REVIEW ARTICLE

Acetaminophen/paracetamol: A history of errors, failures and

false decisions
K. Brune1, B. Renner1, G. Tiegs2
1 Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Germany
2 Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Germany

Correspondence Abstract
Kay Brune
E-mail: Acetaminophen/paracetamol is the most widely used drug of the world. At
brune@pharmakologie.uni-erlangen.de the same time, it is probably one of the most dangerous compounds in
medical use, causing hundreds of deaths in all industrialized countries due
Funding sources
to acute liver failure (ALF). Publications of the last 130 years found in the
None.
usual databases were analyzed. Personal contacts existed to renowned
Conflicts of interests researchers having contributed to the medical use of paracetamol and its
None declared. precursors as H.U. Zollinger, S. Moeschlin, U. Dubach, J. Axelrod and
others. Further information is found in earlier reviews by Eichengrün,
Accepted for publication Rodnan and Benedek, Sneader, Brune; comp. references. The history of the
22 September 2014 discovery of paracetamol starts with an error (active against worms),
continues with a false assumption (paracetamol is safer than phenacetin),
doi:10.1002/ejp.621
describes the first side-effect ‘epidemy’ (phenacetin nephropathy, drug-
induced interstitial nephritis) and ends with the discovery of second-
generation problems due to the unavoidable production of a highly toxic
metabolite of paracetamol N-acetyl-p-benzoquinone imine (NAPQI) that
may cause not only ALF and kidney damage but also impaired development
of the fetus and the newborn child. It appears timely to reassess the
risk/benefit ratio of this compound.

dered why the antipyretic effect had not been

1. Discovery by error and serendipity
1.1 Acetanilide
In 1884, an important discovery took place in Stras-
bourg (Germany, later France). At that time, the
medical clinic of Strasbourg was headed by the famous
professor Adolf Kussmaul. Two young assistants, A.
Cahn and P. Hepp, asked his advice on how to treat a
patient who suffered from many ailments, among
those fever and worm infestation (Cahn and Hepp,
1886). Kussmaul suggested to try naphthalene, which
had been recommended as an intestinal antiseptic
(Sneader, 1985). The two young physicians followed
the advice and were disappointed by the result – most
ailments remained, including the worms. Much to
their surprise, they observed, however, that the fever
of the patient fell shortly after the administration of
the putative naphthalene. The two physicians won-
described before. Researching the source of the ‘naph-
thalene’, they learnt that (the local) pharmacy
had provided them with acetanilide (Fig. 1) instead
of naphthalene – an error with long-lasting
consequences!
Consequently, Cahn and Hepp tested acetanilide in
rabbits and dogs (at that time, an animal ethics request
was not needed) (Cahn and Hepp, 1886). They
observed reliable but short-lasting antipyretic activity.
Both species did not suffer from (visible, acute) toxic-
ity. The young physicians then dared to try acetanilide
in 24 patients (certainly without informed consent).
They were excited as all of them showed a reduction
of fever. Acetanilide turned out as effective as
phenazone, which had been successfully put to the
marketplace two years before (Filehne, 1884). Most
patients tolerated the treatment well. The only
problem Cahn and Hepp observed was that some

© 2014 European Pain Federation - EFIC® Eur J Pain •• (2014) ••–•• 1

130 years of aniline analgesics
What’s already known about this topic?
• Aniline-derived analgesics, particularly paraceta-
mol, go along with a variety of unwanted drug
effects. Fatal acute liver damage may occur at
overdose and in at-risk groups.
• Paracetamol interferes with the production of
prostaglandins. This may further the develop-
ment of intestinal ulcers, kidney disfunction and
hypertension.
• Paracetamol is the only non-opioid analgesic rec-
ommended to pregnant women and their off-
spring. Recent evidence links the use of
paracetamol during pregnancy and in newborns
to an enhanced incidence of asthma, psychologi-
cal and physical development, and attention-
deficit/hyperactivity disorder (ADHD).
• Experimental research demonstrates that
immune regulation and the neuronal develop-
ment during pregnancy may be distorted by
paracetamol.
What does this review add?
• This review shows that the discovery of the
aniline analgesics was not a consequence of sys-
tematic research and cautious toxicological
evaluation but rather the result of serendipity,
errors and failures. The growing list of unwanted
drug effects can be explained by the blockade of
the production of prostaglandins and N-acetyl-p-
benzoquinone imine (NAPQI). This highly reac-
tive intermediate is produced in the mother and
most likely the fetus. It may be the culprit of the
known hepatotoxicity and the cause of the new
signals of second-generation toxicity.
• The production of NAPQI cannot be suppressed
nor can its covalent binding to macromolecules
be avoided. Consequently, paracetamol would
not be admitted to the market today. To keep it as
an over-the-counter (OTC) analgesic is illogical
and dangerous.
patients developed a bluish color of the skin. This
phenomenon was not taken seriously. Enthusiasm
translated into therapeutic action. A small company
close to Strasbourg, Kalle, produced large quantities of
acetanilide for the young physicians. They distributed
it to interested colleagues and soon ‘antifebrin’, as
acetanilide was now termed, was intensively used to
reduce fever.
