Edmond I Eger II, Lawrence J. Saidman and Rod N. Westhorpe (eds.)The Wondrous Story of Anesthesia10.1007/978-1-4614-8441-7_60
© Edmond I Eger, MD 2014
60. The Anesthesiologist and Pain: A Historical Memoir
Program on Pain Research, Education and Policy, Tufts University School of Medicine, 136 Harrison Avenue, 02111 Boston, MA, USA
Department of Anaesthesia and Pain Management, Royal North Shore Hospital, University of Sydney, Sydney, Australia
Daniel B. Carr (Corresponding author)
Michael J. Cousins
Pain has forever troubled humankind. Elucidation of nociceptive mechanisms and pathways, and appreciation of their diversity and adaptability, have been essential to understanding pain. Anesthesiologists have furthered such understanding and treatment, and advanced the appreciation of pain as a public health issue. During the twentieth century, the concepts of post-injury sensitization and hyperalgesia were developed, and the role of humoral mediators recognized. The 1950s saw the emergence of anesthesia departments, facilitating research into acute and chronic pain by specialists whose daily task originated with the elimination of pain during operations.
KeywordsAnesthesiologist and painPain and the anesthesiologistGate control theoryBeecher, HenryBonica, JohnAcute pain service historymultimodal analgesia
Pain has forever troubled humankind. Elucidation of nociceptive mechanisms and pathways, and appreciation of their diversity and adaptability, has been essential to understanding pain. Anesthesiologists have furthered such understanding and treatment, and advanced the appreciation of pain as a public health issue.
During the twentieth century, the concepts of post-injury sensitization and hyperalgesia were developed, and the role of humoral mediators recognized. The 1950s saw the emergence of anesthesia departments, facilitating research into acute and chronic pain by specialists whose daily task originated with the elimination of pain during operations.
Henry Beecher observed injured soldiers during World War II, noting that post-injury pain intensity and the dose of opioids needed to control their pain were both less than with comparable civilian injuries. He argued that the meaning of the injury, not the injuryper se, dictates the intensity of pain. In the 1960s, Melzack and Wall described the gate control theory, providing a neurological basis to Beecher’s concept. They proposed that rostral descending pathways modulate nociceptive afferent traffic at the spinal segmental level.
John Bonica pioneered pain advocacy, research and practice. His comprehensive 1953 monograph summarized available knowledge on pain. In 1973, he convened an international meeting that led to the formation of the International Association for the Study of Pain (IASP) and founding of the journalPain. Anesthesiologists were influential in widening the focus of IASP from chronic pain to acute and cancer pain. Recognition that physical, psychological and environmental factors play a key role in all pain and its treatment remains Bonica’s lasting legacy.
From 1950 to 1990, control of acute and post-operative pain received inadequate attention despite knowledge of effective treatments. Ready’s watershed description of an organized acute pain service in 1988 accelerated the initiation of multidisciplinary pain teams in developed countries. Increasing understanding of the pharmacokinetic and pharmacodynamic properties of opioids and other analgesic drugs, together with an appreciation of the neural mechanisms governing pain perception, led to the use of multiple classes of analgesic and adjuvant drugs. This “multimodal approach” aims to optimize acute pain management and prevent the transition from acute to chronic pain. The IASP publishedManagement of Acute Pain: a Practical Guide in 1992.
Anesthesiologists have advanced new concepts in pain management during the past 40 years, reported their findings in thousands of studies, and applied them to improve outcomes. In 2010, the IASP, through the Declaration of Montreal, affirmed that access to pain management is a fundamental human right.
Since prehistory, pain has driven sufferers to pursue relief by any available means. Anesthesiologists have played a central role in advancing the understanding and treatment of pain, a primal experience shaped by meaning, and social and religious contexts [1–10]. This chapter describes pioneers in anesthesiology who extended pain management outside the operating room, to improve pain sufferers’ quality of life by applying lessons learned from anatomy, physiology, pharmacology, neuroscience, and the study of human behavior . We also describe how anesthesiologists recently framed pain as a public health problem and played an advocacy role in achieving access to pain management as a fundamental human right . Anesthesiologists have led governmental and nongovernmental initiatives, championed pain education for health professionals and the public, [13,14] and elevated the standard of pain research and its subsequent translation into clinical practice .
In 1954, John Bonica described two roles for the anesthesiologist managing pain: first, as a technician skilled in performing specific diagnostic or therapeutic procedures “whose contribution will, of necessity, be an exercise rather than a discipline”; second, “as the individual who is responsible for the over-all management of the patient” . The development of methods and techniques for regional anesthesia and neural blockadeper se are described elsewhere in this volume. In the spirit of Bonica’s distinction, the present chapter focuses on the anesthesiologist’s roles in advancing the science of pain and translating new knowledge to benefit patients.
