Pain: Historical Perspectives

For more than 50,000 years, pain has been part of the human experience. Pain has had different meanings for different people. Likewise theories about the causes and mechanisms of pain reflect the state of knowledge of the societies devising the theories. In all ages pain has been a very real and immediate concern, but always the attitudes and responses of people have been shaped by magical, demonological, theological, philosophical, and practical influences in varying degrees and with shifting emphasis. It is our purpose to capture and examine some of these changing interpretations of pain through time.

Pain as a specific object of scientific inquiry was unrecognized until the early modern era. Attention was paid instead to illnesses and cures, anatomy and physiology. Until recently scientists sought a sensorium commune, an undetermined site somewhere in the body where the nature of pain would be revealed. However, in every language more than one word can refer to pain. Awareness of pain and suffering has been part of the feelings of compassion, sympathy, and forgiveness that serve to bond us with each other. Now, instead of looking for a locus for pain we are developing explanatory models that take into account contemporary knowledge of physiology, psychology, and technology.

As the hunter-gatherers migrated from northern African to Asia, Europe, and eventually the Americas, their small communities found ways to deal with the illnesses and accidents that occurred to people subject to environmental stress and human frailty. Wars and conflicts led to the development of curative potions and surgical techniques, some of which remain in use to this day. By performing rituals the communities appealed to their gods for help against their enemies, whether human or natural. The people appointed members of their groups to become proficient in the ways that would satisfy their gods and help individuals feel less pain. These early communities used heat and cold, mud packs and poetics, intoxicants and analgesics, simple techniques of extracting foreign bodies, and bone-setting procedures to deal with pain. They also had trephinations and ceremonial mutilations such as circumcisions, castrations, and piercing operations that suggest well established surgical skills.1

Evidence of their practice remains in fossils, carvings and cave paintings, and primitive tools. In the fertile crescent of land between the Euphrates and Tigris rivers known as Mesopotamia, a practical system of writing was first invented. The Code of Hammurabi portrays the expectations for a stable and organized society in which medical practice relied on omens, divination, and astrology. It was eminently safer to diagnose and treat in accordance with revelations conjured out of livers and other entrails of sacrificed animals than to rely on surgical skills, for it was expressly stated in the Code: “If a surgeon has opened an eye infection with a bronze instrument and so saved the man’s eye, he shall take ten shekels. If a surgeon has opened an eye infection with a bronze instrument and thereby destroyed the man’s eye, they shall cut off his hand.” Scientific medicine was a descriptive art that designated the heart as the seat of intelligence; the liver, of emotion; the uterus, of compassion; and the stomach, of cunning.2 Disease was a punishment for bad behavior. Sacrifice and prayer were required to atone for these transgressions. Pain therefore was a sign with multiple meanings. It indicated that a person was suffering, yet may or may not deserve sympathy and assistance, depending on the cause of the pain. Injuries were treated, whereas internal pain might be a result of the “intrusion” of spirits or the “withdrawal” of life-sapping forces.3

As people migrated throughout the world, they settled in fertile valleys at the mouths of great waterways. Their small groups evolved into civilized societies. Under the growing stimulus of accumulating knowledge and technology, medicine flourished in early settlements along the Nile, Indus, and Yangtze and Hwang Ho rivers.

Egypt

Because of their ability to transform reeds into papyri and make stable dyes and inks, the Egyptians were able to pass on their medical practices, as seen in the Beers, Berlin, and Edwin Smith papyri. These writings give only a fragmented glimpse, but clearly reveal little cameos of medical practice.4 A rational empiricism is exhibited in the therapeutic decisions of the Edwin Smith papyrus, copied by scribes in the sixteenth century bc from earlier medical writings ascribed to the era of Imhotep of the Third Dynasty. Imhotep built pyramids and was the “blameless physician” whose apotheosis later served as the prototype for the Greek deification of Asclepios.5

Unfortunately the high level of clinical competence shown by the Smith papyrus and the amazing spectrum of pharmaceutical knowledge of the Ebers manuscript were not sustained in later periods as Egyptian medicine declined under the growing influence of religious mysticism and demonology.6 The Egyptians’ concept of pain was a complex elaboration of the beliefs of early societies. Anthropomorphic spirits of the dead with sinister intent to cause pain were dispatched by the gods and other forces of darkness into human orifices or through pores to wreck havoc within. The left nostril was a favorite portal of entry.

Despite the mystical explanations for pain, the Egyptians attempted to develop anatomical and physiological models as well. Their society did not forbid human dissection, which reached its highest expression in the masterful works of morticians rather than physicians. The former were a secretive group who did not broadcast their techniques but left only their products for our edification. Nevertheless, there are numerous references in the papyri from which we may draw reasonable assumptions.

The brain was totally ignored as a vital organ, although paresis of the opposite side of the body resulting from head injury is described in the Smith papyrus.6 The brain was the one organ destroyed or discarded in the embalming process, which more or less signifies the esteem it engendered. The Egyptians elevated the heart to a state of preeminence over all organs. With its vessels reaching out into all areas, the heart was credited with being the seat of all motor and sensory activity. There was no knowledge of a nervous system. The heart and its vessels were believed to serve these functions, which included the appreciation of pain from obvious causes such as gross injury, although the anatomic references are often intermingled with confusing mystical associations.7

India

Unlike ancient civilizations that enjoyed a prominent moment in history and then faded into obscurity, those that arose along the waters of the Indus and in the river valleys of China have endured and have projected many of their ancient medical practices into the present. In both countries, anesthetic techniques and analgesics were old when western practices were new.