Wider use went along with more reports of the
‘bluish skin’, which was later identified to result from
2 Eur J Pain •• (2014) ••–••
K. Brune et al.
methemoglobinaemia (Sneader, 2005; Prescott, 1996).
Not surprisingly as the chemical aniline, from which
acetanilide was synthesized, was already known to be
haematotoxic. It initiated methemoglobinaemia, thus
interfering with the oxygen transport by haemoglobin
as many other aminophenols (Kiese and Pekis, 1964).
Consequently, a search for safer chemical derivatives
began.
1.2 Phenacetin
It is to be credited to O. Hinsberg (1913) to have
synthesized phenacetin (Fig. 1). Together with a phar-
macologist from Freiburg, A. Kast, he showed that the
new compound worked as acetanilide but was less
toxic (Hinsberg, 1913). In addition, it could be pro-
duced at low costs, as Bayer and other companies were
flooded with large amounts of para-nitrophenol,
which is a by-product of the production of dianisidine
(needed to produce the new synthetic ‘aniline dyes’).
C. Duisberg (1913, director of Bayer) reported that
Bayer was searching for customers of the useless para-
nitrophenol. He states that it was pure luck (Duisberg,
1913) that O. Hinsberg together with A. Kast found
that phenacetin can be produced easily from para-
nitrophenol and that it is both more effective and safer
than acetanilide. O. Hinsberg and A. Eichengrün (the
head chemist at Bayer), on the contrary, claimed that
thorough thinking and the application of systematic
synthetic chemistry led to the discovery of phenacetin
(Eichengrün, 1913). In the end, it does not matter
who contributed most to the discovery of phenacetin,
Duisberg or Hinsberg; in the end, it became a very
successful drug (Fig. 2).
Interestingly, two other new synthetic drugs,
phenazone and aspirin, were also found by serendipity
and brought to the market under false assumptions.
Aspirin, phenazone and phenacetin were synthesized
in Germany and distributed worldwide in tons
quantities.
1.3 Aspirin, phenazone and phenacetin, the
first synthetic analgesics
Aspirin (introduced 1899 by Bayer), phenazone
(Filehne, 1884) and phenacetin (Hinsberg, 1913)
relieved pain and fever reliably, fast and without
apparent dangers. They added to the worldwide repu-
tation of the emerging German drug industry as
described by Tainter (1948). He states: In 1884, Ludwig
Knorr, while searching for a synthetic substitute for quinine,
prepared antipyrine, i.e., phenazone, a compound whose
analgesic powers probably have not been fully utilized.
© 2014 European Pain Federation - EFIC®
K. Brune et al. 130 years of aniline analgesics

Figure 1 Aniline and its metabolites (adapted

and modified from Prescott, 1996).

Figure 2 The fathers of phenacetin (pictures

of O. Hinsberg could not be found). (Sources:
Wikimedia)

© 2014 European Pain Federation - EFIC® Eur J Pain •• (2014) ••–•• 3

130 years of aniline analgesics
Figure 3 J. Axelrod and B.B. Brodie investigated the metabolism of phen-
acetin and suggested that paracetamol is the safer drug. (Source: Wikipe-
dia, The AMINCO-Bowman SPF: Biography Section)
Knorr’s synthesis of antipyrine marked the beginning of the
famous German drug industry and ushered in Germany’s
forty-year dominance of the synthetic drug and chemical
field. Aminopyrine (Pyramidon®), a still more potent com-
pound closely related to antipyrine, was synthesized a few
years later in 1896 by Knorr and Stolz. This remained the
most powerful analgesic of synthetic origin until recent times.
Indeed, phenazone and its derivatives sold by Hoechst
(now Aventis) boosted the revenues of this company,
similarly Bayer profited from both, aspirin and
phenacetin (Brune, 1997).
Bayer and other companies tried to find more drugs
with an even better effect/side-effect profile; one was
paracetamol (synthesized by Bayer). From the begin-
ning, it was suspected to be a metabolite of phenace-
tin. Bayer resorted to the advice of J. von Mering
(1893) (Fig. 2), a famous pharmacologist in Stras-
bourg. He got the impression that paracetamol was not
superior to phenacetin; rather, he observed that this
compound retained some of the negative features
of acetanilide, namely methemoglobinaemia (von
Mering, 1893). This turned out later to be an error,
possibly mediated by impurities, but it fostered the
widespread use of phenacetin throughout the first half
of the 20th century.
The situation changed in 1946 when American sci-
entists reinvestigated the phenacetin metabolism.
