Rheumatology 2002;41(suppl. 1):28–34
Arthropathy in art and the history of pain
management—through the centuries to
cyclooxygenase-2 inhibitors
T. Appelboom
Erasmus University Hospital, University of Brussels, 808 route de Lennik,
B-1070 Brussels, Belgium
Abstract
Preserved human remains, artefacts and works of art contain records of the existence and
prevalence of arthropathies, even in the absence of medical texts or formal written accounts,
although these also exist for some epochs and cultures. Example objects from the Museum
of Medical History in Brussels have been used to illustrate the magnitude of the burden of
pain throughout the ages and how rheumatic diseases have indiscriminately afflicted people
regardless of their positions in life or occupations. These include both osteoarthritis (OA)
and rheumatoid arthritis (RA), as well as the seemingly ubiquitous gout and various
skeletal deformities. Adequate pain management has been severely hampered, historically,
by obstacles to a comprehensive and systematic classification of diseases posed by the
social, religious and philosophical mores of the time, which made differential diagnosis
almost impossible to achieve. However, despite this shortcoming, serendipitous events
meant that precursors of modern medicines, such as willow bark extracts, were in routine
use from the earliest recorded times. It has taken several millennia, however, before
empirical treatment has given way to pharmacological rationale. The first clinically
acceptable synthetic derivative of the active principle in willow, aspirin, became available
only at the turn of the nineteenth century, while non-steroidal anti-inflammatory drugs
(NSAIDs) did not arrive on the market until some 60 yr later. At the cusp of the twentieth
and twenty-first centuries, physicians have a wider choice of analgesics available than ever
before, including the cyclooxygenase-2 inhibitors, which represent the first major advance in
NSAID development since the synthesis of the latter compounds themselves.
KEY WORDS: History of medicine, NSAIDs, Cyclooxygenase-2 inhibitors, Osteoarthritis,
Rheumatoid, Arthritis, Art, Pain.
seamen of Christopher Columbus. It could be speculated
that these men brought back the triggering agent which
then found a favourable biotope and susceptible hosts
in Europe, who subsequently developed an aberrant
immune reaction. However, there is evidence of the
European antiquity of RA from osteo-archeological
finds dating back to the Stone Age [4]. It could be that the
absence of specific references to RA in texts and artefacts
predating the voyage of Columbus is due to difficulties
of interpretation and to a lack of systematic disease
classification harking back to authors from classic
antiquity, and that it is this non-Linnaean thinking that
accounts for the apparent lack of RA, rather than a true
epidemiological phenomenon.
RA was first adopted as a definitive term by Sir Alfred
Baring Garrod in 1859 [5]. The term is derived from the
Greek words ‘arthron’, meaning ‘joint’, and ‘rheuma’,
meaning ‘flux’, the latter probably a reflection of the
‘equilibrium of humours’ hypothesis originally promul-
Introduction
Art and archaeology can be used to obtain new data,
from which scientific, historical and epidemiological
information can be extracted. This approach can be used
to trace the occurrence of certain diseases in the past.
For example, the earliest recorded case of ankylosing
spondylitis was found in the 3000-yr-old Egyptian
mummy of Ramses II [1]. The word ‘arthritis’ was used in
both classic Greek and Roman literature, and evidence
from historical medical texts has led to speculation that
rheumatoid arthritis (RA) may have been a common
disease as far back as the seventeenth century [2]. RA as a
recognizable entity appeared in the Old World after the
numerous exploratory travels of the sixteenth century [3],
notably after the discovery of the New World by the
Correspondence to: T. Appelboom, Erasmus University Hospital,
University of Brussels, 808 route de Lennik, B-1070 Brussels, Belgium.
28
© 2002 British Society for Rheumatology
Arthropathy in art and the history of pain management
gated by Hippocrates and his contemporaries around
460 BC. Despite this nominal allusion to ancient theories,
Garrod’s work shows that he had a sound understanding
of the distinct associations and potential aetiologies of
RA and gout. For his predecessors—and even among
his contemporaries—classification of rheumatisms was
based on a conceptual causative factor, with an explanation of pathogenesis that remained within the bounds of
the Hippocratic tenets of Galen [6]. Thus the distinction
between chronic gout and rheumatoid polyarthritis has
not always been evident and at least some of the numerous references to gout in historical literature may, in fact,
have reflected instances of RA.