Numerous publications describe the history of pain from scientific, philosophical and literary perspectives. Bibliometric analyses provide objective measures of the number of published articles on pain, the evolution of popular topics, and the impact of these publications (defined as the number of citations according to article, subject or author) [17–21]. We intend to present a personal perspective, emphasizing people, places and events that we have known first-hand. In defense of this approach, we note that Thucydides himself conceded possible bias in writing at greater length about military campaigns in which he had fought, or political debates in which he had participated, but he claimed that the benefit of an eyewitness narrative outweighed the risk of myopic emphasis.
Anesthesiologists and anesthesia have woven much of the fabric of modern pain management. Long before the specialty was recognized as such, inhalational and local anesthetics transformed medical practice. In his graduate thesis in English and Comparative Literature, written in retirement after a distinguished academic career in anesthesiology, Emanuel Papper recounted Davy’s and others’ observations of the analgesic effects of nitrous oxide, a half-century before its clinical application . Papper argued that attitudes of the emerging Romantic era, particularly its focus on the happiness of the individual independent of the group, prompted Western society to overcome prior disinterest in relieving individual suffering. By 1884, when Koller first described local anesthesia, the desirability of relieving intraoperative pain was no longer questioned. Early techniques for neural blockade applied cocaine to surgically exposed peripheral nerves or plexuses [23,24]. The advent of percutaneous approaches to peripheral and neuraxial blockade expanded surgeons’ interest in and techniques of blockade during the late 19th century and early 20th century.
By the outbreak of World War II, differentiated anesthesia units had formed in some academic centers [23–26]. A few of these focused upon neural blockade (e.g., Mayo Clinic ) or Bellevue Hospital [23–24]. In Europe, Leriche linked division of sympathetic ganglia and plexuses with improved blood flow to ischemic limbs and reduction of some forms of chronic pain. These included causalgias or phantom limb pain that had been observed for millennia, but were first described systematically during the US Civil War. By the mid-20th century, the anatomy of nociception was understood well enough to provide a rationale for neurosurgical division of spinal (cordotomy) or central (cingulotomy) pathways, among other neurosurgical techniques for pain relief [28,29].
The German pain researcher Goldscheider questioned Von Frey’s and Muller’s 19th century hypothesis of specific receptors for pain. Goldscheider proposed that a single set of nerve receptors mediated both the sensation of non-painful touch and its central summation to become pain . In the early 20th century, Henry Head, a British neurologist, distinguished between rapid, well-localized touch sensations (“epicritic”), and the slower onset of dull, poorly localized, highly aversive sensations (“protopathic”), characteristic of regenerating injured nerves. Sherrington, a contemporary of Head, introduced the term “nociceptor” and the concept of descending inhibition. Working in St Louis, Missouri in the 1930s, Erlanger and Gasser identified distinct neuronal populations with differing conduction velocities, within peripheral nerves. Their classification of neurons, using Roman letters A to D to describe groups according to axonal conduction velocity, and Greek letters alpha to gamma to delineate subgroups, remains in use today. During these studies, Zotterman and Adrian employed the oscilloscope to record an action potential from a single nociceptive neuron.
In the first half of the 20th century, researchers investigated phenomena we now term post-injury sensitization and hyperalgesia [30–31]. Anticipating the current practice of multimodal analgesia, the UK internist, Lewis, postulated in the 1930s and 1940s that humoral mediators (including histamine, bradykinin and substance P) of injury, in the vicinity of a primary lesion, enhanced sensitivity to stimuli. Others during these pre-war decades, including Livingstone in Oregon, and Hardy and Wolff at Yale University, focused upon activation of a neuronal pool of variable excitability within the spinal cord, as the basis for post-injury hyperalgesia (excessive sensitivity to pain). Research on hyperalgesia and sensitization echoed prescient clinical observations at the beginning of the 20th century by George Crile, surgeon and founder of the Cleveland Clinic . Crile proposed that using local anesthesia to block transmission of nociceptive impulses from the periphery to the central nervous system, could avert the debilitating effects of surgery or trauma. Crile’s hypothesis (“anoci-association”) anticipated not only the concept of central sensitization, but also the benefit of regional anesthesia in inhibiting what were later identified as catabolic and immunosuppressive postoperative stress responses. He argued that untreated pain facilitated the development of central sensitization and the stress responses (see below). Not surprisingly, recognition of the importance of regional anesthesia and pain control by its leadership, led the Cleveland Clinic to continuing prominence in these fields.