Lester and Greenberg at Yale together with Flinn,
Brodie and Axelrod (Axelrod, 1988) (Fig. 3), in New
York, showed that paracetamol was the main (and
active) metabolite of phenacetin, a claim originally put
forward by Hinsberg and Treupel (1894). Brodie
believed that paracetamol is the safer and more active
4 Eur J Pain •• (2014) ••–••
K. Brune et al.
drug as compared to phenacetin, as phenacetin could
lead to aniline, but paracetamol not (Flinn and Brodie,
1948). Still, paracetamol was not the end of the meta-
bolic cascade. It was eliminated as glucuronide or
sulfate, but some paracetamol was oxidized to NAPQI
(N-acetyl-p-benzoquinone imine), a highly reactive
compound, which we will have to deal with later.
Anyway, from the data accrued by the Axelrod group,
it was plausible that paracetamol (in the United States,
acetaminophen) could be the better drug, free of
methemoglobin production, but retaining the full
analgesic/antipyretic power of phenacetin. Regretta-
bly, this conclusion was partially false.
These observations supported the market introduc-
tion of paracetamol/acetaminophen. Interestingly, the
comparatively small problem of methemoglobin pro-
duction was remedied, but the liver toxicity of parac-
etamol was overlooked until 1966 (Davidson and
Eastham, 1966). The metabolization of phenacetin to
paracetamol is slow, allowing for the detoxification of
most of the emerging paracetamol (Fig. 1) into harm-
less glucuronides or sulfates. Only small amounts of
the toxic, reactive NAPQI are produced from phenace-
tin (Fig. 1). The introduction of paracetamol led to a
re-evaluation of the toxicity of phenacetin. This was a
very timely as a frightening observation in Switzerland
hinted at serious kidney problems from the intensive
use of phenacetin.
1.4 Phenacetin, the culprit of the first
side-effect epidemy?
Relieve of pain and fever was achieved by the use of
the new synthetic, antipyretic analgesics. Aspirin
(introduced 1899), phenazone (1884) and acetanilide,
later substituted by phenacetin (1887), dominated the
drug market during the first 50 years of the 20th
century. They were the most widely used and pre-
scribed drugs in most countries (and they still are). All
of them were found by serendipity, often under false
assumptions. The attempts for further improvement
led to the use of pharmacological analogues. In the
United States, United Kingdom and Australia, aspirin
and other derivates of salicylic acid were the standard
analgesics. In continental Europe and parts of Asia,
phenazone and derivates (aminophenazone, dipyron)
were the prevailing drugs. When the major metabolite
of phenacetin, paracetamol, was introduced (1953),
few consumers switched to the new compound, but
the situation changed soon.
Firstly, the economic situation of Europe and the
United States improved and the demand for consumer
goods with it. In Switzerland, the traditional watch
© 2014 European Pain Federation - EFIC®
K. Brune et al.
Figure 4 H.U. Zollinger, S. Moeschlin and U.C.
Dubach discovered the analgesic-induced
kidney damage (phenacetin kidney, Saridon®-
kidney). (Sources: 550 Jahre Universität Basel
(Festschrift), Der Spiegel, Juli 1958 and Who is
Who: Kantonsspital Basel, CH, 1991)
industry gained momentum. New mechanical watches
were assembled under time constraint (job work),
mostly by women.
The job work led to headache and exhaustion after
a few hours of assembling small and delicate mechani-
cal watches (Moeschlin, 1957, 1958; Dubach et al.,
1975, 1991). An effective method to overcome pain
and fatigue was a break, coffee and a piece of bread
covered with butter and punched into the butter
‘headache pills’. Most prominent was a brand pro-
duced by Hofmann-La Roche, called Saridon®. [At
that time, Saridon® contained caffeine, phenacetin,
propyphenazone and barbiturates (Zollinger, 1955).]
At the same time, it was customary in Switzerland that
elderly women had their coffee in one of the nice
coffee shops. They supplemented their coffee with a
couple of headache pills, which they could get directly
from the waiter. These and other habits, not only in
Switzerland, increased the use of headache pills,
which typically consisted of the three ingredients:
phenacetin (or phenazone, propyphenazone), aspirin
and caffeine. Nobody was afraid of any harm as all the
components and the mixtures of them were regarded
safe, useful and pleasant – a major error as turned out
later.
It is the merit of scientists from Switzerland (Fig. 4)
who observed an increase in incidence of interstitial
nephritis in the population of Basel and nearby
regions. They described the pathology of this ‘disease’
(better: chronic intoxication). It occurred often in
young (30–50 years old) women (many workers in
the watch industry) who suffered initially from mild
hypertension, later from interstitial nephritis going
along with pigmentation of the skin and early death
from cardiac infarction and/or cardiac insufficiency.
Spühler and Zollinger (1953) speculated about a
change in the environment, including the widespread
use of barbiturates and antibiotics (Spühler and
Zollinger, 1953). Moreover, they realized that in most
© 2014 European Pain Federation - EFIC®
130 years of aniline analgesics
cases the disease started with headache, which was at
first episodic and later almost permanent. Today, we
call it ‘rebound headache’ (Rapoport et al., 1996).