A series of rheumatic conditions has struck the
imagination of artists who not only reproduced what they
saw, but also used their creativity to express pain and
changes in the quality of life (QOL). Paintings, sculptures, ceramics, sketches and writings depicting or
describing medical deformities can be analysed not only
through the lorgnette of the art historian, but also from
the point of view of the rheumatologist.
Such historical epidemiological evidence can be found
as far back as the pre-Columbian era (3000 BC–AD 1492)
in ceramics showing injuries, hunchback and pain rictus,
and in mummies that have been analysed using computer
tomography (CT) scans and retrospectively diagnosed
with osteoarthritis (OA) [7]. Evidence of arthropathological disease has been identified in Egyptian mummy
heads [8] and also strongly suggested in Egyptian tomb
art dating back to 1350 BC [9]. RA was frequently
depicted in seventeenth century paintings by Rubens [3],
who probably himself had chronic polyarthritis and may
have found some cathartic relief through representation
of the visible symptoms in his subjects. Many of his
works clearly portray the ravages of RA, particularly
those involving the hands and wrists. Renoir [10, 11]
and Dufy [12] both had RA, and many other prominent
figures from the spheres of the creative arts, politics and
even sovereignty were afflicted by a variety of rheumatic
diseases, of which gout appears most often [13–16]. This
heritage opens up new avenues for research and discussion. When considered in parallel with the history of pain
relief, notably the relatively recent development of
non-steroidal anti-inflammatory drugs (NSAIDs) and,
latterly, the arrival to market of their more specific
successors, cyclooxygenase-2 inhibitors (coxibs), it is
clear that throughout history many people with painful
arthropathies would have benefited greatly had these
compounds been available to them.
Rationale and methodology
From the permanent exhibition in the Museum of Medical History, Erasmus University Hospital, University
of Brussels, relevant items were selected to show how the
QOL of people living a few centuries ago, in a discrete
geographical region and belonging to a specific culture,
may have been affected by painful arthopathies and also,
in some examples, by acute pain of a different origin. It
is posited that their QOL would have been dramatically
29
improved if NSAIDS, and especially the new coxibs, had
been available.
Results of evaluation
The pre-Columbian era (3000 BC–AD 1492)
Tumaco expression of pain. Artists from the Tumaco
region, situated along the coast and on the border
between Columbia and Ecuador, paid much attention to
depicting diseases, which were not considered a social
handicap. Indeed, such imagery often adorned the
attributes of power, such as jewellery, hats and breastplates (Fig. 1A). In these pieces (500 BC–AD 500), some
subjects have one hand on the temporal region of the
face, which is sometimes deformed by a rictus of pain
and by wrinkles, signifying old age. For art historians,
these details are consistent merely with signs of general
ailment. For physicians, especially rheumatologists, this
posture is reminiscent of the symptomatology associated
with temporal arteritis, an inflammatory disorder frequently associated with polymyalgia rheumatica.
In terms of treatment, ancient pre-Columbian civilizations believed strongly in supernatural forces, both as
a factor in disease aetiology and as a key tool in its
management. Depicting deformity as art on everyday
objects was designed to ‘transfer’ the disease from the
affected individual to the item in question, thus effecting
a cure. Many such artefacts have been discovered in
ancient tombs and are thought to have had a shamanic
purpose. There are no records regarding the efficacy of
this therapeutic approach, although if successful, it might
represent one of the earliest examples of the placebo
effect.
The hunchback. The vase from Colima (300 BC–
AD 200) shown in Fig. 1B depicts a human figure with a
hump, being also small in stature and with short legs.
From a medical perspective, a diagnosis of achondroplasia cannot be excluded. People with deformities were
well accepted in ancient pre-Columbian society and often
had a superior status in the group. With ageing, spinal
deformities and achondroplasia can be associated with
spinal stenosis, accompanied by low back pain radiating
to the lower limbs. Pre-Columbians derived their remedies
from medicinal plants and their health depended on the
local flora. In Peru, for example, willow tree decoctions
were used for the treatment of fever and rheumatism,
constituting an early example of ‘NSAID analgesia’,
albeit one based on serendipity and not on any understanding either of the aetiology of the disease, or of the
mechanism of action of the treatment.
