A Capsule History of Pain Management

SPECIAL COMMUNICATION

Marcia L. Meldrum, PhD Pain is a complex clinical problem. Assessment depends on verbal report,

AIN IS THE OLDEST MEDICAL and the patient’s physical perceptions may be modified by cognitive and af- problem and the universal fective factors. The salience of pain as a problem in its own right has grown physical affliction of man- since 1945 and new therapeutic alternatives have developed from research kind, yet it has been little un- and from new theoretical perspectives. This short historical review of the Pderstood in physiology until very re- highlights of the history of pain management gives particular emphasis to cently. The philosophical, political, and the 20th century and to chronic and cancer pain. religious meanings of pain defined the suffering of individuals for much of hu- JAMA. 2003;290:2470-2475 www.jama.com man history. Pain is the central metaphor of Judeo-Christian thought: the changed attitudes.2 Was it not a posi- form longer and more complex proce- test of faith in the story of Job, the sac- tive good to relieve pain? The skilled dures, and most patients thought an- rificial redemption of the Crucifixion. surgeon took pride in his ability to oper- esthesia a divine blessing. Still, for much In the utilitarian dialectic of the 18th ate rapidly, minimizing his patient’s of the mid-19th century, the practice and 19th centuries, pleasure was bal- agony. But a few experimenters real- was not universal. Physicians used a anced against pain to determine the ized the possibilities of the sedative “calculus” to determine which pa- good of society. gases, particularly ether, often used as tients were of the correct sensibility to But pain was also a medical prob- an analgesic for toothache. Following need or benefit from the use of anes- lem. European physicians did their best an unsuccessful attempt by his col- thesia.1,3 to relieve their patients’ pain, most of- league Horace Wells, the American den- The anesthesia story illustrates the ten through the judicious use of opium tist William T. G. Morton gave his complexity of pain as a phenomenon or, after 1680, laudanum, the mixture famous demonstration of anesthesia and the way in which its cultural mean- of opium in sherry introduced by with ether on October 16, 1846. The ings have often complicated its treat- Thomas Sydenham. But they also in- British obstetrician James Young ment.4 But the acceptance of surgical flicted it when necessary, to relieve evil Simpson proposed the use of chloro- and obstetrical anesthesia promoted a humors or to amputate diseased limbs. form in childbirth and surgery soon general consensus that the relief of The physician valued pain as a symp- after, in 1848.1 bodily pain was a positive good, if sec- tom, a sign of the patient’s vitality, of The introduction of surgical anes- ondary to curative therapy. By the mid- the prescription’s effectiveness. “[T]he thesia was one of the great revolutions 1800s, pain had become the topic of 3 greater the pain, the greater must be our of modern medicine, but not all phy- interrelated medical discourses that confidence in the power and energy of sicians were immediately enthusias- have continued to the present day: the life,” one commented in 1826.1 That tic. There was an extended debate over symptomatic relief of acute pain, the men, women, and children endured the ethics of operating on an uncon- palliation of severe pain in those suf- physical suffering was inevitable; the scious patient in both Europe and the fering and dying from progressive dis- meaning, rather than the fact of pain, United States about the possibility that eases such as cancer, and the relief of was what mattered to the good life. the relief from pain might actually re- intractable chronic pain from disor- In the early 1800s, however, the utili- tard the healing process. Religious writ- ders such as tension and migraine head- tarian philosophy, with its emphasis on ers called anesthesia a violation of God’s reducing the pain of the greatest num- law, whom they believed inflicted pain Author Affiliations: Department of History, Univer- sity of California-Los Angeles, Los Angeles. ber, combined with the new philoso- to strengthen faith and to teach the new Corresponding Author and Reprints: Marcia L. phy of individual rights and the Roman- mother the need for self-sacrifice for her Meldrum, PhD, Department of History, University of California-Los Angeles, 6265 Bunche Hall, Box 951473, tic poets’ insistence on the importance children. But the surgeons could not Los Angeles, CA 90095-1473 (e-mail: mlynnmel of individual experience, gradually long resist their new power to per- @earthlink.net).

