Beecher as Clinical Investigator: Pain and the Placebo Effect

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1 Beecher as Clinical Investigator: Pain and the Placebo Effect Fabrizio Benedetti Perspectives in Biology and Medicine, Volume 59, Number 1, Winter 2016, pp (Article) Published by Johns Hopkins University Press DOI: For additional information about this article Accessed 8 Jun :35 GMT

2 Beecher as Clinical Investigator pain and the placebo effect Fabrizio Benedetti ABSTRACT Among the many contributions by Henry Beecher to science and clinical practice, pain and the placebo effect certainly represent two of the most important aspects. On the one hand, Beecher considered the pain experience not only as arising from the peripheral injured tissues, but also as an emotional experience that is capable of modulating the nociceptive input. On the other hand, he analyzed the placebo effect at an unprecedented level for that time. His ideas sparked from his work on wounded soldiers during World War II. In spite of the unusual situation and the lack of sophisticated experimental tools on the battlefield, Beecher succeeded in putting forward several important concepts, and his ideas still pervade modern health care and research. To be both a clinician and a scientist what is usually called a clinician scientist or clinical investigator is easy neither from an ethical nor from a methodological standpoint. On the one hand, it requires care, cure of the patients, and good ethical practice. On the other, excellent skills in experimental design Department of Neuroscience, University of Turin Medical School, and Plateau Rosa Labs, Italy/ Switzerland. Correspondence: Fabrizio Benedetti, Department of Neuroscience, University of Turin, Corso Raffaello 30, Turin, Italy. fabrizio.benedetti@unito.it. This work was supported by grants from Compagnia di San Paolo Foundation and the ICTH Initiative. Perspectives in Biology and Medicine, volume 59, number 1 (winter 2016): by Johns Hopkins University Press 37

3 Fabrizio Benedetti and data analysis are necessary. In addition, the correct choice of a disease as a model to be studied is very often hampered by the obvious ethical constraints of working with human beings, thus limiting the experimental armamentarium in the hands of the clinician scientist. Yet, Henry Beecher succeeded in both. He was an excellent clinician and scientist and put forward ideas and concepts that today still pervade many clinical and experimental approaches. This article focuses on two major contributions and their consequences in modern clinical practice and research: the psychological component of pain, and the placebo effect. The Meaning of Pain One of the most important aspects of Beecher s scientific and clinical activity is within the field of pain and analgesia in the scenario of World War II, particularly on the Venafro and Cassino Fronts and at the Anzio Beachhead in Italy (Beecher 1946). As an anesthesiologist and pain therapist on the battlefield, Beecher soon realized that only a few soldiers carried into a combat hospital complained of enough pain to require morphine, even though they were neither in a state of shock nor unable to feel pain. Furthermore, he found no correlation between the intensity of pain and the extension of the wounds. He studied 215 wounded soldiers who had one of the following five kinds of severe wounds: (1) extensive peripheral soft-tissue injury; (2) compound fracture of a long bone; (3) a penetrated head; (4) a penetrated chest; or (5) a penetrated abdomen. Whereas 69 patients (32.1%) had no pain, and 55 patients (25.6%) had slight pain, 40 patients (18.6%) complained of moderate pain, and 51 patients (23.7%) of bad pain. Therefore, more than half (76.3%) presented moderate/slight or no pain at all, in spite of the extensive wounds. Not surprisingly, Beecher also observed a close parallelism between the number of soldiers reporting bad pain and those wanting pain relief medication. In fact, 58 soldiers (27%) wanted pain relief therapy, whereas 157 (73%) did not want pain relief (Beecher 1946). Some recent findings seem to disagree with Beecher s conclusions, although there are important differences in the study designs. For example, Beecher asked casualties about their pain on arrival at the combat hospital, whereas in the study by Aldington, McQuay, and Moore (2011) casualties were asked their recollection of pain weeks after injury and, moreover, had experienced a greater degree of injury severity. When Beecher returned to his practice in the United States after World War II, he compared the pain in the soldiers to posttraumatic pain in civilians with similar wounds (see also the placebo effect discussion below). He found that the requirement for analgesia was significantly higher in civilian patients compared to the soldiers on the battlefield (Beecher 1960). Therefore, there was no direct relationship between the severity of the wound and the intensity of pain. According to Beecher, the most plausible explanation for this discrepancy between 38 Perspectives in Biology and Medicine

