Paracetamol toxicity: epidemiology,

prevention and costs to the health‐care

system
C.L. SHEEN, J.F. DILLON, D.N. BATEMAN, K.J. SIMPSON, T.M. MACDONALD

QJM: An International Journal of Medicine, Volume 95, Issue 9, September 2002,

Pages 609–619, https://doi.org/10.1093/qjmed/95.9.609
Published:

01 September 2002

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Abstract
Paracetamol has been used as an analgesic and antipyretic for many years, with toxicity first
noted in the 1960s. Since then the incidence of poisoning has increased, and paracetamol is
now the most common drug in self‐poisoning, with a high rate of morbidity and mortality. The
use, abuse and ways of reducing paracetamol toxicity are reviewed, but in view of the potential
for harm, serious consideration should be given to changing the legal status of paracetamol,
possibly to a prescription‐only medicine.
Topic:

 acetaminophen
 acetaminophen overdose
  analgesics
 antipyretic therapy
 epidemiology
 morbidity
 mortality
 poisoning
 toxic effect
 legal status
 prevention
Issue Section:
Commentary

History

Paracetamol (acetaminophen) was discovered in Germany at the end of the 19th

century, but was not widely used until midway through the 20th. The toxicity of
over‐the‐counter (OTC) analgesics was noticed in the 1960s and 1970s, but
paracetamol was considered safe at normal dose. There were few, if any, reports
of abuse involving paracetamol and the use of paracetamol steadily increased,
replacing the more toxic analgesics available at the time (acetanilide and
phenacetin).1 Consumption throughout the world has increased. In the Nordic
countries, usage increased five‐fold between 1978 and 1988, and in 1994/95 the
rates in some developed countries were >20 g/person/year, although in countries
such as the UK, the US, Canada, Australia and New Zealand, consumption was
<8 g/person/year.2,3 In the UK, consumption was reported to have increased from
1500 million 500 mg tablets per year in 1967/68 to 4000 million such tablets in
1993/94.2 An estimate of more recent consumption, including prescribed
paracetamol and combination tablets and paracetamol purchased without a
prescription, is 3500 million 500 mg tablets in 2000 (IMS Health, Sheen
unpublished data). Paracetamol did not undergo the stringent toxicity testing
prior to its introduction that now occurs during drug development. It was not
until 1966 that hepatotoxicity due to paracetamol was first reported in humans. 4,5
Is paracetamol a tolerable and effective drug?

Paracetamol is now used in many forms either alone or in combination with other
drugs (usually opiates) for analgesia and in other mixtures such as cold ‘cures' for
its analgesic and antipyretic properties. Not only must a drug be effective but it
must also be tolerable, i.e. without severe or excessive side‐effects. Only one
randomized controlled study has directly compared the tolerability of
paracetamol to those of aspirin and ibuprofen.6 This study concluded that
paracetamol was no better tolerated than ibuprofen, although it was better
tolerated than aspirin. Since 1990, a number of trials have shown paracetamol to
be an effective antipyretic, but its analgesic effectiveness compared to other
painkillers, including ibuprofen (another frequently used and readily available
analgesic) is variable (Tables 1 and 2).1,7–109 In adults, paracetamol can only be
considered a mild to moderate analgesic.

Table 1
Summary of results of randomized controlled trials using oral or rectal
paracetamol
 Acute pain Chronic
(n=76) pain (n=17) References

Better than
placebo 14 6 Acute pain 16–29, chronic pain 30–35

Worse than
placebo 0 0

Equivalent to
placebo 6 0 Acute pain 36–41

Better than
another drug 3 0 Acute pain 42–44

Worse than Acute pain 17,19,23,28,45–67, chronic

another drug 27 10 pain 31,33,34,68–74

Equivalent to Acute pain 18,20,24,25,27,39,40,75–

another drug 25 6 92, chronic pain 30

No effective
analgesia 12 0 Acute pain 97–108

Totals are greater than n, as some studies compare paracetamol with another drug
and placebo.
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Table 2
Randomized controlled trials comparing ibuprofen with paracetamol