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ache; osteoarthritis; rheumatoid arthri- duced as aspirin in 1899, proved to be cer recognized that “severe constant pain tis; diabetic neuropathy; postherpetic remarkably safe and well tolerated by will destroy the morale of the sturdiest neuralgia; trigeminal neuralgia; recur- patients and highly effective as an an- individual,” they were “often loathe to rent lower back, abdominal, and pel- algesic and antipyretic. Bayer aspirin be- give liberal amounts of narcotics because vic pain; and the causalgiform disor- came an over-the-counter drug after the the drug addiction itself may become a ders (reflex sympathetic dystrophies). expiration of the American patent in hideous spectacle”12(pp7-8) and advised 1917 and the appropriation of Bayer’s that “every effort should be made to put Opiates Throughout subsidiaries abroad during World off [narcotic use] until all other mea- the 19th Century War I; it effectively supplanted the opi- sures have been exhausted” and the Opiates, throughout the 19th century, ates for the treatment of mild to mod- patient’s life “can be measured in were the standard treatment for acute erate pain.9,10 weeks.”12(pp13-33) pain from injuries and for recurrent pain, For the severe pain of cancer, opiates such as headache or toothache. Fried- remained essential. Although the topic The Ordeal of Chronic rich Wilhelm Sertu¨ rner had synthe- was not much discussed in 19th cen- Intractable Pain sized the “somniferous principle” in tury medical literature, the available evi- If patients with cancer and their physi- crude opium in 18045; morphine was in- dence is that a number of physicians ad- cians faced a terrible dilemma, patients dustrially produced in Germany in the vocated vigorous use of analgesics in with chronic “pain without lesion” con- 1820s and in the United States a decade seriously ill and dying patients; the cri- fronted a different, but equally agoniz- later. Alexander Wood in 1855 devised tiques these writers directed at their col- ing, ordeal. Nineteenth-century physi- a syringe with a hollow needle for sub- leagues suggest that this was not al- cians neither ignored nor trivialized these cutaneous injection, which was of im- ways the common practice. “Seldom pains, which persisted in the absence of mediate practical benefit. The syringe does it afford more pride and pleasure evident pathology and often failed to re- made frequent administration so conve- to be a physician!...[O]ne of the chief spond to treatment with opiates. They nient that it probably contributed to the blessings of Opium is to help us in grant- proposed a number of creative etiolo- overuse of morphine.6 Opium and alco- ing the boon of a comparatively pain- gies of nerve malfunction, including hol-based compounds, in the form of liq- less death,” wrote the Bath physician Franc¸ois J. V. Broussais’ concept of func- uids, pills, and “headache powders,” were John Kent Spender in 1874, adding, tional lesion (1826), Benjamin Brodie’s unregulated and available over the “[T]he medical man who (from igno- hypothesis of spinal irritation (1830s), counter in local pharmacies; many people rance or timidity) withholds hypoder- and the idea of a disorder of Gemeinge- used them to self-medicate. By the 1870s, mic medicine from a patient afflicted fu¨hl, or cenesthesis, an individual’s abil- physicians had begun to express con- with cancer, is...totally without ex- ity to correctly perceive his internal sen- cerns about “the morphine habit” or cuse.” Herbert Snow, while chief sur- sations.13 S. Weir Mitchell, the US “narcomania” and its “repeated indul- geon at the London Cancer Hospital (the neurologist who wrote classic descrip- gence inducing bodily and mental pros- Royal Marsden) in the 1890s, argued tions of pain syndromes such as phan- tration and mental perversion.”7 In 1898, that the “morphia habit” would slow the tom limb pain and causalgia based on his the Bayer Company of Germany intro- progression of the cancer and con- Civil War observations, strongly as- duced diacetylated morphine under the demned the approach of other physi- serted the reality of his patients’ physi- trade name Heroin as a cough remedy. cians, which he described as “operate, cal illness, despite their unexplained pain Early reports proclaimed that this new or failing this, do nothing.”8(pp21-34) and odd behavior. Of causalgia, the burn- compound had less habit-forming po- The conflict between the physician’s ing pain in an extremity that persisted tential than morphine. But by 1910, desire to relieve the patient’s pain and after an injury had healed, he wrote that young working-class Americans had fear of inducing addiction persisted in it was “the most terrible of all the learned to crush the pills into powder and medicine throughout the 20th century. tortures which a nerve wound may in- inhale it to achieve a concentrated high. Patients equated morphine use with a flict....Under