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Title: The Placebo Effect: History, Biology, and Ethics
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URL Source: http://www.medscape.com/viewarticle/852144
Published: Oct 10, 2015
Author: Patrick Lemoine, MD, PhD
Post Date: 2015-10-10 02:05:46 by Tatarewicz
Keywords: None
Views: 70
Comments: 3
The placebo effect itself is elusive. Though we can hope for it, no one can predict it. Even its definition is ambiguous. The placebo pill—and centuries of various snake oils—has nothing to do with the placebo effect, or the difference between the expected effect of a treatment and the one we observe. The history of placebos is filled with mix-ups and errors. So it is not surprising that the term itself is based on a translation mistake[1]: Jerome was responsible for translating the Bible into Latin (eventually called the Vulgate, meaning it was written in the everyday language of the time), which until then had been in Greek. The soon-to-be saint made a mistake in Psalm 16 (line 9), writing Placebo Domino, "I shall please the Lord," rather than Ambulabo coram Domino, "I shall walk before the Lord." We should really be talking about the ambulabo effect, not the placebo effect! But regardless of the term, the history of the placebo marched ahead all the same. From the 13th century on, bereaved families would chant the verse to pass the time during the recitation of the Office of the Dead. At some point, people began to mock the chanters, branding them as "placebos" for this apparently bizarre behavior. As society became more secular, the lord lost his capital "L" and Placebo was defrocked, instead donning the dress of the courtier. Decidedly pejorative, the word was then used to refer to flatterers and sycophants; in short, all those who sought to please by any means possible. In the 16th century, a curious method was used to confuse the possessed: the placebo relic. In order to avoid over-the-top exorcisms administered by overzealous clerics, when an individual showed questionable signs of diabolical possession, he or she would be given false relics. If, upon seeing the relics, the "possessed" acted as if they were authentic, the healer deduced that their seizures were the result of their morbid imagination, not the work of the Devil. The idea of controlling a dubious clinical manifestation by administering a treatment that is both inactive and deceiving probably arose from this practice. Until recently, some doctors used placebos to confuse hypochondriacs whose symptoms closely mimicked those of actual maladies and might be triggered, in a very real way, accidentally. We have since learned that this test is not reliable and that it is even dangerous because organic symptoms can react to placebo while the aforementioned functional symptoms may not respond to it. This could cause delays, or even errors, in diagnosis. In 1752, James Lind (1716-1794), a Royal Navy doctor, published his A Treatise of the Scurvy after performing, though he didn't know it at the time, the first experiment to use placebo groups. He devoted the rest of his life to trying to convince the Admiralty—and the school of medicine—of the merits of his discovery. Inventor of what would one day be called the "controlled trial," Lind selected 12 sailors suffering from scurvy. He divided them into groups of two, assigning each group one of six different treatments for 15 days: The first group received cider, the second an elixir of vitriol (sulfuric acid), the third vinegar, the fourth seawater, the fifth lemons and oranges, and the last a mixture of garlic, mustard, and horseradish root. The lucky patients belonging to the fifth group healed within days. Cider also performed miracles but not as quickly, it seems. The other four groups were placebo groups, and the assigned treatment proved fatal. From a moral standpoint, one hopes that Lind did not know for certain that four of his six groups received an inactive product, as he did choose substances that at the time were thought to be therapeutic. Another example involves Franz Anton Mesmer. In 1784, Louis XVI appointed a commission headed by Benjamin Franklin to evaluate the effectiveness of the physician's famous "baquet," a sort of covered tub that allowed Mesmer to perform magnetic passes for several patients at a time. The conclusion was that "all is not imagination, but [that] the imagination is in everything." Again, it is possible that Mesmer acted in good faith and believed that his tub was effective because in reality it is thanks to his own conviction that he generated spectacular cures for his prestigious patients. Medicine Embraces Placebo It took until 1785 to see the word "placebo" appear in the first medical dictionary, the Motherby's New Medical Dictionary, where it is defined as "a commonplace medication or method." The word "commonplace" should probably be taken to mean trite. Finally, in 1958, the word placebo appears officially in France in the seventeenth edition of Garnier and Delamarre's Dictionary of Technical Terms of Medicine and later in mainstream dictionaries. But it was only with the advent of double-blind controlled trials with random assignment that placebos gained scientific respectability. Up to that point, a sulfurous whiff of quackery hung around the word. The most recent research has also helped to understand how a state of mind, a suggestion, or an expectation on the part of the physician or the patient can induce objective and measurable changes. In a famous article gathering the data of 15 studies of 1082 patients with extremely varied pain, Beecher[2] showed that a placebo analgesic is effective, on average, in 35.2% of cases, within the range of 4% and 86%. The pain that was the least organic (experimental pain triggered in a laboratory on healthy subjects) but also the least intense showed the weakest response to the placebo, while particularly distressful organic pain, like angina, proved to be most sensitive to placebo. Indeed, a major driver of the placebo effect is expectations: A healthy person who knows they are experiencing experimental pain that can be stopped whenever they want is surely less motivated to activate a "placebo strategy" than an ill person suffering from a more or less well-controlled but very worrying ailment. Since Beecher's article was published, many publications have quantified, in disease after disease, the effectiveness of the placebo and the importance of the placebo effect, depending on the patient's and the physician's psychological context. Other research has attempted to provide psychological, ethological, anthropological, or sociological explanations of its mechanisms of action, all based primarily on the suggestion, enthusiasm, and expectation of the doctor, who can induce the patient's reaction himself. Yet it is the biological interpretations that have shed the most unexpected—and convincing—light on this amazing phenomenon that, with the power of thought, can change parameters such as white blood cell count, cholesterol, gastric acidity, pupil size...and so on and so forth! The Animal Approach Past work[3] has shown that rats exposed to uncontrollable electric shocks – meaning those from which they cannot escape -- as compared with controllable shocks, demonstrate impaired immune function, as demonstrated by reduced lymphocyte count. This work has also found that simply warning the rats that a shock is coming – by conditioning them with, say, with a flash of light – helps preserve their immune response in response to a grafted malignancy. Furthermore as one study showed,[4] rats exposed to uncontrollable shocks also exhibit increased susceptibility to malignancy. The researchers divided rats into which malignant cells were grafted into into three groups. The first group served as a control group and was put in a standard cage with no special features. The second batch was put in a cage with a wire mesh floor connected to a generator emitting random electric charges. Given the unpredictability, they had no way to control their stress. The third group was put in a cage equipped with the same device but with a lever that allowed the rats to instantly interrupt the current, both at home and in the second group's cage. The amount of electric shock, pain, and therefore stress was found to be the same in the second and third cages, the only difference being that the rodents in cage number 2 had no control. After 4 weeks, all of the animals were sacrificed. In cage number 1—the control cage—the tumor had taken hold in 54% of rats; in cage 2, it had grown in 63%; in cage number 3, the cancer took hold in just 27% of the rodents. It is clear from this study that undergoing a painful and stressful stimulus without the possibility for control fosters tumor growth, while the same stress experienced under the same conditions, but with the possibility to control the stimulus, has an anticancerous effect. A painful, inevitable, incomprehensible, unpredictable event disrupts the immune system and increases the likelihood that an experimental cancer will take; this is the foundation of the nocebo effect (the opposite of placebo), the absence of information and sense of control in animals. Consistent control of the event strengthens the immune system and successfully curbs the development of cancer; this is the placebo effect. Collectively, the aforementioned animal work shows that a systematic warning before a negative event – or a sense of control over a negative situation -- gives subjects time to psychologically prepare and influence their health for the better. Similarly in humans, it has been shown that an enthusiastic and convincing prescription (suggestion) of a placebo can alter many parameters, such as blood pressure, in the long term.