Ibuprofen Paracetamol Pain

Author Date dose dose Result type Notes Reference

Ibuprofen Single
Behotas S 1992 400 mg 1000 mg better Acute dose 47

1200 or Equivalent
Bradley JD 1991 2400 mg 4000 mg effect Chronic 93

1200 or Equivalent
Bradley JD 1992 2400 mg 4000 mg effect Chronic 94

Further
analysis
of
1200 or Equivalent Bradley
Bradley JD 2001 2400 mg 4000 mg effect Chronic 1992 96

Milgrom C 1993 2400 mg 3000mg No effect Acute 103

Single
dose
using
Ibuprofen soluble
Packman B 2000 400 mg 1000 mg better Chronic ibuprofen 33
 Single
dose
using
Schachtel Ibuprofen soluble
BP 1996 400 mg 1000 mg better Chronic ibuprofen 74

No better
Torabinejad than
M 1994 500 mg 500 mg placebo Acute 41

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How common is paracetamol poisoning?

Hospital admissions due to poisoning have steadily increased from the

1950s.110 Since the mid‐1970s. there has been an increase in the number of
paracetamol overdoses, such that paracetamol has now become the substance
most frequently used in deliberate self‐poisoning in the UK.111 In Oxford, UK, the
proportion of overdoses with paracetamol increased from 14.3% in 1976 to 42%
in 1990, and in 1993, 47.8% of all overdoses involved paracetamol or
paracetamol‐containing drugs.111,112 It has also become increasingly common in
other countries including Denmark and Australia.113,114 In Scotland, the rate of
paracetamol overdose increased almost 400% between 1981–83 and 1991–93,
and was higher in more deprived areas.115,116

Paracetamol overdose is a significant cause of hospital admission, but severe

liver damage is infrequent, and when it does occur the prognosis is generally
good. A study in one hospital in Western Australia between 1985 and 1990 found
306 admissions for paracetamol overdose. Severe liver injury (defined as an
alanine transaminase >45 IU/l, a prothrombin time >18 s and encephalopathy)
occurred in 6.9%, but all recovered with supportive therapy and no patient
required a liver transplant.117 However, in a study of patients admitted to a
specialist liver failure unit in the UK between 1987 and 1993 with a diagnosis of
acute liver failure due to paracetamol poisoning, only 30% fulfilled clinically
defined transplant criteria.118 Patients with poorer outcomes and those listed for
transplant tended to present later to hospital and to have taken a larger
overdose.114,118 In a prospective trial of 80 patients admitted between 1992 and
1993, 25 had acute liver dysfunction (as defined by an INR >1.2 with or without
abnormal liver function tests) following consumption of more than 25 tablets
(12.5 g) of paracetamol. Of the 80 patients, 60% had obtained tablets from blister
packs, 46% from loose preparations and 6% of the patients had used both
types.111

In 1977, 144 deaths in England and Wales were attributed to

paracetamol.110 Between 1993 and 1997, this had increased to approximately 500
deaths attributable to drugs containing paracetamol per year in England and
Wales.119 Over the same period of time, the mean annual number of deaths from
road transport accidents (RTA) was 3291 (data from Office for National
Statistics; www.statistics.gov.uk). There is much public concern and Government
action to reduce RTA deaths, but little publicity is given to a minor analgesic that
caused a sixth as many potentially avoidable deaths as RTAs.

While some drugs have limitations imposed on their availability for small
adverse risks, paracetamol is not looked upon with the same critical concern. An
example of this is terfenadine. In 1997, its availability was changed from OTC to
prescription‐only, due to the risk of cardiac arrhythmias. However, an
observational historical cohort study calculated that more cardiac arrests and
ventricular arrhythmic events occurred with other OTC antihistamines compared
to terfenadine. Also, there was no increase in the risk of life‐threatening
ventricular arrhythmias when terfenadine was compared to ibuprofen.120

Accidental or intentional?