The oldest of the sacred books of India, the Rig-Veda, reputedly written as far back as 4000 bc, describes hundreds of methods deriving from mineral, plant, and animal sources, including anesthetics and analgesics still in use. Practical healing and vigorous therapeutic measures ranging through a versatile surgical repertory culminated in Susruta, the great physician and surgeon who lived about 600 bc. It was a time when disease had a locus in anatomy, and physiologic explanations aided in the diagnosis of disturbed function. A crude concept of the nervous system centered on the heart, from which ducts radiated to all sensory organs and all excitable parts. Susruta’s writings reflect some awareness of pain pathways connected with this misconceived center.8 The advent of buddhism in the fifth century bc cast a pall over scientific discovery and directed medical thinking into spiritual channels. Physiologic phenomena were unreal and pain was denied existence. The slow, steady crawl of scientific progress in anatomic matters was abruptly arrested by religious dogma just as it seemed poised on the threshold of new adventure, and the creative energies of Indian medicine were diverted to other interests.9

China

From very early times the Chinese viewed the human predicament as a microcosm of the harmonious universe. Harmony prevailed in life when the polarity of yang and yin was in proper balance. Nei Ching, the Chinese canon of medicine, reflects the very ancient concern with maintaining a state of equilibrium between opposing forces. There is no clear distinction between mythology and historical reality in these writings, and mystical numerology, remindful of Pythagorean precepts, strongly influences an oversystematized medical taxonomy.10 Yang represents maleness, light, heat, aggressiveness, and strength, whereas yin exemplifies femaleness, darkness, cold, passivity, and weakness. There are five elements in nature (earth, water, fire, wood, and metal), five organs in the body (heart, lungs, liver, spleen, and kidneys), and five winds that inhabit the arteries. Natural laws regulating the universe also participate in the functioning of human physiology as reflected in the forces of yang and yin. The brain is simply the marrow of the skull, playing no part in vital activities. The heart is the major organ because it is the storehouse of the blood and airs. It contains the vital energy and intelligence that circulate to all areas, announcing the state of health of the body in a variety of pulses. Clinical practice depends on an astute appreciation of subtle messages conveyed in these pulsations. There are 365 parts of the body, and each has a precise focal representation so important to the therapeutic arts of moxibustion and acupuncture.

Pain has no particular center, but disturbance in yang or yin, especially excesses of heat or cold, usually relate to the heart and vessels. Emotional overindulgence upsets yang or yin and begets pain in the particular organ allotted the psychologic function involved. Rage upsets yin in the liver, and violent joy is hurtful to yang in the heart. Excessive grief disturbs the lung, and evil thoughts provoke the spleen. “Moderation in all things” obviously was as important to yang and yin as it was to healthy coexistence of mind and body in Hellenic Greece.7 The anatomy of pain had a situational, multifocal orientation for ancient China, leading to therapeutic responses practiced today throughout the world.

Greek ideas in medicine, as in art, architecture, astronomy, literature, and philosophy, still excite and exalt us. Pain-relieving drugs and healing arts are woven into the fabric of Homeric legend and Greek mythology, from which Greek medicine originated. Mythology and legend provided a strong base for early medical practice in other ancient societies as well, but the Greek emphasis on individual achievement allowed creative thinkers to emerge from anonymity.7

Greek tragedy of the fifth century bc teaches us not only about pain but also about suffering in the most physical and blunt way. The presence of a person in pain, badly wounded and shattered, added to the truth of the story. Euripedes had Hippolytus come back on stage suffering after his frenzied attempts to escape a bull that had risen from the sea. Greek society participated in theater as a matter of course that was both civil and religious. It accepted pain as an explicit part of everyday life.11

Greek science began at about the same time in the sixth century bc in Ionia. As in the Greek theater, the line between mythology and history became more distinct. In science, myth and religious dogma yielded to rational natural laws. The legacy of Thales (624–545 bc) and his philosophical colleagues was a new, open-minded world view that filtered down from philosophy to science and ignited an intellectual explosion that reverberated through time and space into every aspect of human inquiry. The first great medical figure was Alcmaeon (c. 500 bc) of Croton. Alcmaeon was a student and disciple of Pythagoras (566–497 bc), the mystic numerologist and patron saint of theoretical science. Pythagoras had already established a brotherhood and center for the arts and science in this ancient Greek colony at the southern tip of the Italian peninsula, when Alcmaeon added his medical school. Relying on the findings of animal dissection, Alcmaeon elaborated a theory of sensation that had the brain as its center. He postulated a mechanism of consciousness dependent on variations in cerebral circulation for sleep and wakefulness. His concept of the nervous system consisted of a network of ducts and vessels carrying sensation in the form of particles of elements that invaded the body through several sensory organs to the sensorium in the brain.9 The views of Alcmaeon, an early empiricist, were neglected by the rationalist society that preferred the more noble mental gymnastics of Plato and Aristotle in physiology to the results of vulgar dissection.

However, there were other empiricists practicing in the fourth century bc. Democritus (460–362 bc), who taught that all matter was composed of ever-changing atoms of the elements of fire, air, earth, and water, applied this theory to sensation and pain. Sensation was a state of awareness of the soul occasioned when elementary particles invaded the body’s pores and ducts. The size, shape, and movement of particles determined the nature of the perception. Thus, pain was an intrusion of sharp-hooked particles in a state of agitated motion disturbing the normal calm of the soul atoms. Democritus scattered body and soul atoms over a universe in which life and death did not exist, where everything was always changing and only the total quality of matter remained constant. He did concede that the center of reason and consciousness was in the brain; emotions, in the heart; and lust, in the liver.3

The Hippocratic Corpus reflects the medical spirit and methods of the physician Hippocrates (c. 460–360 bc) of Cos. Hippocratic medicine was practical and rational, stressing an expectant attitude while trusting in the marvelous healing power of nature.2 Anatomy was rudimentary, and physiology was based on a proper balance of the four elements, the four qualities (hot, cold, moist, dry), and the four humors present in every body. Pain was a manifestation of conditions disturbing the natural state of equilibrium in the healthy body. The brain was considered some sort of gland that excreted mucous matter that played a part in regulating body heat. With his disciples, Hippocrates paid considerable attention to the problem of pain, continually seeking effective measures for easing human suffering at the clinical level. They experimented with drugs, including opium, mandrake, and hemlock, and actively employed cooling techniques and physiotherapy. To ease the pain of surgery, they sometimes produced unconsciousness by compressing the carotid arteries, the name deriving from Karoun, the Greek word for deep sleep. Always stressing moderation, Hippocrates cautioned his students and colleagues to observe carefully, proceed slowly, and exercise restraint in treatment, a philosophy expounded in his aphorism “First do no harm.”7,12,13

In contrast to the pragmatic and empirical approach of Hippocrates, who used methods that remain familiar, the speculative physiology of Plato (427–347 bc), lacking the necessary substratum of anatomy, as with all Greeks since Alcmaeon, frequently appears obscure to the contemporary reader. In Timaeus, Plato presents a model of the brain and mind. The fundamental blending of mortal body with immortal soul entails a rather complicated commotion of atoms and elements in relation to a percipient soul scattered among a multiplicity of organs.7 Pain is perceived by the soul in its several sites from the intrusion of the four elements, streaming into the body from without in disharmonious and violent motions.

