalariaMalaria 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 D-conjugate vaccine and hexavalent diphtheria-tetanus-3-component acellular pertussis-hepatitis 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.

Word Count: 5667

REFERENCES

Introduction1. 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 pain-related symptoms in upper respiratory tract infection. Current Medical Research and Opinion2006;22(12):2411-2418Adverse 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-11-times-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–

Mortality30. 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 gram-negative severe sepsis: a retrospective cohort study. Internal and emergency medicine, 7(5), 463-470.

Viral Infection35. 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 convulsions41. 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. 149:632-637.

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.

Malaria45. 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 10-valent 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 post-immunisation 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.