4 Beecher as Clinical Investigator soldiers and civilians was related to the meaning attached to the injuries. Whereas to the soldier the wound meant surviving the battlefield and returning home, the wounded civilian often faced many negative consequences, such as diminishment of activities and loss of income. Beecher was really a pioneer in this sense, because he realized that the context around the patient makes the difference, and that the meaning of pain can turn a negative into a positive experience (Carlino, Frisaldi, and Benedetti 2014). Indeed, today we know that the different meaning that is attributed to a symptom can be crucial. For example, cancer pain can be perceived as more unpleasant than postoperative pain (Cormie, Nairn and Welsh 2008; Ferrell and Dean 1995; Smith, Gracely and Safer 1998), and this can be due to the different meanings of cancer on the one hand and of surgery on the other. Whereas the former often means death, the latter is associated to healing and recovery, a comparison that is very similar to Beecher s studies. Similarly, different religions attribute different meanings to pain and suffering, and this may lead to different pain experiences (Henderson 2000; Koffman et al. 2008; Whitman 2007). The attribution of different meanings to pain has also been tested in the laboratory, and the involvement of the opioid/cannabinoid systems and of the reward neuronal circuit has been found when pain is perceived as a rewarding experience (Benedetti et al. 2013; Leknes et al. 2013). Thus Beecher was one of the first investigators who understood that pain can be experienced differently, depending on the surrounding context. He was also concerned about the psychological factors associated to the injuries in the soldiers of World War II. For example, he always considered complex psychological factors, such as anxiety, emotional stress, grief from the loss of friends, fear, physical discomforts of exposure to sounds, lights and adverse weather conditions, inadequate food and fluid intake, loss of sleep, exhaustion. Likewise, he paid particular attention on the emotional consequences of the wounds. For example, will the soldier lose the injured arm? Will he be impotent because of blood around his genitals? Is he going to die because of a wound in his chest? By taking all these considerations into account, Beecher supported not only analgesic therapy but also sedation (Beecher 1946). The Placebo Effect One of the Beecher s seminal papers, The Powerful Placebo (1955), was published in a particularly productive and revolutionary period for placebo research, whereby many new concepts and ideas were put forward (Lasagna, Laties and Dohan 1958; Wolf 1950). This ultimately led to a true biology of the placebo effect later in the 1970s, and in the modern era of placebo research (Benedetti 2014a, 2014b; Levine, Gordon, and Fields 1978). The importance of Beecher s 1955 paper is even more evidenced by considering that placebo has always been winter 2016 volume 59, number 1 39

5 Fabrizio Benedetti conceived as a comparator in the methodology of clinical trials or, alternatively, investigated by psychologists as an example of the power of mind and imagination. Beecher succeeded in both, putting the placebo effect within the context of clinical research and considering placebos as powerful tools of the physician s armamentarium. As an anesthesiologist, Beecher worked both at the Massachusetts General Hospital and on the battlefield. As an army doctor during the World War II, his experience with wounded soldiers suffering from acute and severe pain gave an important impetus to placebo research. Basically, Beecher was faced with the problem of a lack of strong analgesics on the battlefield, particularly morphine, so sometimes he used placebos to treat his soldier patients. Of course, the soldiers were told that the inert substance Beecher had administered was a powerful painkiller. Many of them appeared to respond to the placebo, thus boosting Beecher s curiosity about the phenomenon. In particular, he noted that saline solution by injection had 90% of the effectiveness of morphine in alleviating the pain associated with acute injury, compared to civilian hospitals, where the placebo effect dropped to 70% of the effectiveness of morphine in postoperative pain, and with subsequent administrations drops still lower (Beecher 1959; Orne 1969). Therefore, Beecher concluded that the placebo effect may be extremely powerful, and that it interacts with the experimental/clinical situation in which it is being investigated. In his 1955 paper, he reviewed 15 controlled trials involving 1,802 patients. Defining positive outcomes as the per cent satisfactorily relieved by placebo, Beecher reported effect sizes ranging from 26 58%, with an average of 35%. The notion that about one-third of patients respond to placebo has since permeated medical texts and teachings. Nonetheless, today we know that the notion that one-third of patients respond to placebos should be abandoned (Benedetti 2014a). Indeed, one of the main problems in Beecher s conclusion was that no comparisons between placebo groups and natural history groups were considered. Without a control condition to assess the natural history of pain, spontaneous remission cannot be ruled out. Therefore, the best explanation we have today for Beecher s conclusion of one-third placebo responders is that the pain reduction observed in the placebo groups included many factors, such as spontaneous remissions, regression to the mean, and real placebo responses. Despite these limitations, Beecher s view represents a milestone for the placebo effect in medical practice, and it was certainly important for boosting the interest of the scientific community. Today we know that robust placebo responses occur in a number of painful conditions, such as neuropathic pain (Benedetti 2014a; Petersen et al. 2012; Quessy and Rowbotham 2008). In addition, in an analysis of five studies in which 130 patients received a placebo treatment, 7 37% of patients in the placebo group showed greater than 50% of the maximum possible pain relief (McQuay, Carroll, and Moore 1995). These data were obtained in the postoperative setting, and they are 40 Perspectives in Biology and Medicine