such torments[,]...the The frightening spread in street use, loss of autonomy that the strong should most amiable grow irritable, the soldier coupled with rising alarm over iatro- resist at all costs. A classic illustration is becomes a coward, and the strongest man genic addiction to morphine, encour- when the Finch children in To Kill a is scarcely less nervous than the most aged the medical profession’s support of Mockingbird11 spend weekends reading hysterical girl.”14 The patients reported the Harrison Narcotic Control Act, to their sick neighbor Mrs DuBose who pain at the slightest touch; when they al- passed in 1914.8(pp33-55) is fighting to wean herself off morphine lowed him to treat them, Mitchell tried Bayer’s chemists had also acetylated before she dies. Their father, Atticus, the ammonia blisters, electricity, and mor- salicylic acid, a plant compound used book’s noble hero, praises her courage. phine, with some success. Many of the in headache powders, which had of- Physicians shared these attitudes. men still suffered pain 30 years later.15 ten left the patient with severe gastric Although those few writers who dis- As neurologists more tightly de- distress. The new compound, intro- cussed pain relief for patients with can- fined their field through the develop-

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ment of specific diagnostic tests and Medicinal Chemistry at National Insti- iche, his original use of procaine may identification of meaningful signs in the tute of Diabetes and Digestive and Kid- have been suggested by a football coach, later 1800s, they began to eliminate un- ney Diseases.8(pp57-83) Under the leader- who had often given blocks to injured explained chronic pains from their pro- ship of Lyndon Small, Nathan Eddy, and players.16,17,24 The first anesthesiolo- fessional purview, while alienists and Everette May, the program has tested gist to open a nerve block clinic for pain psychoanalysts found these disorders many new analgesics, including oxy- relief was Emery Rovenstine, at Bel- useful clues to mental or emotional dis- codone, meperidine, methadone, and levue in 1936.25 ease.13 This disciplinary shift was fur- pentazocine. But the strong nonaddict- ther supported by the development of ing morphine derivative has continued New Ideas Generated at Wartime neurophysiological evidence that sup- to elude the researchers.8(pp57-83) World War II, which provided an un- ported the idea of “true” pain as a di- There were a few clinicians between precedented opportunity for organized rect, proportional response to a spe- the first and second world wars who teams of clinicians to observe and work cific noxious stimulus. Specificity theory found specificity theory too limiting with complicated injuries, was a water- became the standard model taught in and the available therapeutic options shed in the management of pain. Liv- US medical schools.16,17 By the 1920s, inadequate. The French surgeon Rene ingston, who treated 1279 nerve injury therefore, those who suffered from un- Leriche, who treated many patients with cases at a California naval hospital, called explained chronic pain syndromes were nerve-injury—his “pariahs of pain”— the war years “the most exciting and pro- often regarded as deluded or were con- during World War I, proposed careful ductive of my life.”17(ppviii-x) In 1947, he demned as malingerers or drug abus- resection of the arteries near the in- established a research-based pain clinic ers. As morphine and other narcotics jury, followed by a large injection of at the University of Oregon; among the were heavily regulated and prolonged procaine (the precursor of cocaine, syn- fellows he trained was the young psy- administration was sanctioned only in thesized in 1905) to block all sensa- chologist Ronald Melzack.17(ppviii-x) the dying, the only options available for tion. Only if the procaine failed to pro- It was at Anzio and other World War most patients suffering from chronic in- vide substantial relief did he advocate II battlefields that Henry K. Beecher, the tractable pain were psychotherapy or ligation of the periarterial sympa- Harvard anesthesiologist, observed that neurosurgery—ligature, resectioning, thetic nerve fibers or of the sympa- seriously wounded soldiers reported or crushing of the nerve fibers—to pre- thetic ganglia supplying the limb. A much lower levels of pain than had his vent the transmission of sensation to the number of neurosurgeons had adapted civilian patients in his Massachusetts spinal cord and brain. Surgeons pro- his method as a diagnostic procedure General Hospital recovery room. Based gressively refined these operations, de- by the late 1930s, moving immedi- on his inference that clinical pain was veloped between the 1870s and the First ately to sympathectomy if the pro- a compound of the physical sensation World War, to vitiate only the nerves caine injection provided relief.23 Or- and a cognitive and emotional “reac- involved in the specific pain disorder; egon surgeon William Livingston tion component,” he challenged labo- but the procedures were disabling and refused to rush into the operating room ratory studies in healthy volunteers and drastic remedies.18-20 but treated his unhappy patients with argued that pain could only be legiti- Harvard pharmacologist Reid Hunt multiple procaine injections, some- mately studied in the clinical situa- realized the need in clinical practice for times as many as 8 over a period of 2 tion. These observations formed the ba- a strong nonaddicting analgesic, a drug years or more. He found that this se- sis for a new analgesic testing method, that would fill the empty niche between rial blockade often resulted in perma- using double-blinded crossover trials aspirin and the narcotics; he hypoth- nent remission. Livingston fiercely re- and simple numerical scales to quan- esized that “a thorough study of the mor- fused to “deny such cases an organic tify patient report, developed by Beecher phine molecule might show a possibil- basis and to ascribe the symptoms to and refined by Raymond Houde ity of separating the analgesic from the psychic causes for which the patient and Ada Rogers at Memorial Sloan- habit-forming property.”21,22 His idea may be responsible.”17 Kettering .26-29 sparked the development of the Com- Regional nerve blocks had been used The young anesthesiologist John mittee on Drug Addiction, formed under during surgical procedures before 1900. Bonica found himself handling pain the aegis of the National Research Coun- Rudolf Schlosser had experimented problems that baffled him at Madigan cil in 1929, with the financial support with alcohol blocks for trigeminal neu- Army Hospital in Washington, during of the Rockefeller-backed Bureau of ralgia in the early years of the century the war. Consulting with other col- Social Hygiene, to supervise a research and others tried the same method for leagues, he found that they knew little project initially based at the Universi- cardiac pain in the 1920s. The thera- more than he did, but that each ben- ties of Virginia and Michigan. The anal- peutic use of an anesthetic rather than efitted from discussion with the oth- gesic development program moved to the a neurolytic block appears to date from ers. This experience was the genesis of new National Institute of Health in 1938 the work of Leriche and Livingston. Al- Bonica’s 20-year campaign for multi- and is today part of the Laboratory of though Livingston gave credit to Ler- disciplinary pain clinics and an inter-

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disciplinary pain field, which would tween the periphery and the brain. The Hans Kosterlitz and John Hughes43 iso- promote the sharing of clinical and neurophysiological specifics of their lated enkephalin. laboratory evidence. His opening 1953 model were less important than the By 1972, John Bonica, who had been salvo was the monumental work The challenge to the specificity theory and trying to build an interdisciplinary pain Management of Pain,16 which gathered the implication that clinical reports of “world” for 20 years “was about to give together all available information about pain unrelated, or out of proportion, to up....[D]octors said, ‘Pain is a symp- the etiology, diagnosis, and treatment any external stimulus could be ex- tom of disease, and that’s it.’” But the of human pain.30 As a practitioner, plained in terms of neural mecha- surge of interest that followed the gate Bonica refined and promoted the use nisms. In the words of Isabelle Bas- control article motivated him to act.30 of therapeutic nerve blocks. A small zanger,37 Melzack and Wall’s model He invited 300 researchers and clini- number of other anesthesiologists, in- opened gates in disciplinary barriers and cians—everyone he could find who was cluding Duncan Alexander in Texas offered a plan for “the construction of working on or had written about and Mark Swerdlow in Manchester, En- a world of pain.” The observations and pain—to a 3-day meeting in May 1973 gland, were also working with these methods of clinical medicine and psy- at an isolated convent near Seattle, methods, starting pain or nerve block chology would form “two new axes” Wash. He drew on the energy and in- clinics in the 1950s and early 1960s. around which a conceptual “complex- terest of the assembled participants and The use of serial anesthetic blocks en- ity almost beyond comprehension” won their endorsement of an interdis- abled the physician to manage many dif- could be mapped. ciplinary organization, the Interna- ficult pain problems without having to Interest in the gate model, both sup- tional Association for the Study of Pain, resort to surgery.16,30,31 portive and antagonistic, drew atten- and a dedicated research journal, Pain. The United Kingdom in this period tion to pain as a problem. The psycholo- Bonica had himself nominated as the saw the