Many of the patients were suffering from this type of
chronic headache and ingested headache pills (often
Saridon®) regularly – without much relieve. In con-
tradistinction to what is written in many articles, in
the original paper, Spühler and Zollinger (1953) did
not suspect a causal relationship between the use of
analgesics and interstitial nephritis, although one-
third of their (first) 44 patients had consumed analge-
sics regularly. It was the merit of a clinician, S.
Moeschlin (Fig. 4), to pinpoint the relation between
‘Saridon’-abuse and kidney decay (Moeschlin, 1957,
and quoted in ‘Der Spiegel’, July 1958). It was only
shortly after their publication that a worldwide
increase of interstitial nephritis was observed and a
connection between the use of analgesics (mostly
combinations) and nephropathy (analgesic nephropa-
thy, phenacetin nephritis, Saradon nephritis) was pos-
tulated (Nanra, 1980; Kincaid-Smith, 1981; Dubach
et al., 1991).
The observation from Switzerland and many other
countries indicated that phenacetin was the major
culprit of interstitial nephritis, hypertension and
death. Consequently, beginning in the 1950s of the
last century, paracetamol supplanted phenacetin. It
was hoped that the abuse potential would be lower
and the kidney toxicity absent. There was indeed
some reduction of the ominous interstitial nephritis,
but the coincidence of the reduction may rather
reflect the intensive attempts, on the one hand, to
hinder consumers to abuse combination analgesics
and, on the other hand, to get those who were
habitually consuming these compounds, decondi-
tioned and detoxified (Drukker et al., 1986; Feinstein
et al., 2000). It turned out again that combination
analgesics taken regularly not only lost their anti-
headache activity but rather induced headache
Eur J Pain •• (2014) ••–•• 5
130 years of aniline analgesics
attacks (Rapoport et al., 1996). In the end, it
appeared that kidney problems were solved
and paracetamol could be used as a safe and
active analgesic, even in pregnant women and chil-
dren. Regrettably, this assumption was wrong
again.
Paracetamol does not cause methemoglobin pro-
duction (Prescott, 1980) but it turned out to be hepa-
totoxic due to its very reactive intermediate (NAPQI,
Fig. 1), which is produced in the liver and kidney cells
via the CYP P450 metabolizing enzymes, preferentially
in the liver and kidney. Hundreds of death cases and
thousands of hospital referrals result from overdosing,
voluntarily and accidentally every year (Moynihan,
2002; Lee, 2004).
2. The scientific evaluation late or
too late?
2.1 Kidney and liver toxicity: specific
for paracetamol
Following the ban of phenacetin, paracetamol/aceta-
minophen gained increasing market shares. The mar-
keting claim that paracetamol does not go along with
the usual unwanted drug effects of the competitor
aspirin was convincing. In later years, the non-
steroidal anti-inflammatory drugs (NSAIDs) were
introduced. They caused gastrointestinal (GI) toxicity,
kidney damage, bleeds, asthma-like reactions and car-
diovascular problems, including hypertension, cardiac
infarctions and cardiac insufficiency in long-term use
in high anti-inflammatory doses. They looked there-
fore less acceptable than paracetamol in low analgesic
doses. The putative better tolerability of paracetamol
furthered sales and use. Moreover, since paracetamol
lowered fever without obvious acute side effects,
safety claims were widely accepted without epidemio-
logical proof. Negative clinical reports were rare and
serious events were declared the result of overdosing.
Paracetamol was the recommended drug for pregnant
women and newborn children as well as for aged and
frail patients suffering, e.g., from osteoarthritis (OA)
(Zhang et al., 2010). Dipyron, an alternative to parac-
etamol, was shown to cause – very rarely – agranulo-
cytosis (Kaufman et al., 2006) and therefore banned
in many countries. Aspirin, contrary, may cause
Reye’s syndrome, leading to the termination of the
worldwide use of children’s aspirin (Eder et al., 2006).
Regrettably, this ban of aspirin has started an intensive
use of paracetamol in children and by that possibly a
worldwide epidemy of asthma, attention-deficit/
6 Eur J Pain •• (2014) ••–••
K. Brune et al.
hyperactivity disorder (ADHD) and retarded child
development (see later).
2.2 Inhibition of prostaglandin synthesis:
paracetamol an NSAID?
It was only recent science that shed new light on the
molecular basis of effects and side effects of paraceta-
mol. Several research groups could disentangle the
mode of action of the weak analgesic paracetamol.
Vane and colleagues found that paracetamol blocks
prostaglandin production in brain microsomes
(Flower and Vane, 1972). Using the ex vivo whole
blood assay (Tacconelli et al., 2002), we and others
could show that paracetamol inhibits prostaglandin
production by cyclooxygenase (COX) not only in the
central nervous system but also in the peripheral
tissues of human beings (Hinz et al., 2008).