Aristotle (384–322 bc), son of a physician, was uninterested in medicine but nevertheless able to write on biology. There is no reference to human dissection in his works, which deal exclusively with the comparative anatomy of animals. A teleological point of view permeates his thinking on structure and function. De Partibus Animalius, his major physiological treatise, reiterates the premise that everything has a design or purpose. It sometimes is difficult to reconcile the exquisitely detailed differentiations of form and function in his comparative anatomy with this mistaken ideas concerning the brain and heart. For Aristotle the heart was the seat of intelligence, emotion, and sensation; the brain was a thermostatic sponge that cooled the heart to prevent overheating. Vital heat in the heart’s blood controlled sensitivity to pain. Flesh was the end organ from which pain sensation was conveyed by blood vessels to the heart, where it was perceived and dealt with in accordance with the heart’s enormous proclivities for regulating reception and response. Aristotle compounded his mistake about the function of the heart and brain by coining the term sensorium commune, which implied a unitary theory and site for pain.

Aristotle died in 322 bc. His theories influenced the Romans, including Galen, as well as religious philosophers of the Middle Ages such as Aquinas. The powerful effect of his prodigious output in all fields of knowledge gave his works a force of dogma that misdirected physiologic research for 2,000 years.3,7,9

Alexandria

Alexander the Great was Aristotle’s most famous student. He died in 323 bc, a year before his teacher, at the age of 35. In 322 bc, he founded the city of Alexandria on the Nile River delta. Under the suzerainty of Ptolemy, a spirit of free inquiry drew scholars from all over the world. Ptolemy’s successors became the new dynasty of Egypt. They built museums and a library, which in the early second century bc had over 500,000 volumes, the largest collection in the ancient world. Mind and technical skills were united for intensive study of the human body in health and disease. The practice of human dissection in preconfucian China and prebuddist India had never progressed to a level of fruitful revelation. Meaningful study of pain and discovery of a functioning nervous system were not possible under conducive circumstances.11

Drawn to Alexandria by the inviting intellectual climate, Herophilus (315–280 bc) of Chalcedon was the first great talent to address these problems. His extensive anatomic dissections on human cadavers identified the brain as the seat of motor and sensory function. He clearly distinguished between nerves and arteries and traced the course of nerves to and from the brain and spinal cord. Moreover, he recognized the function of these nerves in motor and sensory activities. His laboratory findings led him to speculate on the site of the soul; he placed it in the fourth ventricle.13–15 These original observations were first challenged, then brilliantly expanded, a generation later by Erasistratus (310–250 bc) of Cheos. Erasistratus went into great detail describing and differentiating the cerebrum and cerebellum with their deep-lying system of ventricles and connecting foramina. He differed with Herophilus on the proper dwelling for the soul, placing it somewhere in the cerebellum. He commented on the rich convolutions seen in the development of the human brain and hypothesized as an association with intellectual capacity. He noted the constant tripartite company of artery, vein, and nerve along pathways to subservient organs and other discrete anatomic parts. He identified the heart as a central pump propelling blood and air to all parts of the body and discredited it as a sensory organ.3,9,15

After Cleopatra’s death in 31 bc, the Roman Emperor Augustus took over Alexandria. The city soon competed with Constantinople for the trade of the eastern Roman Empire. The major museum and most of the library was burned in ad 270 in a civil disturbance. In 391, the Roman Emperor Theodosius I ordered the library to be sacked again. Any remaining parts were destroyed in 640 by the Muslims under Caliph Umar I.11

All the original texts of these great contributors have disappeared. Fragmentary accounts from Galen and other diverse sources have justified the recognition of Herophilus as the father of human anatomy and of Erasistratus as the founder of experimental physiology. Celsus, the encyclopedist of the early Empire recounted their practical interests in pain:3,9

Moreover, as pain and also various kinds of disease arise in the internal parts, they hold that no one can apply remedies for these who are ignorant of the parts themselves: hence it becomes necessary to lay open bodies of the dead and to scrutinize their viscera and intestines . . for when pain occurs internally, it is not possible for one to learn what hurts the patient unless he has acquainted himself with the position of each organ or intestine; nor can a diseased portion of the body be treated by one who does not know what that part is.

Centuries would pass before these ideas would gain any significant recognition.

Rome

During the early years of Rome, people appeared to be unimpressed by the development of medical science in other parts of the world. Pain was something to be borne with magnanimity and stoic indifference, as is usually characteristic of the warrior mentality. For hundreds of years, ancient herbal lore and prayers or incantations to a variety of household gods served the Romans’ unpretentious medical requirements. As the Roman legions spread out over the known world, the culture and finer representations of the conquered were preserved and absorbed. Greek medical arts were part of the bounty, and although the Romans never exhibited an enthusiasm to participate, they did often encourage and actively patronize some of the more gifted Greek practitioners. In a long poem, “De Rerum Natura,” Lucretius (97–54 bc), an Epicurean disciple, brought a wide spectrum of Greek science to the attention of literate Romans. His physiology of pain, based on the atomic theories of Democritus, stimulated considerable interest despite the Romans’ preference for pragmatic action.15 They were also content with compilation and commentary as so admirably demonstrated by the works of Celsus (ad ?–100) and Pliny the elder (23–79). It remained for Galen (130–200), a Greek physician from Pergamon, to rescue the grand achievements of the Alexandrians and to restore the concept of a central nervous system to explain the physiology of sensation.