Thus, by World War II, a substantial foundation supported the growth of pain research and treatment. Observations of combatants and veterans during World War II were pivotal to the careers of pioneers such as Henry Beecher and John Bonica. Progress in this field accelerated in postwar developed nations witnessing the return of veterans (many of them with chronic pain from wounds), and a baby boom demanding better obstetric pain relief. By the 1950s, many departments of anesthesiology had differentiated from their surgical antecedents. Circumstances were ripe for clinicians, clinical researchers, and research scientists in or affiliated with these departments to address major gaps in scientific knowledge and clinical practice. Bacon documented the relatively low, constant number of citations to both pain and conduction anesthesia from the early part of the 20th century until about 1950,  when a steady upsurge of citations began, roughly doubling in each subsequent decade . We describe how this progress unfolded in the past 60 years using selected highlights of pain research and practice in which anesthesiologists and their basic science collaborators have changed medical practice.
Boston: Beecher, Analgesic Trials, and the Placebo Effect
Beecher was a Midwesterner born with the improbable surname of Unangst . A month before entering Harvard Medical School, he legally changed his surname to Beecher (the maiden name of his maternal great-grandmother) perhaps to be more acceptable to Boston’s Brahmin society, and possibly to distance himself from his irresponsible father with whom he had a strained relationship. Beecher was a high-energy iconoclast. His research was influenced by early positions teaching chemistry and physiology, award-winning laboratory studies in respiratory physiology as a medical student, and a year (1935) studying in Copenhagen with the 1920 Nobel laureate in medicine August Krogh. In 1936, and without training in clinical anesthesia, Beecher became the first Anesthetist-in-Chief at the Massachusetts General Hospital (MGH), and chairman of this new department within the Department of Surgery. In 1938, he published a 388-page monograph on the physiology of anesthesia.
During World War II, Beecher was mobilized to Europe where he made an insightful observation concerning pain at the 1944 Anzio beachhead. Beecher noticed that battlefield casualties had less intense pain and required less morphine than civilian counterparts suffering equally severe injuries. He surmised that the soldiers thought, “I have survived and will go home and not return to the front line!” Despite major nociception, the soldiers’ pain was minimal’implying that the meaning of the injury and not the injuryper se dictates the intensity of pain. Two decades later, when working at MIT, on the other side of the Charles River from Boston, Melzack and Wall supplied a neurological basis for Beecher’s insight in their now classic 1965 paper describing the gate-control theory . They proposed that rostral descending pathways modulate nociceptive afferent traffic at the spinal segmental level.
Pain research fascinated Melzack, and he generously encouraged others involved in such research. He became President of the International Association for the Study of Pain (IASP). Wall could be intimidating on first meeting, and in his role as the first Editor-in-Chief of the journalPain. He could be devastatingly critical of sloppy work or adherence to outdated concepts. Both he and Melzack became warm friends of the current authors (MJC & DBC), and inspired many pain researchers who remain active to this day.
Beecher’s personal library was placed “up for grabs” before it was to be discarded by his successor Richard Kitz, on Kitz’s retirement . A young staff anesthesiologist, DBC, grabbed as many books as he could. These volumes covered neurochemistry, central nervous system metabolism, regional blood flow, oxygen consumption, pharmacology and physiology, mental health issues including opioid addiction, mathematical biophysics modeling synaptic conduction, and the biological basis of fatigue and stress. Just as Beecher’s group found that a single pencil stroke made by a patient on a visual analog pain scale could offer insight into that person’s perceptions, Beecher’s underlining and marginal scrawls in these rescued volumes document a deep, career-long interest in neuroscience. One of the earliest of the volumes is a 1929 printing of Haldane’s and Huxley’sAnimal Biology . Unlike later volumes that all bear the stamp “Property of the Department of Anesthesia of the Massachusetts General Hospital” along with the purchase date and Beecher’s signature, this has none, suggesting that it was acquired before the department was organized. The handwritten notes are identical in appearance (including sole use of pencil, never pen) to those in later volumes bearing the MGH stamp. The notes are concentrated in sections on neuronal physiology. A copy of Page’s 1937 monographThe Chemistry of the Brain, purchased in 1940, shows Beecher’s questions about the validity of the methods then used to assess cerebral metabolism, particularly their inability to observe regional vasoconstriction . Bartley’s and Chute’s 1947 monograph onFatigue and Impairment in Man  is heavily underlined in sections on sleep deprivation as a means to induce psychosis. A 1953 research monograph on metabolic and toxic diseases of the nervous system,  is densely highlighted’but only in the chapter on psychoses produced by administration of drugs, with stars drawn alongside specific descriptions of the effects of LSD and mescaline. “Get” is scrawled next to several chapter references on delirium and clinical studies of hallucinogens. Of the latter, one of these has “8/17/57” written alongside’just four days after the volume’s receipt date. The near-immediate attention Beecher gave to this chapter coincides with his active, secret research funded by the Central Intelligence Agency (see below).