beginnings of another medi- gist Richard Sternbach38 argued that first president-elect and led the new cal initiative that presented pain as a physiological and affective perceptions group through its formative years.30 The complex multidisciplinary problem. of pain should be understood as learned organization today has more than 6700 The physician Cicely Saunders,32,33 who responses of the nervous system, inter- members representing more than 100 had dedicated her life to the care of the active with the individual’s learned be- countries and 60 disciplinary fields (L. dying, was planning a model hospice haviors in coping with pain experi- Jones, written communication, Au- that would provide exemplary pallia- ences. A learning theory of pain gust 28, 2003). tive care and would incorporate teach- suggested a therapeutic approach based The formation of the International ing and research programs. She frankly on relearning or conditioning. One such Association for the Study of Pain facili- avowed the regular giving of strong nar- method, the childbirth education tech- tated a confrontation between 2 groups cotics, including heroin and the Bromp- niques of Grantly Dick-Read and Fer- focused on the treatment of cancer pain: ton cocktail mixture of morphine and dinand Lamaze, was already well estab- the Houde and Rogers team at Memo- gin, as the proper regimen to ensure that lished in obstetrics by the 1960s. In the rial-Sloan-Kettering,44(pp263-273,302) which a pain-free patient could maintain qual- early 1970s, Wilbert Fordyce and his col- had conducted extensive and rigorous ity of life in the last days8(pp85-98) Saun- leagues39 introduced operant condition- research on the differential effects of ders’ concept of “total pain,” a clinical ing into the treatment of chronic pain, various analgesics (many originating phenomenon that compounded physi- using physician attention as a reward to from the decades-long search for a cal and mental distress with social, spiri- help patients learn to self-manage their strong nonaddicting drug), and Ci- tual, and emotional concerns, echoed pain and to resume normal function- cely Saunders and her colleagues at the and transcended Beecher’s formula- ing through graded activity. new St Christopher’s Hospice, who were tion of a “reaction component,” de- Also in this period, David Mayer, promoting the regular use of heroin and manding a holistic concept of manage- Huda Akil, and John Liebeskind40,41 at morphine in doses strong enough to al- ment focused on the individual the University of California-Los Ange- leviate all pain. In the mid-1970s, Kath- patient.34 les reported that stimulation of cer- leen Foley44(pp59-78) at Memorial Sloan- tain areas of the brain produced anal- Kettering created the first taxonomy of Formation of the Pain Field gesia in animals, an effect reversible cancer pain. Her analysis refuted the ca- In 1965, the Canadian psychologist with the narcotic antagonist nalox- sual assumption that “advanced can- Ronald Melzack and the British physi- one. This observation supported the as- cer is painful,” showing that different ologist Patrick Wall,35 building on the sumption that there were endogenous patients suffered from different kinds ideas of the Dutch surgeon Willem neurochemical reactions to pain that of pain, some related to the progres- Noordenbos,36 published their classic might be useful therapeutically, a sion of the disease and some to other “gate control” article, proposing a spi- premise soon realized when Candace causes. At the same time, the studies of nal cord mechanism that regulated the Pert and Solomon Snyder42 identified Robert Twycross44(pp291-300,617-633),45 at St transmission of pain sensations be- the opiate receptor in neural tissue and Christopher’s demonstrated the supe-

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rior reliability and efficiency of oral cognitive-behavioral theory shares with cal evidence to synthesize targeted morphine over heroin and reported the learning theory the assumption of re- medications that will block the forma- absence of tolerance or addiction in can- ciprocal relationships between sensation or activity of a specific com- cer patients, even with long-term use. tion, cognition, emotion, and behav- pound in the nervous system impli- In 1982, the new head of the World ior, it makes the additional assumption cated in the development of persistent Health Organization Cancer Unit, Jan that “individuals are active informa- pain. Some of these new targets in- Stjernswa¨rd, brought together a small tion processors able to change the way clude inflammatory mediators, so- group of cancer pain consultants, in- they think, feel, and believe.”48 Such pro- dium and N calcium channels including Bonica, Foley, Swerdlow, and grams have been markedly effective in volved in afferent fiber transmission, Twycross, to develop a practice regi- improving mood and function and de- and specific neuropeptide agonists