Although physicians have sought to alleviate pain for centuries, the history of pain research
and modern pain treatment begins in the 1800s. The enigma of pain, which Albert Schweitzer
called "the most terrible of all the lords of mankind," has yielded slowly to determined
investigators and clinicians.

Many substances, usually in combination, were used to alleviate pain. Most of these pain relievers were from
plants; they were often powerful and when taken in overdose, deadly. One of the most commonly used
substances was opium derived from the poppy flower, Papaver somniferum. Amongst other substances used
were alcohol or wine, mandragora or mandrake from the plant Atropa mandragora, belladonna from the deadly
nightshade, and marijuana or Cannabis indica. Extracts from such plants as hellebore, henbane, datura, and
hemlock were used carefully, their strength being recognized.

Opium was used throughout the 19th century, often as laudanum or tincture of opium, which is a combination
of opium and alcohol: "Laudanum: The common name for Tincture of Opium, and the form in which that drug
is most frequently administered. . . It is narcotic, sedative, and being made with spirit, is also, to a certain
extent, stimulant and anti-spasmodic. For relieving pain, wherever situated, to diminish irritation, and to
procure sleep, it is the best of the medicines we possess."

People treated themselves and their families for pain, buying over-the-counter patent medicine remedies.
Most of these were alcohol or opium-based compounds. For severe or post-operative pain, the physician
might inject morphine, which had been isolated from opium in 1806. Towards the end of the century, German
chemical companies introduced new compounds: acetanild and the salicylates, which effectively relieved
moderate pain, although not without side effects. The salicylates, for example, might induce gastric pain, even
ulcers. In 1899, the Bayer Company introduced a stable, easily tolerated salicylate, acetylsalicylic acid, which
under the trade name aspirin quickly became the best selling medication in the world.

In 1803 Friedrich Wilhelm Serturner (1783-1841) isolated crystals of a powerful analgesic agent from crude
opium. Serturner named the chemical morphine, after Morpheus, the Greek God of dreams. It could be
introduced on the point of a lancet or a solution could be washed into a wound.

In the 1850's Charles Gabriel Pravaz (1791-1853), a French surgeon, and Alexander Wood (1817-1884) of
Edinburgh independently invented the syringe. Injections of morphine were generally used for local pain.

The real wonder drug proved to be a compound found naturally in willow tree bark or meadow grasses. In 1897
Bayer chemist Felix Hoffmann developed a stable form of this natural compound which could be safely used by
most people, without side effects. Acetylsalicylic acid (ASA), sold by Bayer under the trade name "Aspirin,"
was the first reliable and effective such pain killer or analgesic.

Charles Bell, the Scottish anatomist and neurosurgeon seen, described the motor role of the anterior or
ventral nerve root of the spinal cord in his privately-circulated pamphlet, A New Idea of the Anatomy of the
Brain, Submitted for the Observation of his Friends (1811).

Magendie, the pioneer of experimental physiology in France, published a brief yet momentous paper on the
functional discreteness of the spinal nerve roots ("Experiences sur les foncions des racines des nerfs
rachidiens") in his own journal in 1822. He demonstrated that the posterior or dorsal roots appeared more
specifically related to sensation and, without knowing it at the time, confirmed Bell's conclusions about the
anterior nerve root.

Johannes Muller (1801-1858), professor at Berlin, numbered some of the most famous names in 19th
century physiology among his students, including Helmholtz, DuBois-Reymond, Schwann, Virchow, Kolliker and
Remak. His formulation of the Law of Specific Nerve Energies appeared in the second edition of his Handbuch
der Physiologie des Menschen fur Vorlesungen (Coblenz: J. Holscher, 1835-1840), translated here by Edwin
Clarke and UCLA's Charles Donald O'Malley:

". . . (T)he same cause, such as electricity, can simultaneously affect all sensory organs, since they are all
sensitive to it; and yet, every sensory nerve reacts to it differently; one nerve perceives it as light, another
hears its sound, another one smells it; another tastes the electricity, and another one feels it as pain and
shock. One nerve perceives a luminous picture through mechanical irritation, another one hears it as buzzing,
another one senses it as pain. . . He who feels compelled to consider the consequences of these facts
cannot but realize that the specific sensibility of nerves for certain impressions is not enough, since all
nerves are sensitive to the same cause but react to the same cause in different ways. . . (S)ensation is not
the conduction of a quality or state of external bodies to consciousness, but the conduction of a quality or
state of our nerves to consciousness, excited by an external cause."

Max von Frey (1852-1932) used human hairs or other bristles mounted in a handle to map cutaneous
sensitivity on a piece of skin on the back of the hand. His investigation found discrete pain spots (circles)
which did not coincide with pressure points (triangles; "Haare"=hair).

In 1898 the British physiologist, Sir Charles Scott Sherrington (1857-1952), proposed the key concept of
nociception: pain as the evolved response to a potentially harmful, "noxious" stimulus. His landmark work, The
Integrative Action of the Nervous System (New York: Scribner, 1906) included examples in which various
sensory stimuli (such as those which normally elicit pain or nociception vs. those evoking the scratch reflect)
compete in the production of various behavioral responses using the same motor pathways, in what he called "
the struggle between dissimilar arcs for mastery over their final common path."

Sherrington insisted that the essential function of the nervous system was the coordination or integration of
activities of the various parts of the organism. The function of pain, to the twentieth-century scientist, was
no longer to heal, to punish, or to ennoble, but to provide a mechanical warning of actual or potential damage
to cells and tissues in a specific body area. Despite Sherrington's emphasis on integration and competition,
the idea of a specific pathway for pain, linking peripheral receptors to spinal neurons to brain receptors, and
producing a motor response of one-to-one intensity, the telephone exchange model, became dominant in
neurophysiology.

In 1872, American neurologist S. Weir Mitchell described a bizarre symptom complex resulting from wounds to
peripheral nerves in his book, Injuries of Nerves and Their Consequences (Philadelphia: J.B. Lippincott): "
Perhaps few persons who are not physicians can realize the influence which long-continued and unendurable
pain may have on both body and mind. . . Under such torments the temper changes, the most amiable grow
irritable, the bravest soldier becomes a coward, and the strongest man is scarcely less nervous than the most
hysterical girl. Nothing can better illustrate the extent to which these statements may be true than the
cases of burning pain, or, as I prefer to term it, Causalgia, the most terrible of all tortures which a nerve
wound may inflict."

Mitchell performed a number of experiments. He wrote: "I recently faradised a case of disarticulated shoulder
without warning my patient of the possible result. For two years he had altogether ceased to feel the limb. As
the current affected the brachial plexus of nerves, he suddenly cried aloud, 'Oh, the hand, the hand!' The limb
is rarely felt as a whole; nearly always the foot or the hand is the part more distinctly recognized. . . In nearly
all there is some feeling, such as pain, itching, or other sensation."

W. K. Livingston had learned at Harvard that pain was a specific response to an unpleasant stimulus, a warning
of tissue damage. One of the problems that puzzled him early in his career was visceral pain: patients might
experience no apparent pain from tissue damage to certain internal organs but would report "referred pain" in
another part of the body. He studied other pain phenomena, such as causalgia and phantom limb pain, which
presented similar enigmas. Livingston's research in these areas is described in his books, The Clinical Aspects
of Visceral Neurology (London: Baillere, Tindall & Cox, 1935) and Pain Mechanisms (New York: Macmillan,
1943), in which he proposed that pain, far from being a simple reaction to a single stimulus, could involve a
complex and diffuse, but interactive, set of neural responses, which Livingston called "the vicious circle."