‘Rascar Capac’. A pre-Columbian mummy from
Arica in Peru dating from the thirteenth century and
given the name ‘Rascar Capac’ by the Belgian writer
Georges Remy (alias Hergé, author of the cartoon series
Tintin), had previously been examined by CT scanning
[7]. A three-dimensional reconstruction (Fig. 1C) reveals
degenerative changes of the right sacroiliac joint with a
transitional anomaly of the right lumbosacral junction,
signs consistent with OA. There is no direct evidence that
30
T. Appelboom
FIG. 1. The impact of pain on mankind, shown here through depictions of pain states on archaeological artefacts, representations in
art and CT scanning. (A) Tumaco expression of pain. (B) Colima vase depicting figure with hump. (C) CT scan of ‘Rascar Capac’,
pre-Columbian mummy from Arica in Peru, showing degenerative changes consistent with OA. (D) Egyptian mummy head with
decayed and abscessed teeth. (E) Unsigned English caricature of Sir John Falstaff with gout. (F) ‘The Dentist at Work’ by Rombouts.
(G) Drawing of hand with rheumatoid arthritis by Garrod.
the anomaly caused pain, but if that had been the case,
pre-Columbian civilisations are known to have treated
rheumatic pain with a variety of interventions including
multipuncture, cauterization, scarification, blood letting,
massage, the application of coca leaves and thermosudotherapy [17]. It is likely that some or all of these
Arthropathy in art and the history of pain management
treatments would have been intrinsically painful and/or
uncomfortable, and may have constituted examples of
‘the cure being worse than the disease’.
The Egyptian period (c. 1500 BC)
The decayed and abscessed teeth in an Egyptian mummy.
Examination of Egyptian mummies frequently reveals
pyorrhoea, decayed teeth and alveolar abscesses
(Fig. 1D). One reason for this phenomenon is provided
by the Egyptians’ practice of mixing mineral extracts
with their food, thus producing dental abrasion. Cardamom extract and the ingestion of cooked mice were
recommended for these problems, although likely efficacy
of these interventions is, at best, questionable. Gum
lesions were cauterized and the abscesses perforated for
draining, both quite sound approaches as far as they
went, albeit undoubtedly painful ones.
The Renaissance (1400–1590)
Sir John Falstaff. Sir John Falstaff is one of the most
famous comic characters in English literature at the turn
of the sixteenth century, appearing in four of Shakespeare’s plays. In an unsigned sketch (Fig. 1E), his left
foot is wrapped and resting on a footstool. This is the
typical representation of gout in English caricature.
Gout has been a prominent rheumatic condition
throughout history, especially during the time of the
Roman Empire, and according to Nriagu [18], saturnine
gout probably contributed to the fall of the British
Empire. Colchicum automnale, used by Greco-Roman
physicians and which had been abandoned as a treatment
for some time because of its excessive purgative sideeffects, came back into use at the beginning of the
eighteenth century as the major component of a drink,
Eau d’Husson (named after Nicolas Husson, a French
officer who in 1783 boasted the efficacy of a ‘new’ secret
remedy against gout).
‘The Dentist at Work’ by Theodore Rombouts (1597–
1637)—an eighteenth century engraving of a seventeenthcentury painting. During the seventeenth century,
Scultetus (1595–1645) developed new forceps (the
cagnolo) which derived from Celsius’ instrument. These
new forceps were able to lift the gum before extracting the
tooth (Fig. 1F). However, no anaesthesia was available;
decoctions of gum guaiac, derived from the New World
tree Guaiacum officinale and containing as the active
principle a monoethylic esther, guaiacol, and tobacco
from the New World were used both as antiseptic and
analgesic agents; and medicinal plant extracts were
introduced into the ear since it was believed that the veins
of the teeth went through the ear; or the ear was
cauterized to block the vein and the pain.
‘Drawing of a hand with rheumatoid arthritis’ by
Garrod. The Frenchman Landre-Beauvais is accredited
with reporting the first case of RA in 1800, but, as
described earlier, the most sophisticated differential
diagnosis between RA and gout was made by Sir Alfred
Baring Garrod in 1859. In his treatise, The Nature and
Treatment of Gout and Rheumatic Gout, Garrod points
31
out the characteristic features of arthritis and the extraarticular involvement of RA, supported by an illustration
showing a symptomatic hand (Fig. 1G). Garrod’s treatment plan included, notably, quinine sulphate, opium
tincture and the application of leeches.
A brief history of pain and its management
The burden of pain through the ages
The impact of pain on mankind can be traced over the
millennia, through depictions of pain states on archaeological artefacts, representations in art and literature
and, latterly, descriptions of symptoms in scholarly and
medical texts. Management of painful diseases long
remained largely a reflection of the beliefs and attitudes
of the time, rather than having any basis in physiological or pharmacological understanding. Religious,
philosophical and political considerations were deeply
influential on scientific thinking and practice [19].