Although most paracetamol poisoning is due to the wilful ingestion of

supratherapeutic doses with the intention of committing suicide, a proportion of
patients present with toxicity due to incorrect dosing for therapeutic intent or
accidental overdose. In children under 5 years old, ingestion of toxic substances
is almost invariably unintentional, and is usually due to household chemicals or
drugs belonging to other family members.121 In a retrospective study in America,
reviewing medical charts for 10 years between 1988 and 1997 of children (aged
<18 years) presenting with paracetamol overdose, 53% presented with
unintentional ingestion and 3% with toxicity due to a dosage error. The
unintentional ingestion was seen in young children, from 2 months to 13 years,
whereas intentional overdose was seen in the teenagers, the majority of whom
were female.122 In another American study retrospectively analysing
hospitalizations for excessive paracetamol ingestion, 30% were considered
accidental. The dose taken was half that of those attempting suicide, but over half
of the subjects presented more than 24 hours after ingestion (compared to only
14% of the suicidal patients). Those with accidental poisoning had a higher
incidence of hepatic coma and death, and also spent longer in hospital.123 In the
UK. only 8% of patients with acute liver failure stated they had accidentally
taken an overdose, and most of these patients presented to hospital >24 h after the
event.118 The difference between the UK and USA is difficult to explain, but may
be due to cultural responses to overdose, healthcare funding differences between
the two countries and consequent reporting pressures of the two systems.

Why is paracetamol used in attempted self‐harm?

Paracetamol is the most frequently used drug by those who take an intentional
overdose in the UK.111 However, only 0.1% of all paracetamol overdoses resulted
in death in the US, thus paracetamol can hardly be considered to be an effective
drug with which to commit suicide.124 Of course, paracetamol can be readily
purchased on the high street without the need for a prescription. In Sweden, as
sales of analgesics increased so did the suicide rate (although this relationship
was not shown with paracetamol alone in this study, possibly reflecting
successful treatment of paracetamol overdose).125 Another study showed a
relationship with the sale of paracetamol and the numbers of paracetamol
overdoses in France and the UK.126
Since paracetamol has been available OTC, the public's understanding of the
effects of a paracetamol overdose have changed. In 1976, patients were not aware
that there was a delay of several days before the onset of serious symptoms, and
Gazzard et al. found that had they known this, they would not have used it.127 A
second study in the early 1990s found that most patients recognized that
paracetamol could cause death, but again, most were unaware of the delay in
onset of severe symptoms and many thought that overdose would cause
unconsciousness. This study also confirmed that people took paracetamol
because it was easily available and inexpensive.128 School children between the
ages of 12 and 19 in the UK and the US were aware that paracetamol could be
harmful or fatal although the dose required was greatly overestimated by over
half the children. Belief that sedation was a side‐effect was also common.129 It
seems that education has informed the population about the risk of death with
paracetamol overdose, but not the unpleasant way in which it comes about.

Advertising and awareness of the drug may influence its use. Newspaper reports
and television programmes about a suicide may cause a transient rise in
attempted suicide.130,131 Equally, the media can be a major source of education.132