[5] All risky extrapolations aside, the above findings should strongly encourage clinicians to provide their patients with clear, accessible, and tailored information about the diagnosis and the treatments they receive. In humans, the understanding of what will happen makes it possible to control the stress of disease and its treatment. The Neurobiology of Placebo in Humans Since 1896,[6] we have known that individuals with allergies sometimes sneeze when exposed to artificial flowers, and in The Mystery of Placebos,[5] I described a subject who was allergic to pollen and exposed to intense and prolonged stress (the exodus from Belgium after German invasion in May 1940). The subject did not sneeze for an entire sunny spring, despite his wandering of country roads, confident that he and his family were going to be massacred. The hypothesis is that he experienced an endogenous antiallergic action thanks to significant cortisol and norepinephrine secretion in the face of intense and prolonged terror. In 1978, Levine[7] demonstrated a possible neurobiological pathway associated with placebo through an original method: After undergoing dental extraction, patients received a placebo analgesic. After a random draw, half of the subjects also received naloxone, an opioid receptor antagonist. The other subjects received a placebo naloxone. The result: The placebo analgesic had no effect on the group receiving naloxone—due to saturated endorphin receptors—whereas it proved effective in those who took a placebo naloxone, whose endorphin receptors remained free. So, in this case, an increase in endorphin transmission explained the pain-killing placebo effect. This study was controversial until Benedetti[8] confirmed the conclusion. He recruited 340 healthy volunteers and subjected them to ischemic pain of at least a 7 on a 10-point scale, randomly dividing subjects into 12 comparative groups. The study showed a dose-dependent effect of naloxone: The more receptors are blocked, the smaller the placebo effect. This showed definitively the endorphinic system's role in determining the placebo effect on pain. Endorphins are not the only compounds involved in the complexities of pain physiology. For example, the analgesic effect induced by the placebo may be partially or completely inhibited by cholecystokinin (CCK) and reinforced by a CCK antagonist.[9] Proglumide, one CCK antagonist, was administered postoperatively to patients who were purposely told that this product could increase their pain in order to provoke their anticipatory anxiety. This agent has proved capable of inhibiting nocebo hyperalgesia in a dose-dependent manner, demonstrating the role of CCK in nocebo hyperalgesia. Because CCK is involved in the mechanisms of anticipatory anxiety, it is generally believed that the nocebo effect related to this particular phenomenon is tied to this peptide. PET scanning also makes it possible[10] to visualize the activation of the anterior cingulate cortex, rich in opioid receptors. Placebo analgesia activates the prefrontal cortex, which can be interpreted as the expression of the subjects' expectations, themselves correlated with doctors' expectations, in anticipation of healing. Finally, regarding pain, if a patient is conditioned to respond to an opioid analgesic treatment, the placebo effect of morphine is canceled by naloxone. But if the patient is conditioned to a nonopioid analgesic treatment, naloxone does not inhibit the analgesic placebo effect, confirming the idea that the placebo analgesic can only act through an endorphin effect. Depression and Parkinson Disease When comparing fluoxetine (Prozac®), venlafaxine (Effexor®), and placebo, quantified electroencephalography showed that placebo responders increase their prefrontal activity sooner and to a greater extent than those who responded to antidepressants and in contrast to resistant patients.[11] PET scan data showed increased metabolic activity, though less intense and in serotonin-rich areas, in placebo responders compared with patients treated with fluoxetine. Moreover, fluoxetine, unlike placebo, activated subcortical, anterior insular, and hippocampal limbic areas, hence the hypothesis that the placebo antidepressant acts on the higher functions rather than the more primitive areas, which makes sense given that it is subjects' expectations, related to consciousness and will, that determine the response or nonresponse to placebo. A remarkable study[12] published in Science showed that the more or less brief placebo effect often observed in this disease corresponds to a release of dopamine in the striatum and that in those who respond to placebo as they do to L-DOPA therapy, this release is comparable, albeit smaller, than that produced by L-DOPA. The placebo effect would therefore be