6 Beecher as Clinical Investigator in keeping with the variation of the placebo effect in the acute pain setting found by Beecher in In fact, using the dichotomous measure of greater than 50% pain relief, Beecher found a range of 15 53% in patients who received placebo treatment in five acute pain studies. In a study on the comparison between different analgesics, like morphine, codeine, acetylsalicylic acid, and placebos, Beecher emphasized the problem of the placebo effect and stressed the importance of placebo controlled trials (Beecher et al. 1953). He was probably one of the first authors to consider placebo reactors and non-reactors in clinical research, as well as their importance in the design of clinical trials and the interpretation of the therapeutic outcomes (Beecher 1952, 1959). The existence of placebo responders and non-responders is today one of the main challenges of placebo research, and different mechanisms such as learning, genetics, and personality have been identified that may explain why some people respond to placebos and some other people do not (Benedetti 2014b; Geers et al. 2005; Hall, Loscalzo, and Kaptchuk 2015). Beecher s scientific approach to the placebo effect in the early 1950s was further developed in the late 1950s by Lasagna, Laties, and Dohan (1958), whose studies further boosted interest in the placebo effect. These authors introduced the notion of pharmacology of placebo, describing some of the characteristics of placebo treatments compared to drug treatments, an unusual and innovative idea at that time. Basically, they investigated four main elements: peak effects, cumulative effects, carryover effects, and severity-related efficacy. First, similar time-effect curves, expressed as the maximal effect achieved at a certain point in time, were found for aspirin and placebo in postpartum pain, although the efficacy of aspirin was much higher than placebo. Second, patients suffering from tuberculosis were found to improve in subjective outcomes, such as pep and appetite, following a placebo treatment delivered along with verbal suggestions of improved energy and appetite; most interesting, there was a cumulative effect over time, both for pep and for appetite, namely, a build-up effect of repeated doses, which is typical of drugs. Third, the same study on tuberculosis patients found carryover effects for placebos, which is typical of the long-lasting effects of drugs even after treatment interruption. Finally, the inverse relationship of efficacy to the severity of a symptom, which is a characteristic of drug action, was found for both aspirin and placebo. The investigation of the placebo effect evolved further in the 1970s, extending to the biological mechanisms in a work by Levine, Gordon, and Fields (1978). Beecher s interest in the placebo effect was boosted not only by the observation of high placebo responsiveness of pain, but also of surgery. In fact, he wrote another seminal paper about placebos, Surgery as Placebo (1961), which emphasizes how placebo effects can be robust and substantial in both pharmacological and non-pharmacological therapeutic interventions. Beecher s interest in placebo surgery was also sparked by inherent ethical concerns. Placebo groups in different types of surgery are rare and difficult to investigate, because placebo sur- winter 2016 volume 59, number 1 41