Indeed, such factors are considered to be responsible for
the many delays and wrong deductions of past epochs
[20]. These have effectively postponed a proper understanding of pain aetiology—and hence of effective
medical management—until relatively modern times.
Even the etymological derivation of the word ‘pain’, from
the Latin ‘peona’, meaning ‘punishment’, contains echoes
of the prevalent attitude of the early Christian Church to
pain—that it was synonymous with ‘sin and deserved
suffering’—a premise that still lingers in a modern guise
of ‘underestimation’ of its devastating impact and a
frequently ‘stoical’ forebearance by its sufferers. This is
particularly so for chronic pain states, for which medicine
is only just beginning to find effective and essentially safe
solutions.
Inflammation as a symptomatic and painful disease
manifestation has been recorded from earliest antiquity.
The oldest medical text on record, the Edwin Smith
papyrus dating from Egypt 17 centuries before the birth
of Christ, describes the body’s reaction to injury as
‘shememet’, the word always suffixed by a hieroglyph
denoting ‘fire’, to symbolize the intrinsic redness and
heat [21]. One thousand years later, Hippocrates termed
inflammation ‘phlegmone’, or ‘the burning thing’, but the
first definitive description, still in use in medicine today, is
derived from the Roman author Cornelius Celsus writing
in the first century AD: Rubor et tumor cum calore et
dolore, that is, ‘redness and swelling with heat and pain’
[21].
Nomenclature and disease classification notwithstanding, it is certain that arthropathies have been associated
with varying degrees of pain and disability throughout
the history of humankind. Recent studies have shown
that the majority of the total societal burden of pain
comes from arthritis [22] and that chronic pain is a major
and often disabling problem that impacts on patients’
QOL [22–24]. Since these observations have been made in
a milieu of modern pharmacopoeias and strategic drug
development, it can be conjectured that the historical and
ancient burden of arthropathy-related pain was even
32
T. Appelboom
greater than that experienced today. It is well recorded
that Renoir, for example, was so severely disabled by RA
that he required a specially adapted chair and easel [13].
From ancient anodynes to analgesia today
The oldest known medical prescription, a 4000-yr-old
small Babylonian clay tablet, makes reference to a
revolting-sounding concoction of animal and plant
extracts, supposedly effective for the easing of pain [25].
Ancient Egyptian physicians were among the first to
postulate theories and mechanisms to explain pain [26].
They also described the presentation, diagnosis and
treatment of some painful conditions. For example, they
practised a relatively sophisticated form of dentistry,
including fillings, abscess drainage and fixation as ways
to relieve severe toothache (see above). They also regularly used mixtures of plant origin as topical analgesics
for stiff and painful joints [27], including Salix alba, a
member of the willow family and ancient precursor of
NSAIDs.
Already by the 1970s, Martindale’s Extra Pharmacopoeia had devoted 240 pages to medications for
pain relief and listed >1000 such preparations [25].
The twentieth century saw the development of several
non-opioid analgesics. Phenacetin, which preceded the
widespread use of aspirin, was subsequently withdrawn
due to severe and sometimes fatal nephrotoxicity. It was
succeeded by its much less toxic derivative, paracetamol
(Panadol, Bayer), an agent still in regular use today for
the management of mild-to-moderate pain, including
muscular rheumatism, despite continuing debate and
caution with regard to its hepatotoxic potential, specifically in overdosage.
Now, at the beginning of the third millennium, >30
different categories of analgesics, including NSAIDs and
coxibs, are available to control pain and inflammation.
NSAIDs—latecomers in history
The forerunners of NSAIDs, aspirin and related compounds, remain the cornerstone treatment for arthritic
diseases. Aspirin, or acetylsalicylic acid, is one of a broad
group of compounds termed ‘salicylates’, that have their
origins in several plant species, including willow (Salix
spp.). Ancient Egyptians and Assyrians are known to
have used willow extract to reduce the erythema and pain
of inflamed joints, while the Roman Pliny, in the first
century AD, prescribed the bark of another member of
the willow family, the poplar, for the relief of sciatica [28].