Animal dissection supplemented by practical observations in his role as surgeon to the gladiators led Galen to much personal theorizing about psychological mechanisms. It is not possible to distinguish his own opinions from the knowledge he acquired from Herophilus and Erasistratus, but his systematized organization of data had a compelling ring of authority that appealed to church fathers, who later attached the stamp of dogma to his work. Galen’s experiments on the spinal cord and peripheral nerves were richly rewarding in providing new information about motor and sensory enervation. He concluded that pain was the lowest form of conscious sensation, caused either by dissolution of continuity in tissues (cuts, burns, overdistention of hollow viscera) or by sudden violent commotion in the humors (pressure and tension). Unfortunately, Galen’s physiology was contaminated by Aristotelian teleological influences. Instead of attempting to ascertain how organs and systems functioned, he sought to determine why, and this led his reasoning off in unusual directions. His doctrine of Vitalism, his belief in the transmission of blood from right to left heart through invisible pores, and his concept of suppuration as an essential part of healing sent medical theory off in a centuries-long digression, yet his fruitful experimental physiology, his excellent anatomic descriptions, and his encyclopedic records of the knowledge of his time far outweighed his errors. Roman medicine died with Galen.12,15,16

The Roman Empire in the west ended in 476 when a mercenary army sacked the city of Rome, setting up centuries of political and economic chaos, wars, and famine.17 From its establishment in 330 to its fall in 1453, Constantinople served as a junction between Graeco-Roman culture and the civilizations of the east. Christian beliefs about pain supplanted classical views in the west, while in the cities of Baghdad, Antioch, and Gunde-Shapur in Persia, Islam influenced Arab medicine.

After all the invasions of the barbarian hordes, famine, plagues, and economic chaos, the people of western Europe made Christianity the rallying force that restored some promise of salvation, but its triumph was a defeat for science. Physiologic experimentation died under the force of church dogma that brooked no threat of challenge or contradiction. Pain was perceived in Christian doctrine as a means of purification and redemption; the sufferings of Christ had endowed it with a touch of divinity. Mystical attitudes toward pain promoted martyrdom and gave voluntary suffering an exalted aura of spiritual beauty.18 Nature could never be questioned for its secrets. Medieval philosophers were restricted under the ban of authority to seek truth through logical deduction. The monastic library replaced the laboratory as the source of discovery. Individual monks could make up their own herbal remedies for the patients treated in the villages and towns near the monasteries and cathedrals.19–22

To Gunde-Shapur and other cities in Persia fled refugee scholars attracted by an enthusiastic climated for learning and the generous patronage of the ruling class. Hindu, Chinese, and Persian influences blended with surviving vestiges of ancient near eastern cultures gathered by Jewish and Syrian scholars. This selective corpus of knowledge was richly expanded by Greek and Roman remnants brought by the Nestorians after they were expelled from Edessa in 489. In 529, the year of the founding of the Benedictine Monte Cassino monastery, the Greek Academy was closed by the Emperor Justinian because of its pagan teachings. Many of its teachers escaped to Persia with priceless treasures of Greek learning that would otherwise most certainly have been destroyed. Much of the basic knowledge of the anatomy and physiology of pain was preserved because of the fortuitous coincidence of time and place that made such a magnificent reservoir possible. The miracle is compounded by the subsequent series of events.

After the death in 632 of Mohammed, Muslim armies poured out of the Saudi Arabian desert and conquered all before them in the name of Allah. These religious warriors carried their message triumphantly into Persia and India, and paradoxically exhibited a merciful regard for preserving the culture and properties of the conquered in deference to the veneration for knowledge and learning that their prophet preached. The true greatness of Mohammed is best exemplified in the Islamic doctrine: “Science lights the path to paradise. Take ye knowledge even from the lips of the infidel. The ink of the scholar is more holy than the blood of the martyr.” This statement was the grounding precept for the preservation of antiquity. Islamic centers of learning gathered scholars of all faiths and ethnic backgrounds. The school of medicine founded by the Nestorians in Gunde-Shapur was the first of many spread out over the Arab world, and science flourished. Ancient Greek and Latin texts were translated by Jewish and Syriac philologists into Syriac and Hebrew, and later into Arabic.

Persian centers dominated in the early years of Islam with new developments in chemistry and pharmacology and with the emergence of great medical writers. Al Rhazi (860–932) wrote extensively, elaborating on ancient ideas and contributing new ones. The most influential physician was another Persian: Avicenna, or Ibn Sina (980–1063). His medical textbook, the Canon, exercised a persuasive influence over medical practice for centuries. Avicenna’s notions of pain were drawn from his encyclopedic knowledge of Hippocrates, Aristotle, Galen, and Nemesius, a fourth-century Syrian. He recognized 15 varieties of pain produced by humoral changes that disturbed the natural state of things in the body. Not satisfied with the vague cerebral sensory centers of Galen, he followed the lead of Herophilus, who advocated a fourth-ventricle localization, but Avicenna distributed the sites more generously through the ventricles as suggested by Nemesius. From an extensive Arab pharmaceutical lore he extracted three groups of medicinals for relief of pain: those contrary to the cause, those that exert a soothing effect, and those that have anesthetic properties. Opium, herbage, and mandrake were liberally prescribed.23

By the eleventh century, the scientific and medical leadership had shifted westward to the Moorish capitals on the Iberian peninsula, now Spain. It was largely dominated by Jewish scholars who reached great heights in medicine and philosophy under Islam. Jewish medicine, and pain treatment in particular, was basically rational, practical, and highly effective. With the creative energies of Islam exhausted, the decline of Moorish capitals coincided with a corresponding reawakening of long-dormant cultural interests in western Europe, initially in Italy.3,9,24,25

The fourteenth and fifteenth centuries were a pivotal period in the development of Western civilization. Italian merchants and bankers had long traded with merchants from Persia and Constantinople despite their religious differences. Surrounding the cosmopolitan Mediterranean cities were the feudal states of northern Europe and the Mongol hordes of western Asia. Encouraged by the medieval popes, feudal princes led Crusades to Jerusalem to prevent its takeover by Moslems. Although the Crusaders failed in their goal, they did strengthen the authority and organization of the secular states. Meanwhile, the papacy’s authority was weakened by a series of schisms and rivalries.26 Some Christians appeared to become more interested in sanctity and piety, and in finding ways in which they could ensure their place in heaven. Others found the practice of acquiring indulgences offensive. In 1517 Martin Luther, a priest who was professor of theology at the University of Wittenberg, published his Ninety-five Theses. He allegedly nailed them on the door of the Castle Church in Wittenberg.