7 Fabrizio Benedetti gery is problematic from an ethical standpoint. However, when placebo surgery trials have been done, patients who underwent placebo surgery showed a high rate of clinical improvement, even though in most of these trials it is not possible to distinguish between the real placebo effect, natural history of the disease, and regression to the mean. Again, the 1950s proved to be very productive and innovative years for placebo research. For example, placebo surgery trials were performed for treatment of angina pectoris, a condition in which there is inadequate blood supply to the heart. The placebo surgery approach was rationalized because a common treatment for angina pectoris at that time was ligation of the internal mammary arteries. In the early 1950s, it was believed that blood could find alternative routes into the heart, thus improving heart circulation; however, it was later found that no new blood vessel could be detected in the heart, thus making the validity of the procedure questionable. Dimond, Kittle, and Crockett (1958) and Cobb et al. (1959) decided to perform sham surgery, whereby patients underwent the same surgical procedures for mammary artery ligation, but without actual ligation of the internal mammary arteries. Some patients showed an improvement in terms of pain, physical performance, and electrocardiogram results. Overall, there was a substantial improvement in those that received real surgery, in 67% of the patients; a substantial improvement in the placebo group was present in 83% of the patients. More recent findings confirm that, when a placebo-controlled surgical trial is carried out, the placebo component appears to be substantial. Important examples are vertebroplasty, laser myocardial revascularization in people with coronary heart disease, and arthroscopic surgery for osteoarthritis of the knee (Buchbinder et al. 2009; Kallmes et al. 2009; Moseley et al. 2002; Rana et al. 2005). For example, 165 patients who completed Moseley and colleagues 2002 study were randomly assigned to receive either arthroscopic debridement, arthroscopic lavage, or placebo surgery. For the placebo, skin incisions were made and debridement was simulated, but the arthroscope was not inserted. The investigators found no differences in pain ratings and knee function between the three groups either at one year or two years after surgery. In order to rule out possible confounding factors like natural history, some neurosurgical trials of deep-brain stimulation for the treatment of Parkinson s disease have been performed under strictly controlled conditions by also analyzing either a no-treatment control group or the patient s expectations, and true placebo effects were found (Benedetti et al. 2003; McRae et al. 2004; Mercado et al. 2006). Thus Beecher paved the way to a true science of the placebo effect, and 23 years after his publication on The Powerful Placebo, Levine, Gordon, and Fields (1978) gave rise to the first mechanistic explanation of placebo analgesia, by showing that it could be blocked by an opioid antagonist, thus suggesting the involvement of the endogenous opioid system. Modern placebo research mostly relies on these early studies and on the notion that placebos may produce effects 42 Perspectives in Biology and Medicine

8 Beecher as Clinical Investigator that are similar to those induced by drugs. Indeed, the concept that is emerging today is that placebos use the same receptorial and biochemical pathways that are used by drugs (Benedetti 2014b). The modern concept of placebo is related to the psychosocial context around the patient and to the whole ritual of the therapeutic act. Therefore, what we have learned today is that therapeutic rituals can change the patient s physiology in the same way as drugs do, albeit to a lesser extent. The challenge today is to understand and to map these placebo responses across a variety of medical conditions and therapeutic interventions, both pharmacological and non-pharmacological, in order to better give a mechanistic explanation to different placebo effects. Conclusion From the early pain and placebo studies in the 1950s, we have now moved on to the investigation of placebo mechanisms in conditions other than pain, such as movement disorders, the immune and endocrine systems, as well as physical performance. In addition, following Beecher s earlier observations, we can now investigate the effects of different contexts on pain by using a modern neuroscientific approach. Therefore, what Beecher learned in an unusual non-laboratory condition, on the battlefields of World War II, as well as in pioneering laboratory experiments and clinical observations while at Massachusetts General Hospital, is still present in the modern laboratory setting. This approach will hopefully lead to a better understanding of pain and the placebo effect, and more generally of medicine and human biology. References Aldington, D. J., H. J. McQuay, and R. A. Moore End-to-End Military Pain Management. Philos Trans R Soc Lond B Biol Sci 366 (1562): Beecher, H. K Pain in Men Wounded in Battle. Ann Surg 123 (1): Beecher, H. K Experimental Pharmacology and Measurement of the Subjective Response. Science 116 (3007): Beecher, H. K., et al The Effectiveness of Oral Analgesics (Morphine, Codeine, Acetylsalicylic Acid) and the Problem of Placebo Reactors and Non-Reactors. J Pharmacol Exp Ther 109: Beecher, H. K The Powerful Placebo. JAMA 159 (17): Beecher, H. K Measurement of Subjective Responses: Quantitative Effects of Drugs. New York: Oxford University Press. Beecher, H. K Control of Suffering in Severe Trauma: Usefulness of a Quantitative Approach. JAMA 173: Beecher, H. K Surgery as Placebo: A Quantitative Study of Bias. JAMA 176: Benedetti, F. 2014a. Placebo Effects. 2nd ed. Oxford: Oxford University Press. winter 2016 volume 59, number 1 43