Indeed, as would be expected from a COX inhibitor,
the use of paracetamol goes along with the same prob-
lems as NSAIDs. It increases blood pressure (Forman
et al., 2005; Sudano et al., 2010), aggravates the risk
of GI ulcers (Rahme et al., 2008) and myocardial
infarction (Chan et al., 2006). Inhibition of blood
coagulation may occur particularly when given intra-
venously at relatively high doses (for review, see Hinz
and Brune, 2012). Also, paracetamol has a low pro-
pensity for precipitating so-called aspirin-induced
(pseudo-allergic) reactions, including asthma and
shock (Szczeklik et al., 2003). Moreover, the claim
that paracetamol can be used in the final stages of
pregnancy because it does not inhibit prostaglandin
production is not justified: Recent evidence indicates
that early closure of the ductus arteriosus – a typical
consequence of inhibited prostaglandin production –
can be provoked by paracetamol as well as by ibupro-
fen (Hammerman et al., 2012). This proves again that
paracetamol is a COX inhibitor, which can cause
effects typical for this type of drugs. Indeed, adminis-
tering paracetamol has become an accepted procedure
for actively closing the ductus arteriosus in preterm
newborns (Hammerman et al., 2012). On the con-
trary, paracetamol as all COX inhibitors may contrib-
ute to the (rare) event of a premature (in utero) closure
of the ductus (Simbi et al., 2002). Moreover, as other
COX inhibitors, paracetamol can precipitate pre-
eclampsia (Rebordosa et al., 2010). These are rare
events. But then, paracetamol is used in low, often
ineffective doses. Prostaglandin synthesis inhibition,
however, does not explain the liver damage (including
an increase of transaminases), which may occur even
at permitted doses in apparently healthy consumers
(Watkins et al., 2006; Walton, 2014).
© 2014 European Pain Federation - EFIC®
K. Brune et al.
2.3 Liver and kidney toxicity: NAPQI
Paracetamol is the most widely used analgesic world-
wide, but it is also the predominant reason for ALF in
industrialized countries, including United States (Lee,
2004; Larson et al., 2005), United Kingdom (Tanne,
2006) and Scandinavian countries (Wei et al., 2007).
In the European Community, it appears to be the
prevailing reason for ALF requesting liver transplan-
tation (Gulmez et al., 2013). Moreover, the rate of
ALF transplantation was more than twofold higher for
no-overdose paracetamol exposure than for all
NSAIDs pooled. In addition, paracetamol was involved
in 97% of cases (111 of 114), where transplantation
was attributed to drug use (Gulmez et al., 2013).
The normal detoxification mechanisms, i.e., glu-
curonidation and sulfation (Fig. 1), allow for some
paracetamol to be transformed into the reactive
NAPQI by the CYP P450 system (particularly CYP 2E1
and 3A4; Laine et al., 2009). NAPQI reacts with sulf-
hydryl groups, e.g., in glutathione (GSH). GSH conju-
gation is generally considered to be a detoxification
mechanism. Administration of N-acetylcysteine
(NAC) restores GSH levels and protects from liver
damage, whereas GSH-depleting agents enhance par-
acetamol hepatotoxicity (Mitchell et al., 1973). In
contrast, protein adduct formation with NAPQI is a
mechanism of paracetamol toxicity (Jollow et al.,
1973). Protein adducts can be measured in the liver
and in serum. NAPQI may, in e.g., very slim under-
nourished persons or alcoholics, cause acute liver
decay and death from standard doses (Moore et al.,
2013). Even healthy young volunteers ingesting stan-
dard doses of paracetamol show an increased release
of transaminases – a sign of liver toxicity (Watkins
et al., 2006). This liver toxicity was not seen with
phenacetin. Indeed, several researchers wondered if
by eliminating phenacetin from human use, ‘the
wrong pig’ was killed.
Paracetamol overdose also induces renal toxicity
(Curry et al., 1982; Mazer and Perrone, 2008).
Metabolites from paracetamol–GSH conjugates have
been implicated in renal toxicity. Paracetamol–
cysteine conjugates aggravated paracetamol-induced
renal injury (Trumper et al., 1996; Stern et al., 2005).
Recent experimental findings provide evidence for a
signalling role of NAPQI produced in murine lungs
following administration of low non-toxic doses of
paracetamol (Nassini et al., 2010). NAPQI activated
the transient receptor potential ankyrin-1 (TRPA1)
expressed by primary sensory neurons, where it
stimulated the release of the pro-inflammatory neu-
ropeptides. Paracetamol induced neurogenic inflam-
© 2014 European Pain Federation - EFIC®
130 years of aniline analgesics
mation in the murine lung. This effect was absent in
paracetamol-treated TRPA1-deficient mice. Therefore,
NAPQI may also act as a signalling molecule contrib-
uting to the asthma-inducing effect of paracetamol
observed in several epidemiological studies (for
review, see Henderson and Shaheen, 2013).
Paracetamol is eliminated quickly [t50%: ∼1 h, in chil-
dren 1 (newborn) – 8 h]. This made it difficult to
provide proof that a patient suffering from acute liver
decay has ingested paracetamol (James et al., 2006).