Measures to reduce toxicity

In one study, patients admitted with a paracetamol overdose were asked about
factors that might have deterred them from taking the overdose. Although 66%
would still have used paracetamol with the knowledge that it could cause death,
only 35% would still have used it had they known that the harmful effects could
be delayed for several days. Warning labels (‘paracetamol can cause death’)
would only have deterred 25%. Repackaging into blister packs would have had
little effect, and limiting the number of tablets would only 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. If
an antidote were contained within the paracetamol tablet, 64% would not have
taken the overdose.111 Paracetamol use in the UK and France was compared
between 1974 and 1990 to assess whether restrictions were justified in the
availability of the drug.126 At the time, paracetamol was freely available in
England and Wales in unlimited quantities from a pharmacy, and up to 12 g from
supermarkets. In France, paracetamol could only be purchased from pharmacies
and the contents of each pack was legally limited to 8 g. There was a strong
correlation in the UK and France between paracetamol sales and paracetamol
overdose. Case fatality rates, however, were four times higher in England and
Wales than in France. They concluded that the greater availability of paracetamol
was paralleled by increases in its use with non‐fatal and fatal overdose, and
suggested that pack size restrictions should be stricter in the UK. In September
1998, the Medicines Control Agency restricted the sale of OTC paracetamol in
the UK. Pharmacies can sell packs containing a maximum of 32 tablets (16 g)
although up to 100 tablets may be sold at the discretion of the pharmacist. In
outlets other than pharmacies, packs with up to 16 tablets (8 g) can be sold. 133

Effectiveness of the UK pack size restriction

Recent research in England and Wales has suggested that there has been a
reduction in the number of patients listed for liver transplant and of overdose
since September 1998.134–136 However, one study looked only at severe overdoses
referred to a specialist liver unit, and did not consider less severe overdoses,
while another reported only a small number of cases and so may not accurately
represent outcome.134,137 In Tayside, Scotland, using serum paracetamol levels as a
marker of true toxicity, there was no effect from the pack size reduction.138 There
has also been no change in the number of patients being referred to the transplant
unit in Scotland.139 Another study also commented that there was no change in
the mean highest serum paracetamol concentration before and after the pack size
reduction, although this is not commented upon by the authors in the final
conclusion.136

Methionine‐paracetamol combination tablets

Methionine is a glutathione donor required in the metabolism of paracetamol.
Combination tablets were first suggested in 1974, and released on the UK market
in 1987.140,141 The analgesic effectiveness of paracetamol has been shown in the
combination drug, with a slight increase in minor adverse effects such as
drowsiness,142 Other adverse effects of methionine are mild, and include nausea,
flatulence and headache.143 As most paracetamol overdoses are impulsive
methionine would have to be added to all formulations containing paracetamol.
This would mean that a lot of people would needlessly consume methionine, and
the dose required to be effective is unclear. In rats, who are quite resistant to the
hepatotoxic effects of paracetamol, a methionine dose of 10% of the paracetamol
dose was protective,144 but an equivalent effective dose cannot ethically be
determined experimentally in humans. In the UK the only paracetamol‐
methionine combination available is Paradote (Penn Pharmaceuticals). This
contains 100 mg methionine and 500 mg paracetamol (i.e. 20% methionine).
Concern has been expressed that long‐term methionine intake could promote
carcinogenesis.145 Methionine is metabolized to homocysteine, and raised plasma
homocysteine concentrations have been associated with endothelial
dysfunction,146 stroke,147 and coronary heart disease.148 The dose at which these
effects occur is not clear. In healthy adults, 100 mg/kg L‐methionine caused a
significant increase in homocysteine levels.149,150 In a study looking at the effects
of dietary methionine and homocysteine levels in healthy males, an intake of a
mean of 2112 mg of methionine a day for 7 days had no significant effect on
plasma homocysteine levels.151 Thus the dose needed to have an effect on
homocysteine levels would appear to be considerably greater than the 800 mg
that would be ingested with the 4 g recommended maximum daily dose of
paracetamol.

Another paracetamol‐methionine combination tablet was withdrawn from the UK

market after it was placed on the list of drugs not available for prescribing at
NHS expense. It was felt that it was expensive, there were alternative drugs to
paracetamol available and that allowing the product to be prescribed would have
no effect on self‐poisoning if the paracetamol tablets were obtained OTC.
The net cost per tablet of Paradote is over six times that of generic paracetamol.
This would perhaps deter a person planning an overdose, if it were the only form
of paracetamol available. The cost might also limit the availability of an effective
analgesic for appropriate use to much of the population.