Beecher assembled a remarkable team to initiate modern analgesic trials. Many methods they introduced or refined remain in use today. Louis Lasagna, the first author of this group’s influential 1954 study quantifying the magnitude of the placebo response in postoperative analgesic trials,  became “the father of modern clinical pharmacology”, an FDA advisor (one of three consultants who developed the current regulatory framework of phase 1–3 trials to demonstrate safety and efficacy of medications prior to FDA approval), and a pain researcher in his own right (e.g., inventor of the vertical “pain thermometer” scale) . Lasagna advocated rigorously controlled clinical trials, yet privately described such trials as “hothouse medicine” whose results were often over generalized to real-world patients. In print, he pleaded for “the naturalistic study of medicines”, anticipating the current emphasis on comparative effectiveness research. Lasagna later became a graduate dean at Tufts, where he founded its Center for the Study of Drug Development, and was instrumental in inaugurating its Master of Science program in pain research, education and policy. In the mid 1990s DBC heard a lecture by Lasagna, during which he uncomfortably revealed that in the Cold War era of the 1950s, Beecher and his group conducted secret studies of the effects of LSD in healthy subjects, research supported by the Central Intelligence Agency. Each week’s results would be placed in a sealed envelope and handed to a government courier in civilian garb who had traveled from Washington to Boston solely to receive them. Perhaps it was a sense of guilt at participation in this classified program’identified 50 years later in newly declassified documents as the CIA’s notorious MKULTRA project, exploring drugs for mind control’that led Beecher in the 1960s to advocate for the ethical conduct of clinical trials . Beecher not only underlined those sections in his books focusing on hallucinogens, sleep deprivation and other means to induce psychosis, but devoted a lengthy chapter to psychotomimetic drugs in his classic 1959 textThe Measurement of Subjective Responses in Man . In retrospect, the almost disproportionate comprehensiveness of that chapter is another clue to his intense yet clandestine Cold War research.
Statistical Studies and the Emergence of International Collaboration
Donald Todd, a Beecher protégé and co-author of the 1954 study of deaths associated with nearly 600,000 anesthetics in 10 institutions,  devoted his later career to clinical care of patients with pain. DBC once asked Todd why death was selected as the sole outcome analyzed in the 1954 study. He chuckled and replied “because it was the only outcome whose definition everyone could agree upon”. His use of regional anesthesia to diagnose and treat painful conditions dated from a 1940s collaboration with William Sweet, a neurosurgeon and pioneer in pain studies. This collaboration led him to provide anesthesia care for trigeminal thermal or glycerol ablations, cingulotomies, and to test the effect of local anesthetic sympathetic blocks prior to planned surgical sympathectomy. Todd formed a “diagnostic and therapeutic nerve block unit” that DBC joined in 1986, at Kitz’s suggestion. The suggestion acknowledged DBC’s prior research fellowship in endocrinology and peptide chemistry, measuring β-endorphin. That work resulted in reports on neuro-immune interactions and the effects of physical exercise upon β-endorphin secretion (the 1981 “runner’s endorphin” publication) . The nerve block unit expanded to a multidisciplinary pain clinic following the Seattle model (see below), to which a clinical fellowship was subsequently added. The blueprint for the evolution of this nerve block unit into a multidisciplinary center was provided in the mid-1980s, through a comprehensive consultation arranged by Kitz with his friend MJC. At that time, in his capacity as President of the IASP, Cousins was codifying desirable features for various types of pain treatment facilities worldwide. The authors’ personal interactions and multiple collaborations date from this time.