Instead of looking for miracles and good works, Luther believed that people had it within themselves to achieve goodness. Luther’s doctrines and the subsequent Reformation are relevant to the history of pain because they helped to change peoples’ orientation about themselves. Individuals became objects worthy of study.

Luther noted in his Theses that people were buying indulgences to help finance the construction of St. Peter’s in Rome. Italian Renaissance artists were not only painting religious frescoes and designing cathedrals, they also were changing how they were painting by adding a harmonious coordination of perspective, movement, and color. The people of the Renaissance were living in a period of excitement, for they had survived the plague that swept through Italy in the fourteenth century.27,28

While the Chinese fleet was retreating from the Indian and Pacific oceans, explorers from western Europe sailed the Atlantic. The invention of printing most advantageously facilitated communication, as navigation broadened geographic perspectives. After the fall of Constantinople in 1453, fleeing Greek scholars fanned out over Europe to give the humanist movement the necessary impetus. A closer intermingling of the arts and sciences provided mutual benefits. Interest of the legal profession in autopsies spurred the revival of human dissection, which in turn was raised to a higher plane by the involvement of physicians in art and of artists in dissection. Berengarius, Vesalius, and Eustachious were notable anatomists with uncommon artistic skills, and of course Leonardo da Vinci was a skilled dissector whose great original anatomic discoveries and physiologic speculations were mislaid for centuries. Leonardo’s extensive dissections on cadavers were conducted in secrecy for a very practical reason: survival. The specter of heresy still muted the creative urge. Leonardo’s dissections focused on the ventricles, brainstem, and spinal cord. He also left voluminous notes on peripheral nerves and their functions. He described but did not recognize the significance of the sympathetic nervous system or the reflex arc. Experimenting with frogs, he found persisting sensations and motion after decerebration, but almost instant death when he pithed the medulla. He concluded that it must be the site of the soul. He regarded pain as a component or particularly intense aspect of the sensation of touch. His animal experiments included sensory mapping of anesthetic areas produced by cutting specific nerves. From these investigations he was motivated to speculate on the selective protectiveness of pain in vital areas.3,19,29,30

A more open and audacious anatomist was Vesalius, a Belgian lured to Padua by its superior facilities and academic opportunities, whose masterful technique and original, inquiring mind unmasked the absurdities of Galenic animal dissections. His great work, De Humani Corporis Fabrica (1543), brilliantly illustrated by woodcuts of Von Kalcar and superbly printed by Oporinus at Basle, is one the priceless treasures of the Renaissance. He brazenly refuted many established anatomic misconceptions and paid the price in character assassination and exile. No less beautiful in design or accurate in detail are the exquisite copper plates of Eustachius, which, possibly because of the fate of Vesalius, remained unprinted until recovered from the Vatican library 162 years later.20

Religious proscriptions put an effective damper on the employment of pain-relieving drugs, although sporadic accounts of their use appear in the literature. Paracelsus rediscovered ether, the “sweet vitriol” of Ramon Lullus, when he mixed sulfuric acid and alcohol, and he was aware of its sleep-inducing qualities. Surgeons were known to use soporific sponges, and physicians were well acquainted with the narcotic effects of opium, but these were the dangerous times of the Inquisition and Counter-Reformation. Pain was considered an instance of God’s will, and the stake loomed as a threat to those who would ally themselves with the devil’s work. Kings could “lay on hands” to accomplish miraculous cures; the lowly practitioner had to avoid the inquisitors of witchcraft and heresy.31 Nevertheless, carotid compression anesthesia was used by Ambroise Pare. Snow packs and other cold applications were used for local anesthesia, and a small rebellious group, taking courage from the writings and example of Paracelsus, used atropine, belladonna, mandrake, and a host of medicinals for pain, as described in the splendid pharmaceutical books of Cordus and others.3,9

In the seventeenth century the chain of events initiated by Copernicus and substantially implemented by Kepler and Galileo culminated in the synthesis of Newton to complete the scientific revolution. A rash of attempts to systematize all fields of knowledge then appeared. Efforts to demonstrate a system of medicine reflecting the same order as Newton’s universe approached the ludicrous. The mysteries of the central nervous system remained unresolved, but contributions of enormous consequence were made in anatomy and physiology. However, it was not until 1800,when Bell and Magendie defined the roles of the anterior and posterior nerve roots, that pain physiology could step beyond the advances made by the ancient Alexandrians. Meanwhile the foundation was established as scientific methodology and equipment were invented.

Francis Bacon has been credited with devising the experimental method, and criticized for emphasizing the mechanical and technical over the theoretical parts of science. The Royal Society in England and other scientific societies were founded and journals printed. In 1628 William Harvey’s (1578–1657) De Motu Cordis was published. It was as important for physiology as the Fabrica was for anatomy. Not only was the circulation of the blood proven by morphologic, experimental, and mathematical arguments, but physiology itself was elevated on the strengths of this discovery to the status of a dynamic science. Harvey’s genius for inductive reasoning did not sustain him when he ventured into the realm of sensation, where his Aristotelian indoctrination misled him to view the circulating blood as the abode of the soul and the heart as the center of sensation and the seat of all natural motion.

Medieval mysticism continued to exert a crippling influence on scientific thought well into the next century. Iatrochemists made notable contributions to physiology and added to our comprehension of pain while introducing considerable confusion with their mysterious archeus, or spirit forces that governed bodily functions. Von Helmont (1577–1649), a follower of Paracelsus, was so fascinated by the stomach in his original studies on digestion that he made it the dominant organ of the body and resting place of the soul, holding dominion over consciousness, emotion, and pain. Despite the confusing superimposition of the spirits on physiologic systems, the iatrochemists were the first to introduce the idea of a physical transmission of nerve impulses in motor and sensory processes.3

By deducing cogito, ergo sum Rene Descartes (1596–1650) introduced the mind-body controversy that has bedeviled philosophers and scientists for over 300 years. In 1644, he suggested that the pain system resembled an alarm-bell mechanism. For example, a flame sets particles in the foot into activity, and the motion is sent up the leg and back into the head, where some sort of signal is set off. The person then feels the pain and responds to it. Descartes thus proposed what became the traditional theory of pain, or scientific theory. In De Homine (1662), he demonstrated a physiology derived from Galen. Impressed by the delicately poised central position of the pineal gland, he made it the site of the soul and had his sensory-motor response mechanism operate from it.32 Cartesian dualism has led to models of the mind that compete with the theoretical constructs of neurophysiology to explain how we experience pain.