This situation changed when several research groups
could show that paracetamol is bound covalently to
cysteine molecules in different proteins. These
acetaminophen/protein adducts remain in the body
for several days. They can be detected with chromato-
graphic techniques (Madsen et al., 2007). Conse-
quently, the proof that paracetamol has contributed to
an acute liver damage has become easier (James et al.,
2006, 2013; Heard et al., 2011; McGill and Jaeschke,
2013). On the contrary, this technique used in healthy
patients demonstrates that even at normal doses par-
acetamol adducts are produced, which, in turn,
requires the production of NAPQI that obviously is not
completely detoxified by conjugation with gluta-
thione. The adducts of paracetamol allow to speculate
about the contribution of paracetamol ingestion to
otherwise unexplained liver damage. Indeed, it could
be shown that in many unexplained intoxications in
children (James et al., 2006) and adults (Heard et al.,
2011; Khandelwal et al., 2011), paracetamol may
have played a major role, as even days after hospital
admission protein adducts were found. Moreover,
these protein/paracetamol adducts may be produced
in embryos and newborns since the necessary
enzymes are active in the fetus and paracetamol
crosses the placenta barrier freely (Rollins et al., 1979;
Byer et al., 1982; Heard et al., 2011). These observa-
tions gain importance when seen in context with the
multitude of epidemiological and experimental results
indicating long-term problems in children who were
exposed to paracetamol (and NAPQI) during
pregnancy.
2.4 Paracetamol for pregnant women and
newborn children?
Paracetamol has lost the glamour of being well toler-
ated and innocuous to pregnant women and newborn
children. Large analyses of databanks and case–control
studies show that the use of paracetamol during preg-
nancy may increase the incidence of asthma in chil-
dren of mothers having used paracetamol during
pregnancy (for review, see McBride, 2011). Ibuprofen,
Eur J Pain •• (2014) ••–•• 7
130 years of aniline analgesics
investigated head to head with paracetamol in a pro-
spective study, was not associated with an increased
incidence of asthma in contrast to paracetamol (Lesko
et al., 2002). In addition, investigations of the large
databanks of Scandinavian and other countries indi-
cate that paracetamol during pregnancy may:
(1) impair male fertility (Jensen et al., 2010; Snijder
et al., 2012),
(2) hinder psychosocial development (Brandlistuen
et al., 2013),
(3) increase the incidence of ADHD in later life (Liew
et al., 2014).
These observations have to be taken as signals of risk:
Paracetamol use during pregnancy appears to interfere
with the normal development of the newborn. They
show less physical and psychological competence at
the age of 3 years as compared to siblings from the
same mother who had not been exposed to paraceta-
mol during this pregnancy or were exposed to ibupro-
fen (Brandlistuen et al., 2013). Moreover, preliminary
evidence indicates that male children born from
mothers taking paracetamol during pregnancy are
more prone to suffer from cryptorchidism as compared
to boys born without having been exposed to the drug
(Jensen et al., 2010).
It is so surprising that different impairments of child
development and health may be due to a simple drug
as paracetamol. Moreover, paracetamol has been in
mass consumption for decades. Why were these puta-
tive problems discovered only during the last years
with the help of ‘new diagnostic tools and huge data-
bases’? At a first glance, one may wonder if these
problems were not ‘created’ to allow for ‘paracetamol
bashing’. For decades, paracetamol was the only rec-
ommended analgesic for use during pregnancy and
during breastfeeding. Since alternatives were lacking,
an increase in the incidence would have been difficult
to be detected, particularly as all effects may happen in
untreated children as well – but more seldom. Regret-
tably, the belief still prevails that paracetamol is effec-
tive and safe. It gained this position without thorough
toxicological investigation. Its status is based upon the
general believe and not on scientific data. It is fortu-
nate that the Food and Drug Administration (FDA) is
trying to improve the situation by more and more
warnings, reducing the recommended dosing and to
eliminate analgesic combinations at least for children.
It appears that only the availability of large data-
banks containing information about many drugs and
diseases used during and after pregnancy, including
the offspring, allow for detecting a measurable
increase of common, but not too rare problems. Of
course, epidemiology has so far only produced evi-
8 Eur J Pain •• (2014) ••–••
K. Brune et al.
dence of specific risk conditions (see, e.g., Cooper
et al., 2014). The question remains as to how reliable
these observations are and what the molecular mecha-
nism of such long-term effects could be.
More prospective cohort studies (similar to that of
Liew et al., 2014) should be pursued to add final proof
of the observed risks or, on the contrary, could lead to
the rejection of the present claims. Even more con-
vincing would be prospective randomized controlled
trials (RCTs). They are, however, not feasible for
ethical reasons. [Further details of the mechanisms
contributing to these (purported) toxic effects in preg-
nancy and the second generation can be found in a
recent review (Tiegs et al., 2014).]