Frederick Mosteller developed the statistical methods for Beecher’s (and hence the field’s) early analgesic trials. Later, with his colleague Tom Chalmers, Mosteller originated the technique of meta-analysis. In 1990, DBC co-chaired the first US federal clinical practice guideline panel; its topic was acute pain . Mosteller and Chalmers provided support with systematic reviews and meta-analyses, for example, of patient-controlled analgesia  and the respiratory benefits of postoperative epidural analgesia . Bucknam McPeek, another Beecher protégé, personal medical advisor to Mosteller, and senior member of the MGH acute pain team, facilitated an expanded international co-operation. McPeek’s European connections included Edmond Neugebauer and Stefan Schug from Germany, whose productivity in translational pain research, particularly in relation to acute pain and often based upon international collaborations, led them to organize IASP’s Acute Pain Special Interest Group (APSIG) in the months leading up to its 2005 World Congress in Sydney. The APSIG’s inaugural meeting took place at that World Congress. DBC, currently Chair of the APSIG, enjoyed additional collaborations with French and Greek clinical scientists. Chalmers and Mosteller continued to support evidence-based analyses for a subsequent guideline on cancer pain, after which their protégé Joseph Lau at Tufts picked up the task, becoming Director of Tufts’ Evidence-based Practice Center, funded by the Agency for Healthcare Research and Quality . Anesthesiologists were not only involved in the first evidence-based US federal guidelines, but to this day have participated in numerous international evidence syntheses  and related policy efforts such as providing expert guidance and testimony to the US FDA.
The pioneering advances of Beecher and his collaborators continue to guide how medical science worldwide quantifies subjective responses, conducts regulatory affairs such as drug approval, and monitors pain in everyday practice . Today’s routine uses of placebo or sham comparators in analgesic trials, and current neuroscience research on placebo, also reflect Beecher’s influence. One indication of this impact is the selection of publications from Beecher, Lasagna and Mosteller (on placebo) and Lau (on cumulative meta-analysis) by the Editor ofThe Lancet for his personal 27-item “core canon of medical literature” . Others so selected included Hippocrates, Galen and Koch.
In the 1960s, Todd’s colleagues cautiously began using small doses of morphine as an antitussive for patients requiring prolonged controlled ventilation following cardiac surgery . The patients did so well that larger and larger doses of morphine (and later, fentanyl) were given earlier in their course, culminating in what for the time were unprecedented large doses of opioids being given routinely during cardiac anesthesia, as reported by Edward Lowenstein in 1969 . That practice was adopted worldwide.
Boston is replete with academic medical activity, facilitating cross-fertilization. Benjamin Covino’in the 1970s a senior executive at Astra, a global pharmaceutical firm self-termed “the house of regional anesthesia”’decided to pursue clinical training in anesthesiology after years as a clinical researcher and pharmaceutical executive. He completed his anesthesiology residency at the MGH, occasionally swapping on-call dates to catch a flight overseas to a corporate board meeting. Upon completing his residency in 1977, he became the first and still only MGH anesthesia trainee whose initial post-residency position was as an academic chairman (at the University of Massachusetts). In 1979, he succeeded Leroy Vandam as Chairman of Anesthesiology at the Brigham and Women’s Hospital. That hospital’s patients included many with arthritis undergoing joint replacements under regional anesthesia, and many parturients whose labor pain was managed with epidurals. Covino’s department included stellar clinicians along with clinical and preclinical scientists, including Gary Strichartz, the 1987 ASA Excellence in Research Awardee, honored for his work on mechanisms of action of local anesthetics  and other pain-related topics. Many Brigham graduates advanced pain research and practice, including two Past Presidents of ASRA-PM, Michael Ferrante and Mark Lema. Lema, an MD with a PhD in pharmacology, is also a Past President of the ASA. As the long-term Chair of Roswell Park Cancer Institute’s Department of Anesthesiology, Critical Care & Pain Medicine, he has focused upon cancer pain control. He has mentored prominent clinician-researchers including Oscar de Leon-Casasola. Carol Warfield, the Edward Lowenstein Professor (see above) of Anesthesiology at the Beth Israel Deaconess Medical Center, is another Boston-based leader in pain medicine known for numerous educational and organizational activities and a multi-edition textbook on pain.
Other major metropolitan centers had their own pioneers in pain treatment and research. In New York’s Bellevue Hospital, Emery Rovenstine established one of the nation’s first outpatient pain clinics in 1936, focusing on nerve blockade. About a mile away, Raymond Houde’s group at Cornell and Memorial Sloan Kettering Cancer Center advanced analgesic trial design and produced leaders in opioid research. The growth of pain research and care in recent generations led many centers to assemble critical masses of pain clinicians and researchers not only in the Americas but also in the United Kingdom, the European continent, and Asia including Australia (in Adelaide, Brisbane and Sydney).
Bonica, Chronic Pain as Disease, Multidisciplinary Pain Clinics, and IASP
John Bonica, working in Tacoma and Seattle, was the second pioneer of the current worldwide era of clinical pain research and treatment. Like Beecher, he rose from humble beginnings to join the first generation of academic anesthesiologists. Although Giovanni Giuseppe Bonica’s parents Americanized their 12-year-old’s name to John Joseph Bonica when they fled Mussolini’s Italy and emigrated to the US, unlike Beecher, Bonica never discarded his ethnicity . MJC recalls that Bonica’s forceful personality sometimes evoked suspicions of a subterranean connection with a powerful Italian organization, a link for which no justification existed, but that Bonica chose not to refute.
