Geza P. Bálint1,Walter F. Kean2 and W. Watson Buchanan2
1Institute of Rheumatology, Budapest, Hungary, 2University of McMaster, Faculty of Health Sciences, Hamilton, Ontario CANADA.
SMJ 2006 51(1): 51-53
Abstract:
A brief review of the beliefs of Sir William Osler (1849-1919) on the medical therapeutics of his day, and speculation of what they might be today.
Keywords: Sir William Osler (1849-1919), therapeutics, clinical trials, meta-analysis, and evidence-based medicine.
Introduction
Sir William Osler (1849-1919) (Fig 1), born and raised in Ontario, and an 1872 medical graduate of McGill University in Montreal, Quebec, was arguably the most influential physician during the latter decades of the Victorian era and early decades of the 20th century1,2. He is best remembered for his magnum opus, The Principles and Practice of Medicine, first published in 18923, and clinical signs, such as the nodes in the fingers in subacute bacterial endocarditis4, and the diseases, such as polycythaemia rubra vera5, which carry his eponym. Osler was a prolific writer publishing approximately 1500 papers not only on various aspects of clinical medicine and pathology, but also on biology6. Osler’s greatest research contribution was demonstrating that white clots were largely composed of platelets7. While professor of medicine at the Johns Hopkins University Medical School in Baltimore, Maryland, he introduced the clinical clerkship, and taught medical students in the wards. Indeed, he suggested his epitaph might be, “He taught medicine in the wards”1,2. His philosophical essays remain popular reading8 containing as they do most of his memorable quotes9.
We considered it of interest to examine Osler’s views on therapeutics in his day and to speculate on what they might have been today.
Osler’s
materia medica
The medicines available to Osler were few in number as can be appreciated from Table I. In addition, to those cited in the table, there was a plethora of untried and worthless remedies, which prompted Osler to voice criticism of “popgun pharmacy, hitting now the malady and again the patient”, the physician often “not knowing which”10. He considered it important to have a “firm faith in a few good, well tried drugs, little or none in the great mass of medicines in any and every malady”11. Osler was opposed to “polypharmacy, or the use of a large number of drugs (of the action we know little, yet we put them in bodies of the action we know less)”11,12. Those who currently teach clinical pharmacology and therapeutics today would certainly not find fault with these views. It is often stated that Osler was a therapeutic nihilist. This, we believe, is not entirely true, for in truth he was a therapeutic realist.
The
pharmaceutical industry
In 1912 Osler delivered a lecture on hypertension at a meeting of the Southern Medical Society in the Hall of the Royal College of Physicians and Surgeons of Glasgow. After the vote of thanks he rose and jocularly warned the audience, “Don’t let anyone take your blood pressure!”13. Osler would have been amazed how well hypertension can now be controlled both in young Caucasian high-renin patients (angiotension inhibitors/blockers and beta-blockers) and elderly and black patients with low-renin hypertension (calcium blockers and diuretics)14.
It would not have escaped his notice that the advances in treatment in hypertension were largely the result of research carried out in the laboratories of the Pharmaceutical Industry. If alive today Osler would probably have opined that the Pharmaceutical Industry had been the greatest benefactor of mankind, an opinion certainly held by the late Sir Derrick Dunlop (1802-1980)15. He would have appreciated that a few drugs had been discovered in universities, such as penicillin by Sir Alexander Fleming (1881-1955)16 and insulin by Sir Frederick Grant Banting (1891-1941) and Charles Herbert Best (1899-1978)17, but required the expertise of the Industry to make them generally available. Nor would it have escaped Osler’s notice that it was the launching of aspirin18 by the Bayer Company in Germany in 189919 that was the catalyst to the development of the modern Pharmaceutical Industry. It is surprising, however, that he made no comment on this or on the “aspirin wars” (Fig 2) that resulted as countries, especially America, Britain and France, attempted to wrestle the patient from the German Bayer Company20. Although there is evidence that while in England, Osler supported the Liberal Party, and would, as David Hamilton has suggested, almost certainly approved of the National Health Service21. He, however, saw nothing wrong in making an honest income from private practice, and would appreciate the virtues of capitalism as applied to the Pharmaceutical Industry. Indeed he would have been puzzled why so many of the medical profession constantly criticise the Industry, especially having produced so many effective remedies: for example, some 60 cardiovascular drugs and 50 antirheumatic agents.
The absence of efficacious medications led Osler to turn to the vis mediatrix naturae of older therapies consisting of “died, exercise, baths and frictions”22. He believed homo sapiens to have “an unborn craving for medicine…the desire to take medicine is one feature which distinguishes man, the animal, from his fellow creatures”22. He would have been amused that the toxicity of modern antirheumatic drugs had made clinical rheumatologists return to simple physical treatments, such as muscle strengthening exercises, soft soled shoes etc for osteoarthritis of the knee23. Osler was well aware of the advances in surgery in his day. Today, he would have been equally so, but almost certainly would wonder why Sir John Charnley (1911-1982) did not receive a Nobel Prize for his work in developing an effective hip arthroplasy.
Placebo
effect
Osler considered faith as the most precious commodity a doctor could possess. “Faith in the gods”, he said, “or in the saints cures one, faith in little pills another, hypnotic suggestion a third, faith in a plain common doctor a fourth”22. It is of interest that the fourth example where faith, or an modern doctors would term placebo24,25, plays a role is the doctor himself. This was recognised by the Hungarian-born English phyisican Michael Balint (1896-1970) in his 1968 seminal bood, The Doctor, the Patient, and the Illness26, and illustrated in the famous painting circa 1891, by Sir Luke Fildes (1844-1927) entitled, “The Doctor” (Fig 3).