based on activation of endogenous therapeutic substances or medications. Further upstream, dopamine may play a key role because of its involvement in reward pathways in the corticolimbic circuits, including the prefrontal areas, with the expectation of pleasure due to an improvement being a reward in itself. However, it is likely that other neurological and immune systems come into play as well. Prescribing Placebo Ethically? There is a saying in medicine that goes double for psychiatry: "You shall not lie." So the question is: Is it possible to prescribe a placebo without lying? There are two kinds of placebo: a pure placebo and an impure placebo. Pure placebos are substances or interventions with no pharmacologic effect (eg, sugar pills). Impure placebos have pharmacological effects, but their effectiveness for a particular disease is still uncertain. It seems impossible to prescribe a pure placebo without lying, outside of a research context wherein a patient can review the protocol approved by an ethics committee and give their written consent. It's not a problem in this case. Let's look at sleep: Often when patients try to wean off sleeping pills, they just can't stop that last quarter tablet—it's psychologically difficult to stop. It's a bit like when a child learns to swim and refuses to let go of a floating device that the instructor has gradually deflated! An easy way to encourage sleep aid-dependent patients to wean off medication involves the ethical use of placebo: Buy 30 empty capsules (pharmaceutical compounding) from the pharmacy. Once you get home, open them all and fill with fine granulated sugar. Finally, slip the remaining prescribed quarter tablets into 25 of the empty capsules and close them. So there are now 25 active capsules that contain a quarter tablet of the prescribed sleeping aid and 5 capsules of pure placebo. Now mix the capsules and take one each night. The second month, prepare 20 sleeping aid capsules in the same way described and 10 placebo capsules; the third month, 15 sleeping aid capsules, 15 placebo capsules; and so on and so forth until there is (almost) nothing left but placebo capsules. Usually, by this point, weaning is complete, and you can stop entirely. But I do recall one of my patients, a specialist doctor, who for several years continued to take his capsule each night even though there was only one capsule in the month's supply containing a sleeping aid and 29 or 30 capsules of placebo. "It helps me," he said "to know that each night I have even the slightest chance of having my sleeping aid." And it's true that he was able to establish a healthy sleeping pattern after 10 years of taking a sedative hypnotic each night. I always let him do as he wished—taking a quarter tablet of a sleeping aid per month really doesn't pose a problem. And how about impure placebos? Can you prescribe a medication without lying by using it for something other than its official use? Think of the way vitamin C is used to treat maladies other than scurvy, even though there is no scientific proof that it is the least bit effective in other applications. I think the answer is yes, if the prescriber believes in it. This could be seen as both provider and patient under the influence of expectation. Take the example of homeopaths, who are able to maximize the placebo effect. Conclusions Our brain is the administrative headquarters of a formidable, unbelievable pharmaceutical company able to demand and distribute its products throughout our body. We manufacture multitudes of medications: antibiotics, antimitotics, painkillers, antipyretics, anxiolytics, antidepressants, anti-inflammatories, immunostimulants, anticholesterols, antihypertensives, antipsychotics, cancer drugs, and more. We can also activate other parallel circuits involving natural counterparts to more culturally and medically scandalous substances: anandamide (cannabis), alcohol, amphetamines, nicotine, cocaine, LSD, endorphins, and more. The president of this whole enterprise is "me"; our brains; each of us. Poster Comment: Literature shows effectiveness of placebo is continually increasing.
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#1. To: Tatarewicz (#0)
Really fantastic word (etc.) study!! The political applications are obvious and all around us.
Welcome to "Hooked On Phonies" - the rehab clinic for placebo addiction.
John Howard says: There are 4 schools of economics: How to End the Refugee Flood Hooked on Phonies....... WHOA you're in good form today!!!! It's priceless -- perfect.
#2. To: Tatarewicz (#0)
Marxism: steal everything
Keynesianism: steal by counterfeiting whenever needed
Chicago school (Milton Friedman): steal by counterfeiting at a steady, predictable rate
Austrians: don't steal
'Wiped off the Map' – The Rumor of the Century
#3. To: PnbC (#2)
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