9 Fabrizio Benedetti Benedetti, F. 2014b. Placebo Effects: From the Neurobiological Paradigm to Translational Implications. Neuron 84(3): Benedetti, F., et al Conscious Expectation and Unconscious Conditioning in Analgesic, Motor, and Hormonal Placebo/Nocebo Responses. J Neurosci 23 (10): Benedetti, F., et al Pain as a Reward: Changing the Meaning of Pain from Negative to Positive Co-Activates Opioid and Cannabinoid Systems. Pain 154 (3): Buchbinder, R., et al A Randomized Trial of Vertebroplasty for Painful Osteoporotic Vertebral Fractures. N Engl J Med 361 (6): Carlino, E., E. Frisaldi, and F. Benedetti Pain and the Context. Nat Rev Rheumatol 10 (6): Cobb, L. A., et al An Evaluation of Internal-Mammary Artery Ligation by a Double-Blind Technic. N Engl J Med 260: Cormie, P. J., M. Nairn, and J. Welsh Guideline Development Group: Control of Pain in Adults with Cancer: Summary of SIGN Guidelines. BMJ 337: a2154. Dimond, E. G., C. G. Kittle, and J. E. Crockett Evaluation of Internal Mammary Ligation and Sham Procedure in Angina Pectoris. Circulation 18: Ferrell, B. R., and G. Dean The Meaning of Cancer Pain. Semin Oncol Nurs 11 (1): Geers, A. L., et al Reconsidering the Role of Personality in Placebo Effects: Dispositional Optimism, Situational Expectations, and the Placebo Response. J Psychosom Res 58 (2): Hall, K. T., J. Loscalzo, and T. J. Kaptchuk Genetics and the Placebo Effect: The Placebome. Trends Mol Med 21 (5): Henderson, S. W The Unnatural Nature of Pain. JAMA 283 (1): 117. Kallmes, D. F., et al A Randomized Trial of Vertebroplasty for Osteoporotic Spinal Fractures. N Engl J Med 361 (6): Koffman, J., et al Cultural Meanings of Pain: A Qualitative Study of Black Caribbean and White British Patients with Advanced Cancer. Palliat Med 22 (4): Lasagna, L., V. G. Laties, and J. L. Dohan Further Studies on the Pharmacology of Placebo Administration. J Clin Invest 37 (4): Leknes, S., et al The Importance of Context: When Relative Relief Renders Pain Pleasant. Pain 154 (3): Levine, J. D., N. C. Gordon, and H. L. Fields The Mechanism of Placebo Analgesia. Lancet 2 (8091): McQuay, H., D. Carroll, and A. Moore Variation in the Placebo Effect in Randomized Controlled Trials of Analgesics: All is as Blind as it Seems. Pain 64 (2): McRae, C., et al Effects of Perceived Treatment on Quality of Life and Medical Outcomes in a Double-Blind Placebo Surgery Trial. Arch Gen Psychiatry 61 (4): Mercado, R., et al Expectation and the Placebo Effect in Parkinson s Disease Patients with Subthalamic Nucleus Deep Brain Stimulation. Mov Disord 21 (9): Moseley, J. B., et al A Controlled Trial of Arthroscopic Surgery for Osteoarthritis of the Knee. N Engl J Med 347 (2): Orne, M. T Demand Characteristics and the Concept of Quasi-Controls. In Artifact in Behavioral Research, ed. R. Rosenthal, R. L. Rosnow, and A. E. Kazdin, New York: Academic Press. 44 Perspectives in Biology and Medicine

10 Beecher as Clinical Investigator Petersen, G. L., et al Placebo Manipulations Eeduce Nyperalgesia in Neuropathic Pain. Pain 153 (6): Quessy, S. N., and M. C. Rowbotham Placebo Response in Neuropathic Pain Trials. Pain 138 (3): Rana, J. S., et al Longevity of the Placebo Effect in the Therapeutic Angiogenesis and Laser Myocardial Revascularization Trials in Patients with Coronary Heart Disease. Am J Cardiol 95 (12): Smith, W. B., R. H. Gracely, and M. A. Safer The Meaning of Pain: Cancer Patients Rating and Recall of Pain Intensity and Affect. Pain 78 (2): Whitman, S. M Pain and Suffering as Viewed by the Hindu Religion. Pain 8 (8): Wolf, S Effects of Suggestion and Conditioning on the Action of Chemical Agents in Human Subjects: The Pharmacology of Placebos. J Clin Invest 29 (1): winter 2016 volume 59, number 1 45