Remarkable physical strength and endurance complemented Bonica’s dominating personality. Apart from Resh Lakish in imperial Rome, and Bonica in democratic America, history offers few examples of professional wrestlers who went on to careers as distinguished scholars . Bonica began wrestling in secondary school, became New York City’s high school middleweight champion, and two years later the regional intercollegiate champion. His biography in the Professional Wrestling Hall of Fame describes his competing as Johnny “Bull” Walker, and once defeating all 36 members of a college wrestling team in a single day. He wrestled professionally for 14 years (1936–1950), including as “The Masked Marvel” during military service. In 1939, he won the light heavyweight championship of Canada and in 1941 was world champion at that weight. He fought in 1485 professional bouts, and 2000 additional matches in carnivals and circuses where he earned money for medical school tuition by taking on all comers. Chaperoned by her mother Angela, his wife Emma often sold tickets at these carnivals. His wrestling career and numerous consequent operations, including hip replacements, left him with lifelong pain that underlay his interest in pain management.
As with Beecher, clinical observations in World War II proved fundamental to Bonica’s career. In 1944, Bonica entered the Army directly from residency, and was assigned to the then largest military hospital in the world, the 7700-bed Madigan Army Medical Center in Fort Lewis, Washington. His orders stated “You will be in charge of pain control”. He read classic works, corresponded extensively, yet was baffled by the many pain problems in wounded soldiers under his care . He began a regular lunch meeting to which he invited an orthopedist, a neurosurgeon and a psychiatrist to discuss such cases. Years later, he stated “These early experiences convinced me that complex pain problems could be more effectively treated by a multidisciplinary/ interdisciplinary team, each member of which would contribute his/her specialized knowledge and skills to the common goal of making a correct diagnosis in developing the most effective therapeutic strategy” . From this came the multidisciplinary pain clinic. He continued such a clinic as Chairman of Anesthesiology at Tacoma General Hospital after Army service, and later in 1960, as founding Chairman of the Department of Anesthesiology at the University of Washington in Seattle. Influenced in part by early visionaries such as Leriche, Bonica considered chronic pain to be a disease entityper se (see below) in which psychosocial features were substantial. The “father” of operant conditioning, the psychologist William Fordyce, oversaw Bonica’s pain rehabilitation program .
The concept that chronic pain has important psychological and systemic comorbidities is an ancient one. The Roman general and emperor Marcus Aurelius wrote in hisMeditations that “many other things which we find uncomfortable are of the same nature as pain: feelings of lethargy, or a feverish temperature, or loss of appetite” . Robert Burton, in his voluminous 17th-centuryAnatomy of Melancholy voiced similar observations,  as did the US Civil War physician Weir Mitchell. These insights appear to have been nearly forgotten by early 20th century medical research. The slender 1948 monograph on pain by Wolff and Wolf, for example, describes pain solely in nociceptive terms without mention of psychological factors . Its single index entries for both “brain” and “cortex” refer simply to the insensibility of each to direct stimulation. It was the “charismatic entrepreneur”  Bonica who laid the foundation for today’s view of chronic pain as a disease entity best treated in a multidisciplinary fashion.
Building upon Bonica’s early work, MJC and Philip Siddall were the first to assemble and integrate a wide range of basic and clinical (including psychological) evidence that chronic pain is a disease entityper se . They observed that “continuing nociceptive inputs result in a multitude of consequences that impact on the individual, ranging from changes in receptor function to mood dysfunction, inappropriate cognitions, and social disruption” . They maintained that the changes brought about in multiple bodily systems “as a consequence of continuing nociceptive inputs argue for the consideration of persistent pain as a disease entity in its own right.” Anticipating the current interest in pain and its control from the perspective of public health (see below), Siddall and Cousins pointed out that “the best outcomes will be obtained when those involved in the treatment of persistent pain recognize and also tackle the variety of environmental factors that may be contributing to the presence of persistent pain.”