Livingston wrote in his Pain Mechanisms (1943): "I believe that the concept of 'specificity' in the narrow
sense in which it is sometimes used. . . has led away from a true perspective. . . Pain is a sensory experience
that is subjective and individual; it frequently exceeds its protective function and becomes destructive. The
impulses which subserve it are not pain, but merely a part of its underlying and alterable physical
mechanisms. . . The specificity of function of neuron units cannot be safely transposed into terms of sensory
experience. "A chronic irritation of sensory nerves may initiate clinical states that are characterized by pain
and a spreading disturbance of function in both somatic and visceral structures. If such disturbances are
permitted to continue, profound and perhaps unalterable organic changes may result in the affected part. . . A
vicious circle is thus created."

In 1965, a collaboration between two self-described iconoclasts, Canadian psychologist Ronald Melzack and
British physiologist Patrick Wall, produced the gate control theory. Their paper, "Pain Mechanisms: A New
Theory," (Science: 150, 171-179, 1965) has been described as "the most influential ever written in the field
of pain." Melzack and Wall suggested a gating mechanism within the spinal cord that closed in response to
normal stimulation of the fast conducting "touch" nerve fibers; but opened when the slow conducting "pain"
fibers transmitted a high volume and intensity of sensory signals. The gate could be closed again if these
signals were countered by renewed stimulation of the large fibers.

Melzack and Wall remember their collaboration on the Gate Control paper. Melzack: "So in the course of our
talking I said to Pat, 'You know, you and I think a lot alike about a lot of things. Why don't we write a paper
together?' So we wrote a paper that was published in Brain in 1962. And we struggled with that paper, putting
it all together, and it was certainly jointly done all the way through. I think three people read the paper. So we
began to write [a second] paper and sending back drafts back and forth-I'd bring them down, we would argue,
and so on-and then at some stage, we began to organize the paper into components, and the main, the gate
control theory got invented. Anyway, I suggested that we really aim for the top and try Science and see what
the hell happens-the worst that will happen is to get rejected. It got accepted. We were astounded. Well, so,
then you know the rest because some people loved it and most people hated it." (From the Oral History of
Ronald Melzack, 1993). Wall: "At this time, with a completely different background, there was Ron Melzack,
with whom I've really never worked in my life, we'd only got to talking. You ask about the gate control theory,
which is 1965 as published, if you read what we'd published certainly three years before, it says exactly the
same thing in it. And we tossed a coin, and published essentially exactly the same paper, only as Wall and
Melzack [1962] rather than Melzack and Wall [1965], and it was utterly ignored. And then we put out the
Science paper. And as you see, if you read this, we simply tried to bring together everything that we knew and
what was in the literature at the time, knowing very well that we could be wrong, and certainly in the details.
" (From the Oral History of Patrick D. Wall, 1993). In Pain Mechanisms: A New Theory, Melzack and Wall
traced the history of the specific pain pathway back to the 16th century philosopher Rene Descartes's idea of
"pulling on a thread. Gate control offered a new heuristic for pain research, one which integrated
experimental and clinical observations, and inspired many young scientists to begin work on the problem.
Although the model has been much revised since 1965, the idea of the modulation of pain perception within
the nervous system continues to be central to pain studies.

The young anesthesiologist John J. Bonica (1917-1994), assigned to take charge of pain control at Madigan
Army Hospital in Washington State in 1944, found himself seeing "cases that baffled me." He sent the
patients for consultations with colleagues: an orthopedist, a neurosurgeon, a psychiatrist, but "they knew less
than I did." He proposed that the four meet twice a week at lunch for conversation and exchange of
information on difficult pain problems.

The success of this informal collaboration prompted him to establish a multidisciplinary pain clinic at Tacoma
General Hospital in 1947, which he brought to the University of Washington in 1960. Bonica saw the idea of
interdisciplinary collaboration as the key to the understanding of pain. He described his clinic as "a totally
different thing, much more fruitful and efficient. . . The basis of my program is patient care; the frosting is the
research."