Until the end of the eighteenth century, scientists continued the work of their predecessors. They incorporated Newtonian concepts of energy and momentum into their theoretical models, which tended to follow the system proposed by Descartes. Meanwhile Descartes, through his meditations, came to devalue the senses and to attribute all thought and creativity to the mind. His viewpoint came to be debated well into the twentieth century. British empiricists, including John Locke and David Hume, questioned whether any knowledge could be accepted on the basis of introspective evidence. Sensory ideas were the only reliable source of knowledge. Locke described the process of how words came to stand for ideas, which grew out of sensory experience. He then posited a person who could, through reason and reflection, generalize from these ideas rather than from a simple comparison with experience, as had Descartes.

Hume was skeptical about whether there was any causal link between ideas and generalizations; he could only assume that in the future the same pattern would repeat. For Hume the mind was an abstract name for a series of ideas. Before long the central premise of epistemological discussions was that our conceptual apparatus was built up from qualities perceived in the outside world, just as models for pain were set up.

Kant, in his Critique of Pure Reason (1781), attempted to synthesize the empiricist and rationalist schools by suggesting that there was knowledge that existed a priori and was only waiting to be discovered. The person coordinated sensations and ideas into a coherent body of knowledge. Kant doubted that a science of psychology was possible because the mind was affected by studying itself, was impossible to map, and could not have a mathematical basis. His viewpoint was seriously challenged in the next century by developments in statistics and mathematical logic. Russell and the British school of analytical philosophy attempted to clarify how we perceive and use our senses; Wittgenstein challenged them in his Philosophical Investigations of language.33–35

Meanwhile Willis, Borelli, Malpighi, von Haller, and others made significant progress in researching the central nervous system, while Winslow and others described the anatomy and physiology of the autonomic nervous system. By the end of the eighteenth century, new methods of analgesia were started with Priestley’s discovery of nitrous oxide and Sir Humphrey Davy’s observation of the analgesic properties of the gas. In 1806, Serturner isolated morphine from crude opium. Refining the technique of getting pure crystalline drugs from crude mixtures led to the isolation of codeine in 1832. In 1828, Leroux reported the isolation of saline, and Wohler the synthesis of urea. By 1897, Bayer chemist Felix Hoffman developed a stable form of this compound found in willow tree bark or meadow grasses, which was called acetylsalicylic acid.30

Ether, made from sulfuric acid and alcohol, had long been used as a sedative in the treatment of tuberculosis, asthma, and whooping cough, and as a remedy for toothache. William T.G. Morton (1819–1868), a dentist interested in new ideas, revolutionized surgical and medical practice by demonstrating surgery under ether anesthesia at the Massachusetts General Hospital in Boston in 1846. Seeking to find an alternative to ether, which had an unpleasant smell and occasionally needed to be used in large amounts especially in prolonged labor, James Young Simpson (1811–1870), a professor of midwifery at Edinburgh, found chloroform to be efficacious and relatively safe. After Queen Victoria was anesthetized in 1853 for the birth of Prince Leopold and in 1857 for Princess Beatrice, the practice became common among the upper and middle classes. In the 1850s Charles Gabriel Pravaz (1791–1853), a French surgeon, and Alexander Wood (1817–1884) of Edinburgh independently invented the syringe. Injections of morphine were used for local pain. In 1884, Karl Koller demonstrated the local anesthetic efficacy of cocaine.36

By the 1880s, anesthesia with aseptic technique was standard practice in American and European operating rooms. Middle-class patients who usually had been treated at home now sought admission to hospitals for operations. Hospitals were transformed from charitable asylums for the poor into service institutions that were also teaching resources. Neurologists and psychiatrists now had patients whom they could observe for the clinical validity of the theories of pain developed during the century.

In the early nineteenth century the work of Charles Bell and Francois Magendie showed that the posterior roots of the spinal nerves responded to sensations, whereas the anterior roots were associated with motor responses. This idea of specific neural pathways for pain was elaborated in 1839 by Johannes Muller’s theory of “specific nerve energies.” Muller (1801–1858), a professor at Berlin, suggested that the same cause, such as electricity, could simultaneously affect all sensory organs, yet the kind of sensation would be different in each. Muller at first was uncertain if the sensation was owing to energy inherent in the sensory nerves themselves or to special properties at the site of termination in the brain. By the end of the century, it was concluded that the quality of sensation was given by the termination of the nerves in the brain.32

Each sensory nerve then was assumed to have a distinct brain center. Between 1894 and 1895, Max von Frey published a series of articles about a theory of cutaneous senses that became the basis for contemporary specificity theory. He expanded Muller’s concept to four major cutaneous modalities: touch, warmth, cold, and pain. His work was based on Schiff’s experiments in animals in 1858. Schiff noted that the effects of incisions in the spinal cord suggested that pain and touch were independent. Experiments by Funk in 1879 and by Blix, Goldscheider, and Donaldson in 1882 found separate spots for warmth, cold, and touch.23,32

Eventually a search for the “pain pathway” in the spinal cord was made. Experiments with animal subjects suggested that the anterolateral quadrant of the spinal cord was critically important for pain sensation. Spiller observed that a man with a lesion in this area was analgesic in part of his body below the level of the lesion, and persuaded Martin, a neurosurgeon, to cut the anterolateral spinal cord in patients who suffered pain. Anterolateral cordotomy for pain relief appeared successful, and the spinothalamic trace came to be known as the “pain pathway.” Head in 1920 proposed that the “pain center” was located in the thalamus because cortical lesions or excisions rarely abolish pain and can make it worse. Critics of the specificity theory pointed to pathologic pain states such as phantom limb, causalgia, and the neuralgias as phenomena not covered by the theory.32,37