Bonica’s desire to optimize acute postoperative pain control (see below) led to the formation of one of the earliest organized acute pain services based in anesthesiology, described in 1988 by Brian Ready and colleagues . His work on chronic pain led to the founding and expansion of the IASP (see below), now the single largest global interdisciplinary organization focused upon pain. In 1953, Bonica authored a 1500-page monograph summarizing the world’s preclinical and clinical knowledge of pain and emphasizing the distinctive nature of chronic pain . He accomplished this while working full-time in Tacoma! A major theme of this watershed text was that “whereas in acute pain, the pain is a symptom of the disease or injury, in chronic pain the pain itself is the disease” . He lectured extensively about his ideas and served as President of the ASA and the World Federation of Societies of Anaesthesiologists (WFSA). As Baszanger  and others  pointed out, a less obvious but ongoing powerful factor was the worldwide assignment of increasing importance to the wishes of patients and their families for enhanced quality of life and hence improved pain control.
In 1972, Bonica invited an international group of researchers to a meeting, with the goal of founding a global organization to establish pain as a differentiated field of study. To organize the meeting, he recruited his department’s editor, Louisa Jones. The May 1973 meeting attracted 102 international speakers and 237 other delegates to Issaquah, Washington, where the IASP charter (modeled after the charter of WFSA) was promulgated . A Council was established, and planning began for a new journal,Pain. Jones asked Bonica what to do next. His simple response was “You handle it” . Although Jones said Bonica had a reputation as a difficult supervisor, the two worked well together. Jones attributed their collegiality to a similar outlook, resulting from having grown up within a half mile of each other in Brooklyn, New York. DBC and MJC interacted with Jones for decades, in awe of her administrative and editorial capacities and her work ethic, noting her unofficial maternal counseling of members of IASP including its officers.
MJC’s close relationship with Bonica extended from the 1970s into the 1990s. He recalls that:
“I first met Bonica in 1970 when I visited Seattle to discuss my acute pain research carried out under the supervision of Bromage in Montreal. I knew that Bonica had a reputation for being ‘imposing’ and engendered a feeling that one did not want to be ‘on the wrong side of him’. He had a handshake like a steel clamp and had shoulders almost equal in breadth to his height. He listened with some apparent irritation to my research findings and then fired off a series of staccato questions which dashed my hopes of his approval (even though the editors ofSurgery, Gynecology and Obstetrics had already agreed to publish my manuscript). In the end he said ‘Not bad. Keep up the good work. Follow me and I will show you what we do here’. Before I left he gave me some advice for the future ‘Remember always to get your facts straight…and never, never give up’. Subsequently Bonica appointed me as a Regional Vice President and then IASP Councilor. I learned as a junior Councilor ‘Never say no to Bonica’. He involved people from diverse specialties and balanced basic with clinical input. His tireless work in fostering the development of the careers of many IASP members besides myself spanned many others too numerous to name.
“Some interpreted Bonica’s apparent ‘grumpiness’ as being ‘difficult’. More likely the underlying cause was injuries from his wrestling career resulting in his having close to 50 operations and severe chronic pain. His ability to pursue ‘active approaches to pain control’ by keeping busy was an object lesson to any pain patient’he just kept going even after 70 years of age. However, when his beloved wife Emma died he did not persevere much longer. He took the unusual step of calling me, and his other close friends, to say goodbye about 24 hours prior to his death’as always he was in control of the situation.”
We can only speculate to what degree Bonica’s drive to establish the field of Pain Medicine resulted from his own chronic severe pain, poor postoperative pain control after his dozens of operations, or Emma’s near-fatal response to a general anesthetic, poorly administered during delivery . Perhaps part was a reaction to his earning a livelihood for decades by defeating opponents in hand-to-hand combat. He did not comment upon his personal motivations when he wrote “the anaesthetist in his daily practice sees and cares for patients who fear pain and consequently he naturally develops a sympathetic understanding, a considerate feeling for those who suffer. This is, without doubt, the most important and greatest single qualifying attribute” .
As more people entered the fields of pain research and treatment, they built on the contributions of individual postwar pioneers such as Beecher and Bonica, resulting in group efforts on a national or international scale. This pattern of pioneers succeeded by numerous followers is typical of the diffusion of all types of knowledge [17–21,68].
Early Years of the IASP
Anesthesiologists played an integral role in IASP from its beginning. Bonica sought to link basic researchers to clinicians and thus asked Denise Albe-Fessard, PhD (head of a basic pain neurophysiology research group at INSERM, in Paris) to be the First President of IASP. Bonica became President-elect, ensuring long service in three consecutive presidential positions: President-elect, 2nd President and Past-President. He also would continue to serve on IASP’s Executive for that organization’s first nine formative years . Another anesthesiologist from Bonica’s department in Seattle, B Raymond (“Ray”) Fink, served as the first IASP Secretary. Still other anesthesiologists on the first Council were Fausto Molina (Argentina), Joseph Sodipo (Nigeria), Jean Lassner (France) and Hideo Yamamura (Japan). Bonica achieved his vision of IASP fostering interaction among basic scientists and clinicians. IASP presently has more than 8000 members in 126 countries and chapters in 85 countries. Of 12 IASP Presidents to date, besides Bonica only two (MJC and Eija Kalso) were anesthesiologists. On the other hand, given IASP’s tradition of nominating preclinical scientists alternating with clinicians for President, that figure corresponds to half of the clinicians elected.