2.5 Experimental toxicology suggests that
multiple toxicity is unavoidable
This being said, we might resort to additional experi-
mental proof of our assumptions. There are indeed
experimental results that support the claim that par-
acetamol due to its metabolization and mode of action
may be of special toxicity in pregnancy – in contradic-
tion to what we have told to our students and col-
leagues during the last decades:
• Until recently, many scientists believed that the
reactive metabolite NAPQI is produced by CYP p450
enzymes and active only if other metabolic pathways
are overloaded or not operating (Prescott, 1980). This
is not the case. Rather, there is evidence that parac-
etamol is metabolized in the tissue of the mother and
fetus to NAPQI as the fetus is endowed with the nec-
essary enzymes (Schuetz et al., 1993; James et al.,
2013) and paracetamol can cross the placenta freely
(Byer et al., 1982; Weigand et al., 1984).
• The discovery of paracetamol protein adducts and
the ability to measure their concentration in plasma
(James et al., 2006) and tissues (Roberts et al., 1991)
allows for the conclusion that NAPQI is not only pro-
duced but also reacts with important macromolecules
in the fetus. Depending upon the developmental phase
of the fetus or embryo, major damage may occur,
leading to functional impairment during later life.
• On this background, one may speculate that an
impairment of the development of the nervous system,
as observed in mice exposed to paracetamol (Viberg
et al., 2014), may play a role in the observed retarda-
tion of the development of children (Brandlistuen
et al., 2013).
The changes in the maturation of the immunological
system of the fetus may cause an increased propensity
to develop asthma, as immunological stem cells may
not be programmed in an adequate manner (Thiele
© 2014 European Pain Federation - EFIC®
K. Brune et al.
et al., 2013) and thus contribute to the increased inci-
dence of asthma after the termination of aspirin use in
children and pregnant women (Eder et al., 2006).
Finally, the exposure of fertilized zebrafish eggs and
larvae to NAPQI from paracetamol causes serious
damage to the developing fish embryos (Weigt et al.,
2010).
3. Paracetamol in the future
3.1 Alternatives
So far, it has always been argued that paracetamol is a
weak but harmless analgesic with low costs and low
risks. This characterization cannot be sustained
anymore as recent epidemiological research indicates
(Roberts et al., 2014, under review). Also, the claim
that eliminating paracetamol from the market would
deprive many patients of pain relief cannot be
accepted, as less toxic (e.g., Doherty et al., 2011) COX
inhibitors – as diclofenac, ibuprofen, ketoprofen and
naproxen – can take over in most instances. Some
physicians, however, worry that the ‘mild’ side effects
of paracetamol may be traded in for those serious ones
seen with modern NSAIDs. That this is not the case
comes out clearly in a prospective RCT in OA patients
(Doherty et al., 2011). Indeed, ibuprofen was more
effective and less toxic than paracetamol alone.
Paracetamol is by no means harmless. It is the only
over-the-counter (OTC) drug leading reliably to death
at overdose (this is not the case with NSAIDs). Even
the contention that it is safer as compared to its
mother substance phenacetin has never been proven
and the production of small amounts of the toxic
metabolite NAPQI cannot be avoided.
Indeed, in retrospective, the phenacetin-containing
analgesics may have activated two toxic mechanisms:
On the one hand, the kidney protection by prostaglan-
dins produced by the ailing kidney is inhibited by all
components of these analgesic mixtures, except caf-
feine. In addition, some combinations – and regretta-
bly, these are the ones used most widely – contain
paracetamol (or formerly phenacetin), which are both
transformed into the toxic metabolite, NAPQI, in the
kidney. Inadequate prostaglandin production plus
NAPQI adducts in the kidney may conjointly lead to
nephropathy causing hypertension, cardiovascular
events including cardiac infarction and stroke, i.e., all
symptoms that had already been observed by Spühler
and Zollinger (1953), Moeschlin (1957) and Dubach
et al. (1975) and which are regarded typical for
NSAIDs. In the liver, NAPQI alone may do the job.
© 2014 European Pain Federation - EFIC®
130 years of aniline analgesics
3.2 Aniline analgesics: is there a future?
After using aniline derivatives in pain therapy for 130
years, we have to face the fact that besides small thera-
peutic effects, all these compounds are endowed with
high toxicity. All attempts to reduce this toxicity by
reducing the dose, substituting one aniline derivative
to another or, finally, adding an antidote to the active
ingredient (e.g., NAC), do not lead to a satisfyingly
safe medication: Lowering the dose causes dissatisfied
patients and increases the risk of overdosing with
analgesic combinations (compare recent FDA recom-
mendations). Substituting paracetamol for phenacetin
has shifted the target of toxicity from the kidney to the
liver and, as we learnt recently, to the pancreas
(Cavanaugh and Naut, 2014). Adding acetylcysteine
goes along with additional risks (Bateman and Dear,
2009).
3.3 Paracetamol in at-risk groups
If paracetamol unavoidably carries the risk of toxicity,
are there patient groups who benefit especially from
paracetamol? Formerly, all experts including myself
recommended paracetamol for use in specific groups
within the population that might be specifically
endangered to drug-induced damage.