The art of medical therapeutics is essentially the ability of the physician to prescribe himself. Osler had this ability, as had many of his colleagues. Little wonder that the doctor was “the flower” and “most notably exhibited the virtue of the race” as Robert Louis Stevenson (1850-1894) once asserted. In Osler’s day the doctor was seen as a “hero”, despite the fact he was largely devoid of effective remedies. Today’s doctors can achieve much, but paradoxically are seen in a poor light, being considered heartless and too scientific. The American novelist, Kurt Vonnegut (1922 - ) expresses this modern view in his novel Fortitude (1968) when he describes a 100 year old woman, Syliva Lovejoy, a billionaire’s widow, who consists only of a head on a tripod kept alive against her wish by a mass of pipes and wires by her physician, Dr. Norbet Frankenstein. Osler would conclude that medicine can never be completely scientific until it becomes completely inhuman. He would be concerned that technical advances may make doctors mere technicians as currently happening in clinical cardiology where the stethoscope is now absolescent.
Clinical
therapeutic trials and evidence-based medicine
Osler would have approved the effort to obtain the best evidence for the efficacy of both medical and surgical treatments by randomised controlled trials, as first reported in 1948 with the Medical Research Council’s trial of streptomycin in pulmonary tuberculosis27. He would, however, have been aware of the limitations: in particular the selection of “squeaky-clean” patients, and the difference between clinical and statistical significance28,29. Osler was a great admirer of Pierre Charles Alexandre Louis (1787-1872) who is generally credited with the introduction of la méthode numérique, the statistical method, in the study of human disease30, but Osler would have appreciated that it is not the average, but the variance, which is the reality31 and that the results of a trial, however well-designed, may not necessarily be extrapolated to patients in the “real-world”, especially the elderly with co-morbid diseases treated with multiple medications32. Osler would have been quick to point out that the results of any clinical trial require subjective assessment as to their significance33. Osler would have probably questioned whether it was correct to speak of placebo-controlled trials, when patients are told they would receive an inert drug or treatment. Placebo he would argue was a pharmacologically inert drug prescribed with therapeutic intent. Osler would have been in agreement with the late Sir John Henry Gaddum (1900-1965), professor of materia medica at Edinburgh University, that the term placebo is inappropriate in clinical therapeutic trials and should be replaced by “dummies”. The delta of response to a placebo is, of course, greater than a “dummie” drug or treatment.
We suspect that Osler would express doubt as to the value of meta-analysis, which has the same limitations as a single clinical trial, and to the whole concept of evidence-based medicine. Rangachari34 has suggested that the “father” of evidence-based medicine was Louis, and not workers at McMaster University in Hamilton, Ontario35. We would, however, suggest the Scottish Dr. James Lind (1716-1794) who stated in his 1953 Treatise on the Scurvy:
“I
shall propose nothing dictated
Louis was not the originator of the numerical method, for the Aberdeen-born Dr. George Fordyce (1736-1802) in 1793 attempted to improve the evidence of medicine by assisting the formation of a Society for the Improvement of Medical and Surgical Knowledge, while working in London, and with the publication in 1793 of a paper, “An attempt to improve the evidence of medicine”.
We suspect that Osler may have been wary of the masses of data collected on randomised controlled trials by the worldwide Cochrane Collaboration Study, named after the Scottish epidemiologist Archibald (Archie) Leman Cochrane (1909-1988)37, and initiated by Sir Iain Chalmers. Osler would have wondered if the project suffered from a surfeit of facts, to the detriment of ideas.
Ethics
of experimentation
Osler would have strongly approved of the ethical considerations now employed in conducting clinical trials. He was aware that each prescription of a drug is an experiment, as it is impossible to predict in every instance the result38. Osler opined “We have no right to use patients entrusted to our care for the purpose of experimentation unless direct benefit to the individual is likely to follow. Once the limit is transgressed, the sacred cord that binds physician and patient snaps instantly. Risk to the individual may be taken with his consent and full knowledge of the circumstances…”38. He was aware that “enthusiasm for science has, in a few instances, led to regrettable transgression of the rule…”, perhaps having in mind the experiments on yellow fever which proved the mosquito, Aedes aegypti transmitted the disease39.
Patients
as individuals
Osler was a general physician who saw patients not only as a whole, both body and soul, but also as individuals. The latter must certainly have been reinforced by the prescient landmark text of Sir Archibald Edward Garrod (1858-1936) entitled Inborn Erros of Metabolism, first published in 1909, and again more recently40. Garrod stressed the importance of an individual’s constitution in the expression of disease, giving rise to “chemical malformations” such as alkaptonuria, cystinuria and pentosuria. Garrod might therefore be regarded as the “father” of biochemical genetics and molecular biology. Osler, as a practising doctor, was accustomed of applying his clinical judgement on individual patients, and as a result would probably not have been over-enthusiastic about the results of clinical trials conducted on tens of thousands of patients41. Recent advances in molecular biology support Osler’s caution in conducting large-scale trials, with recognition that one gene may increase disease severity while another decreases it, as in Alzheimer’s disease42. Perhaps the most dramatic example of individuality to drug response is that reported with gefitinib in the treatment of lung cancer. A conventional trial showed that the drug gave no better results than conventional medication. However, it was found that several patients responded with reduction in their tumours. Subsequently it was shown that the tumours in these patients who responded possessed an epidermal growth factor receptor kinase enzyme with which gefitinib reacted43.
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