During Melzack’s and MJC’s Presidencies (1984–1990), IASP’s brief increased from a focus largely on chronic pain, to include acute pain and cancer pain. An official NGO relationship was developed with the World Health Organization, with the Norwegian anesthesiologist and researcher, Harald Breivik, in the long-term liaison role. Several task forces were formed by MJC including Acute Pain Management (1984); Pain in the Workforce (1987); Core Curriculum for Professional Education in Pain (1987); and Undergraduate Curriculum in Pain (1987). Membership in IASP was extended to those from developing countries and countries with currency difficulties’increasing international interactions. Anesthesiologists comprised the majority of the considerable increase in IASP membership during this time.
Acute Pain: Services, Multimodal Control, Pre-emption, and Prevention
Anesthesiologists drew attention to inadequacies of traditional acute pain management. Ferrante and Covino (see below) assembled a historical “core literature” of 18 reports, in 1990 documenting the inadequacy of conventional intramuscular injections of opioids for postoperative pain . The earliest of these reports, published in 1952, was a collaboration between anesthesiologists Papper and Rovenstine and the clinical pharmacologist Brodie . This paper reported that a third of conventionally managed patients experienced inadequate postoperative analgesia. Arthur Keats reported a similar incidence (range 26–53%) in 1956 . In 1961, Roy Simpson’s group in London (University College) pioneered the use of postoperative thoracic epidural analgesia,  as did Bruce Scott’s group later in Edinburgh . Two internists, Marks and Sachar, in 1973 found that fewer than half of adult medical inpatients with acute pain received adequate pain relief . An Australian 1983 study by Mather and Mackie (the first in children) similarly reported that 50% of children did not receive adequate pain relief – a disturbing statistic given the universal instinct to comfort the young. In 1986, MJC and Phillips reported on acute pain management in critical care patients, a neglected area with few research publications appearing subsequently . The consistent theme from this literature, is the documentation of poorly controlled acute pain in numerous research studies and editorials, from the 1950s until the first report of a formal acute pain service by Ready in 1988 . Knowledge, drugs and techniques existed to successfully treat 90% of postoperative and other acute pain, [77,78] but only a third to a half of patients were adequately treated . In developing countries, undertreatment of acute pain remains the rule .
Correlative opioid pharmacokinetic-pharmacodynamic (PK-PD) studies on patient-controlled opioid analgesia by Mather at Flinders Medical Centre in Adelaide [79,80] (and see below), focused attention on management of postoperative and other forms of acute pain. Thus, an increasingly sophisticated “acute pain service” began to evolve in 1975. Relying entirely on clinician researchers and research staff of the Flinders Academic Department of Anaesthesia & Intensive Care, the improvement in acute pain management, and encouragement of the surgeons who witnessed the benefit, increasingly drew clinicians into involvement in the acute pain service. Some surgeons initially believed that their residents could handle opioid infusions, resulting in numerous cases of under-dosing and a few overdoses and acute admissions to the ICU.
On commencing his Presidency of IASP in 1987, MJC appointed a Task Force on Management of Acute Pain. Concurrently, the National Health & Medical Research Council (NHMRC) of Australia established a Working Party (including MJC) on management of all forms of pain. The NHMRC recommended a team approach to acute pain management. MJC appointed anesthesiologist Brian Ready from Seattle to Chair the IASP Task Force, resulting in the IASP Document on Acute Pain. Ready’s team, including a nurse, anesthesiologist, and anesthesiology fellow, had published their experience in postoperative pain in 1988  followed by Macintyre’s 1990 publication from Australia,  Sinatra’s from New Haven (US) in 1998,  Schug’s from New Zealand in 1995,  and Rawal’s from Sweden in 2005 . In retrospect, the delay in establishing such anesthesiology-based services is surprising, since the scientific basis of acute pain management had long been known. Patient-controlled analgesia devices, for example, were first described in the late 1960s and early 1970s [84–86]. Publication of correlative PK-PD studies occurred with nearly a 10-year time lag until their application. One might speculate that routine use of PCA devices was awaiting development of clinically useful pulse oximetry, permitting continuous monitoring of the patient’s ventilatory status. The issue of postoperative monitoring to detect opioid-induced hypoventilation remains an ongoing one.