An alternative to the specificity theory was the intensive (summation) theory that Erb explicitly formulated in 1874. He maintained that every sensory stimulus could produce pain if it reached sufficient intensity. The theory was supported by Wundt, Blix, and especially Goldscheider. Goldscheider at first favored specificity, but by 1894, he thought that stimulus intensity and central summation were the critical determinants of pain. Pain occurs when either the total output of cells exceeds a critical level because of the excessive stimulation of nonnoxious thermal or tactile stimuli or by pathologic conditions that enhance the summation of impulses produced by normally nonnoxious stimuli. Abnormally prolonged time periods of summation produced the long delays and persistent pain seen in pathologic pain states. The “summation path” that transmitted the signal to the brain consisted of slowly conducting, multisynaptic fiber chains, and the large fibers that project up the dorsal column pathways carried the tactile discrimination properties of cutaneous sensation.23,32,38

Goldscheider’s summation or pattern theory led to several modifications, which emphasize either peripheral or central mechanisms. In the peripheral pattern theory, pain is considered to be caused by excessive peripheral stimulation that produces a pattern of nerve impulses interpreted centrally as pain. Weddell and Sinclair, in 1955, based their theory on Nafe’s suggestion, in 1934, that all cutaneous qualities are produced by spatial and temporal patterns of nerve impulses rather than by separate, modality-specific transmission routes. The theory assumes that all fiber endings are alike, so that the pattern for pain is produced by intense stimulation. However, the physiologic evidence is that there is a high degree of receptor-fiber specialization.32,39–41

These peripheral-based theories still fail to account for the pathologic pain states, which suggest that some of their underlying mechanisms may be found in the central nervous system. Livingston first suggested specific central nervous system mechanisms to account for the summation phenomena in these pain syndromes. He proposed that pathologic stimulation of sensory nerves that occurs after peripheral nerve damage initiates activity in reverberatory circuits in neuron pools in the spinal cord. This abnormal activity, triggered by nonnoxious inputs, can then generate volleys of nerve impulses that are interpreted centrally as pain.42

Livingston’s general summation theory is especially powerful in explaining phantom limb pain. Amputation initiates abnormal firing patterns in closed, self-exciting neuron loops in the dorsal horns of the spinal cord, which send volleys of nerve impulses to the brain, giving rise to pain. Moreover, the reverberatory activity may spread to adjacent neurons in the lateral and ventral horns and produce autonomic and muscular manifestations in the limb, such as sweating and jerking movements of the stump. In turn these produce further sensory input, creating a “vicious cycle” between central and peripheral processes that maintain the abnormal spinal cord activity. Stress reactions and minor irritations near the site of the operation can then feed into the active site, keeping it in an abnormal, disturbed state over periods of years. Impulse patterns that would normally be interpreted as touch would trigger these neuron pools into greater activity, thus sending more messages to the brain to produce pain. Emotional activity could also trigger these neuron pools into greater activity and more pain. In 1951, Gerard proposed an alternative mechanism for the theory in which a peripheral nerve lesion could lead to a temporary loss of sensory control of firing in spinal cord neurons, which would then start to fire in synchrony, possibly due to the spread of electrical fields, and would recruit additional units as the group moved into gray matter.43

The theory could not account for the fact that surgical lesions in the dorsal horns should stop the pain. However, White and Sweet reported the return of phantom limb pain after cordotomy in 7 of 18 lower limb and 3 of 4 upper limb cases. Even bilateral cordotomy could fail.32 Efforts were made to find a leak in the pain projection system; a multisynaptic propriospinal system was suggested as an alternative by Noordenbos in 1959. Hebb, in 1949, proposed a central summation mechanism in which synchronized firing in the thalamocortical neural circuits provided the signal for pain. The loss of sensory control of the synchronized activities would lead to excessive synchronous firing in brain cells that would distort the normal cognitive and perceptual patterns. The distortion was pain.32,44,45

Similar to the central summation theories is sensory interaction theory, which holds that a specialized input-controlling mechanism that normally prevents summation from occurring can lead to pathologic pain states when it is destroyed. Melzack and Wall, in 1965, noted that this theory, which is derived from Goldscheider’s original concept, proposed the existence of a rapidly firing system that inhibited transmission in a more slowly conducting system that carried the signal for pain. These two systems were identified as the epicritic and protopathic (Head, 1920), fast and slow (Bishop, 1946), phylogentically old and new (Bishop, 1959), and myelinated and unmyelinated (Noordenbos, 1959) fiber systems.46 Noordenbos suggested a shift in the ratio of large to small fibers, arranged in a multisynaptic afferent system, which was a significant departure from the traditional direct system from peripheral neuron to brain.32

As the neurophysiologic research progressed, the philosophers were joined by other neurologists, psychologists, and psychiatrists who were exploring the affective and cognitive dimensions of pain. Freud set up a structural theory of the mind that incorporated the language of nineteenth-century science (i.e., instincts, drives, and energy). He proposed a pleasure principle as the driving force for human activity. Dreams expressed their dreamers’ wishes. When faced with examples of self-destructive or unpleasant experiences, he modified his theory so that there were two competing forces, eros and thanatos. Thanatos represented death, pain, and suffering.47,48 Later psychoanalysts replaced his drive theory for the structural theory of ego, superego, and id. Anna Freud proposed a number of defenses, such as sublimation and repression, that the ego used to deal with unacceptable feelings and thoughts.49 Repression could block a feeling from conscious awareness. Unconscious guilt then would be expressed through self-destructive behavior. Conversion pain symbolized a repressed, probably traumatic, incident. By the 1930s repressed affect was thought to underly psychosomatic illnesses. The pain of arthritis, colitis, and headaches was believed to be caused, in part, by the patient’s inability to express what was unacceptable, such as anger and anxiety. The task of therapy was to explore the basis for these unacceptable affects and then assist the patient to express, tolerate, and master them.50,51

Just as philosophy had empirical and rationalist schools, psychology had a behavioral alternative to psychoanalysis. Pavlov in Russia and then Skinner in proposed models of conditioning based on animal experiments that suggested that pain was accompanied by behaviors and thoughts that reinforced the pain. Because these were learned behaviors, treatment could help people in pain by providing them with ways of acting that were less likely to aggravate the pain.