3.3.1 Elderly
It was and is still recommended as first choice in
elderly, e.g., suffering from OA (Zhang et al., 2010).
Most patients, however, prefer a modern NSAID
(Towheed et al., 2006). Since we know that paraceta-
mol as ibuprofen increases the risk of GI side effects
(Moore et al., 1999; Rampal et al., 2002), cardiovas-
cular problems, pseudo-allergic attacks, etc., this posi-
tion cannot be held anymore. This view is supported
by Doherty et al. (2011) who showed in an RCT that
paracetamol was more toxic and less effective than
ibuprofen in OA. The recent tendency to use NSAIDs
in low doses in elderly and children appears to be a
more meaningful approach. Moreover, a recent RCT
demonstrated that paracetamol does not work in low
back pain (Williams et al., 2014). These findings
appear to change the view of many experts who no
longer suggest paracetamol as first choice in OA or low
back pain (McAlindon et al., 2014).
3.3.2 Children/pregnant women
Most experts recommended paracetamol during
pregnancy and in children. In most countries, parac-
Eur J Pain •• (2014) ••–•• 9
130 years of aniline analgesics
etamol can be given throughout the whole preg-
nancy and also to newborn children. Almost daily
we see new publications coming up showing that the
assumption that paracetamol is an effective and risk-
free drug for these patients may not be true. Instead,
we have to accept that acute and chronic defects and
impairments may occur (asthma, ADHD, child devel-
opment, male fertility). The argument that most of
these studies are not prospective, controlled and
blinded are correct. In addition, they lack informa-
tion on the dose and duration of exposure. Such
RCTs, as much as we would like to have them, are
not feasible for ethical reasons. However, in a few
selected studies, ibuprofen and paracetamol were
tested head-to-head (Lesko et al., 2002; Brandlistuen
et al., 2013). The results are convincing. They show
that in contradistinction to the authors’ expectation,
ibuprofen did not go along with increased propensity
to asthma in contrast to paracetamol which increased
the incidence (Lesko et al., 2002). Recently,
Brandlistuen et al. (2013) could demonstrate that
children having been exposed to paracetamol
showed physical and mental retardation in contrast
to those from the same mothers who were not
exposed to analgesics or to ibuprofen. This list could
be expanded. Wherever we look, we find that par-
acetamol is not the best, but rather a bad choice that
causes problems. Recently, life-threatening skin reac-
tions were reported (De-Giorgio et al., 2013), which
caused a public warning by the FDA.
3.4 NAPQI, an unavoidable toxin
Experimental evidence links these problems to the
production of the highly reactive and dangerous
metabolite of paracetamol, NAPQI. Chemicals
showing the same propensity to release reactive epox-
ides of the imine type are banned from human (drug)
use. Our authorities would not permit new drugs
showing the chemical structure of an epoxide to the
market. These guidelines apply to new compounds.
They are erroneously not applicable to old compounds
as paracetamol. Why? Some argue that definite proof
for many of the problems seen with paracetamol is not
yet available. But then, we should follow the Roman
principle ‘in dubio pro reo’. In this case, not the drug
is the ‘reus’ (culprit) but the child or the elderly
person. They should be protected.
4. Not approvable?
Many experts believe that paracetamol would not be
admitted to the market today. The world has changed.
10 Eur J Pain •• (2014) ••–••
K. Brune et al.
We have guidelines and expect thorough investiga-
tions of new compounds. This is in contrast to the old
ones, which were found by serendipity and entered
into human use without scientific evaluation. We
should apply the same strict rules to the old com-
pounds. The assumption that old, widely used drugs
are safe is not based upon scientific evidence.
Recently, a short comment in the New England Journal
of Medicine indicated that co-administration of parac-
etamol with phenylephrine (for OTC-use) doubles the
bioavailability of phenylephrine, an effect certainly
dangerous and completely unexpected (Atkinson
et al., 2014). This again shows that ‘historical’ drugs
may yield surprising and dangerous effects and we
should not trust that old means safe. Nevertheless,
relating the ubiquitous paracetamol (Modick et al.,
2014) to the worldwide increase of Alzheimer’s
disease (Jones, 2014) appears somewhat far-fetched.
Against this background, more modern synthetic
compounds that have gone through a scientific evalu-
ation during the last 30 years as diclofenac, ibuprofen,
ketoprofen and naproxen – OTC in many countries –
appear safer (in low doses) and more reliable for reduc-
tion of pain and fever. Moreover, these drugs are, to say
the least, not lethal at overdose! Indeed, as pointed out
by others: ‘Today paracetamol would (and should) not
be admitted to human use’ (Lowe, 2005), (see also
Fontana, 2006; Brune et al., 2009; Brown et al., 2012).
Author contributions
K.B. had the idea and organized the first and final draft. G.T.
added the chemical and biochemical aspects. B.R. organized
the text.
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