But it was not until much later in history that the first
modern account of such treatment appeared [21]. In
1763, Englishman Reverend Edward Stone discovered
that the pain and fever of malaria responded to an
aqueous dispersion of powdered willow bark [29], while
a century later, Scotsman Thomas MacLagan began
treatment of ‘rheumatic miasma’ with willow’s active
principle, salicin [30, 31]. In both instances, however, the
rationale was based on conjecture, apposition of flora
with climatic conditions thought to predispose to the
diseases in question and somewhat fortuitous empirical
observation.
Increasing demand for willow bark and other plant
extracts, coupled with limited and often-interrupted
supplies, led directly to the birth of the isolation and
then the synthetic production of the active constituents.
The severe gastrotoxicity associated with early efforts
was a driving force in the subsequent development, by a
father-and-son team of chemists working for Bayer, of
acetylsalicylic acid [21], or aspirin per se, an entirely
synthetic compound containing no willow derivatives
[28]. Bayer Aspirin, as it was originally called, first
entered clinical medicine in 1899 [32]. During the past
century, it is estimated that one trillion aspirin tablets
have been have been taken for a variety of indications,
including pain relief [33].
Aspirin belongs to a class of drugs known as ‘antiinflammatories’, more specifically, ‘non-steroidal antiinflammatory drugs’, or NSAIDs. Arguably the most
familiar, and the earliest of these, is indomethacin, which
unlike earlier empirically derived agents was the product
of pharmaceutical drug development and testing in
animal models of inflammation [34]. Many more compounds of this type have since been synthesized, but
despite extensive clinical use, their mechanism of action
was not understood until the early 1970s, when Vane et al.
determined that aspirin blocked the synthesis of a key
inflammatory cytokine called prostaglandin E [35]. This
seminal research paved the way for the development of
other compounds with better efficacy and safety profiles,
culminating in the novel class of agents called ‘coxibs’.
After Vane’s work had been published, further research
showed that NSAIDs inhibit prostaglandin synthetase,
the enzyme that transforms arachidonic acid to prostaglandins [36]. This assertion was supported by the
phenomenon of NSAID-induced gastrointestinal (GI)
side effects, arising from their interference with the
biosynthesis of those prostaglandins responsible for regulating stomach acid levels and maintaining the integrity
of the gastric mucosa. More recently, two isoenzymes of
prostaglandin synthetase have been identified, referred to
as ‘cyclooxygenase-1’ (COX-1) and ‘cyclooxygenase-2’
(COX-2). Inhibition of COX-2 has been more directly
implicated in mediating an anti-inflammatory effect,
while conversely, inhibition of COX-1 has been linked
with GI adverse events. Whereas non-specific NSAIDs
inhibit both forms of the enzyme, coxibs are selective
inhibitors of COX-2 and as such, should display equivalent efficacy to NSAIDs, but be better tolerated [37].
Clinical trials have indeed demonstrated similar efficacy
[38] and a lower incidence of serious GI adverse events
[38, 39] with coxibs.
Conclusions
Medical, archaeological and cultural records clearly show
that numerous rheumatic diseases have afflicted humans
since ancient times. This assertion is exemplified by
items from the Museum of Medical History in Brussels.
Religious doctrines, ancient philosophies scripted by
influential figures, and associated factors precluded
differential diagnosis and meant that historically,
Arthropathy in art and the history of pain management
accurate disease definitions were either completely absent
or, at best, a somewhat ‘hit and miss’ science. Nevertheless, rheumatic disease in general is synonymous with
swelling, fever, disability and chronic pain, all of which
cause damaging changes to the affected person’s QOL.
Clearly, the burden of pain in general and in relation to
arthropathy in particular, has been considerable throughout the history of humankind.
Treatments have come and gone in the past, often
coming tantalizingly close to the borders of efficacy
based on pharmacological principles. For example,
decoction of willow tree leaves containing salicylic acid
as a treatment for gout and related disorders, mentioned
at the beginning of the first millennium in the book
of the Greek physician Dioscorides, was forgotten until
1763 [40]. This also happened with Colchicum extract,
which was reintroduced into the clinical armamentarium
in 1783 [40]. Today, physicians and rheumatologists have
at their disposal a wider choice of analgesic and antiinflammatory medicines than their predecessors could
ever have dreamed possible and the most recent discoveries are better tolerated and offer a 10 yr improvement in
QOL (Merck & Co., Inc., data on file). It is a pity for Job,
Falstaff and Rascar Capac that such drugs were not
available for them. The new generation of pain relief
represents significant progress in the management of
rheumatic conditions and in previous epochs they might
have changed the face of the world.
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