or men for global education and dissemi- creasing pain and disability levels in such receptors.59 A well-known example is nation. The result was the World Health refractory problems as lower back pain. the selective cyclooxygenase-2 inhibi- Organization ladder: a set of guide- But the subjectivity of pain and cogni- tor, which inhibits cyclooxygenase 2 lines for the physician, recommend- tion and the difficulty of devising a pla- that is localized in inflammatory tis- ing that she or he prescribe analgesics cebo control make the rigorous evalu- sues, but the inhibitor does not inter- on a regular schedule and titrate dos- ation of these methods difficult.49 Some fere with the more ubiquitous cyclooxy- age to the patient’s pain at each of the observers, moreover, have criticized cog- genase 1. Use of these compounds may 3 steps: from a nonsteroidal anti- nitive-behavioral programs for shifting prevent the gastric and renal prob- inflammatory drug, like aspirin, to a the burden of therapeutic responsibil- lems associated with use of the non- weak opiate, like codeine, to a strong ity to the patient, who must alter his or steroidal anti-inflammatory drugs.60 The opiate, like morphine.46 Although many her cognition and behavior to get pain work of Clifford Woolf61 and Gary Ben- adjunct drugs are recommended for pa- relief.37,50 nett62 has pointed to the role of N- tients who fail to respond to opiates or The gate control model had sug- methyl-D-aspartate [NMDA] in creat- who find the adverse effects intoler- gested a neural mechanism to explain ing a state of central sensitization, able, oral morphine—cheap, reliable, how counterstimulation methods used producing chronic pain, and sug- readily available, and with extensive by practitioners for many years, such gested the development of an N-methyl- documentation of efficacy–—remains as skin blistering, electricity, and simple D-aspartate–receptor antagonist for the mainstay of cancer pain treatment touch, might work. The most success- analgesia.63 today. A number of physicians advo- ful modern application has been the The productivity of pain research and cate its carefully managed use for pa- transcutaneous electrical nerve stimu- analgesic development since 1973 has tients with chronic noncancer pain as lation device to stimulate the large sen- not altered the truth of one clinical fact: well, a recommendation endorsed by sory fibers and close the gate. Coun- no one treatment works for every pa- major pain organizations.45 Regula- terstimulation, like acupuncture and tient, even for pain of the same type and tory barriers to morphine use and cli- placebo mechanisms, may produce an- etiology. As Beecher, Bonica, Saun- nician and patient concerns about ad- algesia by activating an endorphin- ders, Sternbach, and many others have diction nevertheless persist in many mediated analgesia system, which is argued, the meanings of pain— parts of the United States and in many part of a cascade of endogenous syn- cognitive, affective, behavioral—are dif- countries abroad.8(pp163-191),47 aptic and cellular responses to stress or ferent for each individual and shape the injury.51-54 pain experience and response to Recent Therapeutic Innovations Clinical observations in depressed pa- therapy. Perhaps these individual vari- Research in the last 30 years has devel- tients suggested that tricyclic antide- ances explain why Portenoy and Foley64 oped a variety of alternatives or ad- pressants such as amitriptyline and found, in a study of opioid analgesics juncts to opiates for chronic pain, in- imipramine, which increase available in chronic noncancer pain, that the cluding neuroactive medications, levels of norepinephrine in the ner- most important treatment factor con- counterstimulation methods, and cog- vous system, could be effective in re- tributing to outcome was “the inten- nitive-behavioral therapies. Behavioral lieving chronic pain. These drugs were sive involvement of a single physi- conditioning or modification pro- already being used to treat headache cian,” and why, with many new grams following the work of Fordyce, when laboratory findings suggested the resources available, pain management have proved helpful to many patients. involvement of norepinephrine in en- remains a challenge for the clinician. These modalities are expensive and time dorphin-mediated analgesia. The tri- intensive, however, and have been re- cyclics are now widely used in the treat- REFERENCES placed or augmented in many multidis- ment of postherpetic neuralgia, among 1. Pernick MS. A Calculus of Suffering: Pain, Profes- ciplinary pain programs by cognitive- other syndromes.55-58 sionalism, and Anesthesia in Nineteenth-Century America. New York, NY: Columbia University Press; behavioral methods, which emphasize More recently, drug developers are 1985. the teaching of coping skills. Although using pharmacological and physiologi- 2. 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