There do seem to be risks of using methionine which need to be evaluated

further. Until these risks are elucidated, it would seem ethically unacceptable to
require all people to take a paracetamol‐methionine combination. Cost and
government policy will also affect the availability and use of these types of
drugs.

Alternative drugs

In adults there is the possibility of substituting an alternative drug such as a non‐

steroidal anti‐inflammatory drug (NSAID). These have been shown to be at least
as effective as paracetamol. There are however, concerns over the adverse effects
of these drugs including, in particular, gastrointestinal bleeding. Over the last few
decades there have been many studies of the risks of haemorrhage. A recent
review of these has highlighted that the risk of bleeding can be stratified (age, sex
and history of previous peptic ulcer) and by the type of NSAID.152 This study did
not include the selective cyclo‐oxygenase 2 inhibitors (e.g. Rofecoxib and
Celecoxib). Recent studies of these drugs has shown that they are effective
analgesics, with a lower incidence of peptic ulcer bleeding.153–156 These newer
drugs may provide a safe and effective alternative to paracetamol, although
recent concern over their cardiovascular safety profile has rather soured their
attraction.157,158

Cost to healthcare systems

The cost of poisonings and the subsequent treatment is significant. In 1985, the
lifetime direct and indirect costs associated with all poisonings in the US was
estimated at $8.4 billion.159 In the US, the direct cost of paracetamol overdose has
been estimated at $87 million annually, and this is likely to be a conservative
estimate. In 1995, it was calculated that the average cost associated with
intentional paracetamol poisoning involving adolescents and adults in the US was
$2172 per case. This allowed for emergency department visits and treatment with
N‐acetylcysteine, and also averaged out the additional costs from hepatic injury,
hepatic failure and the need for liver transplantation, but again is probably a
conservative estimate.160 However, in a children's hospital in Boston, USA the
cost per case of paracetamol poisoning (excluding physician's fees) ranged from
$17 349 in 1992 to $7080 in 1995, the reduction in costs being due to reduced in‐
patient length of stay.159 In a study looking at admissions between 1992 and 1995,
the mean cost of care in patients having taken an accidental overdose was
$19 000, compared to $8500 in patients attempting suicide.123 This difference is
likely to represent the longer length of stay and the cost of treating complications
such as hepatic failure. There are no similar data for the UK, as health care is not
charged for in the same way as the US. However, it seems likely that the cost
burden will be as significant in the UK as in the US and this is supported by a
small study in Tayside, although the overall costs in Scotland are lower than in
the US.161 The mean direct cost per case in Tayside was £181 (excluding costs of
specialist care of acute hepatic failure and liver transplant). If this cost were to
used to represent the UK, then the annual direct cost of hospitalization with
paracetamol poisoning would be approximately £8 million.

Conclusion

Paracetamol is a commonly used, moderately effective analgesic and antipyretic.

In overdose it causes significant morbidity and mortality. The burden to health
care services is considerable, with a high financial cost and many hospital
admissions. According to the Medicines Control Agency Medicines Act Leaflet
(MAL 82, March 1996), which gives guidance on changing the legal
classification of a medicine to the General Sale List, a criterion for inclusion on
the General Sale List is: ‘where the hazard to health, the risk of misuse, … is
small and where wider sale would be a convenience to the purchaser’ (our
italics). It is surprising that paracetamol is available on the General Sale List, as it
appears to fail this criterion for an OTC medication.

Present approaches to reduce toxicity have had variable and moderate effects.
Other methods of reducing this burden must be considered. These could include
public education on the effects of overdose, further research on drug‐antidote
combination tablets and changing the legal status of adult doses from the General
Sales List to the prescription‐only medicines list, or at least restricting it to
pharmacy‐only sales.

Address correspondence to Dr C.L. Sheen, Department of Clinical

Pharmacology, Ninewells Hospital and Medical School, Dundee DD1 9SY. e‐
mail: chris@memo.dundee.ac.uk

References