Sherrington, in 1900, acknowledged that pain was composed of sensory and affective dimensions. He suggested that “mind rarely, probably never, perceives any object with absolute indifference, that is, without ‘feeling’ . . affective tone is an attribute of all sensation, and among the attribute tones of skin sensation was skin pain.” Pain was a primary sensation that had cognitive and emotional reactions.32,52 Hardy, Wolff, and Goodell, in the 1940s, called this model the fourth theory of pain. The perception of pain, like other sensations, was accomplished through “relatively simple and primitive” neural receptive and conductive mechanisms, whereas the “reaction pain threshold” was a complex physiopsychologic process involving the cognitive functions of the individual and influenced by past experience, culture, and psychological factors.53

In 1965, Melzack and Wall proposed the gate control theory, which would take into account the evidence of physiologic specialization, central summation, or patterning, and modulation of input, and the influence of psychological factors. A spinal gating mechanism in the dorsal horn was thought to modulate the transmission of nerve impulses from afferent fibers to the spinal cord T cells. Activity in larger diameter fibers tended to inhibit transmission; it closed the gate. Small fibers opened the gate. A “central control trigger” activated selective cognitive processes that influenced, by way of descending fibers, the spinal gating mechanism. This system carries precise information so rapidly that it not only could affect the receptivity of cortical neurons for subsequent afferent volleys but also, through the descending fibers, influence the sensory input at the segmental gate control system and at other levels of the neuraxis. The rapid transmission enables the brain to evaluate and codify the sensory input before the action system was activated. When the output of the spinal transmission (T) cells exceeded a critical level, the action system was activated. The action system was the complex sequence of behavior and experience characteristic of pain.

Melzack and Wall modified the theory three years later to take into account neural systems beyond the gate. They suggested that the neospinothalamic projecting system in the brain processed sensory discriminative information about the location, intensity, and duration of the stimulus, while impulses from the paleospinothalamic tract and paramedial ascending system activated reticular and limbic structures that provoke the aversive drive and unpleasant affect that triggers action in the organism. Neocortical central nervous system processes, such as evaluation of input based on past experience, exert control over discriminative and motivational systems.46 The gate control theory was a sophisticated mechanical model that reflected the legacy of Newtonian physics and suggested the limits of that system, because pathways could only account for part of the pain experience.

Improvement in the resolution capacity of electron microscopes and the development of advanced imaging techniques in radiology such as magnetic resonance imaging (MRI) signaled the transition from sequential models of pain such as the gate theory to concurrent and simultaneous models, which are based on neurotransmitters, reciprocal pathways, and the images of positron emission tomography (PET) and MRI scans. Wall modified the gate control theory in 1999 by suggesting that the brain analyses its sensory input in terms of the possible action that would be appropriate to the event that triggered the whole nocioceptive process. No action actually needs to take place.54

In the thirty years since the gate control theory was introduced, research has proceeded on the neuronal level. Enkephalins in the spinal cord and endorphins in the brain were discovered in the mid-1970s. Stimuli that elicited pain were thought to do so by releasing chemicals into the tissues. These chemical substances include histamine, bradykinin, prostaglandins, and potassium and sodium ions. In the dorsal horn, pain transmission occurs through the release of substance P, an 11-amino-acid peptide, present in dense core granules in the synaptic terminals of primary afferents in the dorsal horn. Substance P functions as a sensory neurotransmitter for the relay of pain signals to second-order neurons of the spinothalamic system. Enkephalin, an endogenous opioid peptide, is found in neurons of lamina II of the spinal cord dorsal horn and in the trigeminal nuclei of the brainstem. Electron microscopic studies showed that substance P neurons terminated on enkephalin-containing cells. The enkephalins and β-endorphin inhibit substance P release and thus block pain transmission at the level of the spinal cord and brainstem. Opiate receptors have also been found in the periaqueductal gray matter of the brainstem and in the medial thalamus, amygdaloid nuclei, caudate nuclei, and frontotemporal cortex. This distribution can account for the affective and antinocioceptive effects of opioid compounds.

Electrically stimulating the periaqueductal region can inhibit pain transmission by both ascending and descending effects. Descending pathways from large neurons of the brainstem reticular formation also modulate pain transmission at the dorsal horn. The descending pathways contain enkephalin, serotonin, and dopamine and terminate in laminae I and V of the dorsal horn. Other peptides, including angiotensin II and somatostatin, and the inhibitory neurotransmitters, γ-aminobutyric acid (GABA) and glycine, are also found in sensory neurons of the dorsal root ganglia and substantia gelatinosa.54,55

Many of these same neurotransmitters are found to be deficient in depression, anxiety, and psychotic states. Antidepressants act by increasing the cortical levels of neurotransmitters. The early excitement encouraged by the effectiveness of these medications on mood as well as on neuropathic pain has been tempered by the realization that there is no simple pathway to account for depression—just as pain is not the result of nocioceptive stimulation later interpreted by the cortex. However, as seen in patients who underwent prefrontal lobotomies to modify their affective behavior, response to pain was also changed. Patients displayed minimal concern and were not apparently troubled by painful stimuli, although they were able to report on the severity of the stimuli.

Advanced imaging techniques such as PET scanning highlight the simultaneous response to sensory stimuli. Among the earliest studies were those of the anterior cingulate gyrus, where activity was detected on the right side regardless of the site of the pain, including a single nerve neuropathy. This area also is active in directed visual and auditory attention, precise eye and hand movements, and complex speech. Cingulotomies have been performed on patients with treatment-refractory depression.

With the passage of time, the knowledge of pain and effective means for its alleviation increased quantitatively. A mass of overlapping data now await unscrambling and reorganization into a coherent theoretical structure for debate and application to our era. The puzzle is far from solved, especially now that the number of pieces has multiplied exponentially. To cast a glance at the past refreshed and assures us that we are not alone in our frustration. The task has always been arduous, and it is part of a tradition that has attracted the great minds of the past.