The "Placebo Effect"


The word dates to the fourteenth century. It is Latin for "I shall please". Reviews report that Hooper’s Medical Dictionary in 1811 defined "placebo" as: “an epithet given to any medicine adopted to please rather than to benefit the patient.”

The mid-twentieth century saw the development of many pharmaceuticals. Scientists needed a reliable way to differentiate the effects of these drugs from the natural history of disease and other confounding factors. In 1945, Pepper et. al published A note on the placebo in the American Journal of Pharmacy (117:409-412) describing the use of inert substances as controls for testing medications. 

Since 1945, pills that contain no active drug have come to be known as "placebos". Specifically, the American Medical Association uses the definition: "A placebo is a substance provided to a patient that the physician believes has no specific pharmacological effect upon the condition being treated.They are usually made of sugar, thus the term 'sugar pill' has become synonymous with 'placebo'. Ideally, a medical researcher wants to control for all factors that patients experience in a research study, including the act of taking a pill. By using a fake drug - without the patient's full knowledge - in the control group, the effects of the actual drug in the treatment group can be measured.

Placebos are properly used in research. Placebos do not have to be pills. They can be inert injections made to appear like true injectable medications. They can be fake procedures, such as a superficial incision with stitches placed under anesthesia to mimic a surgery. Recently, placebo needles have been devised to simulate the actual placement of acupuncture needles. In short, placebos are fake treatments used to research the effectiveness of 'actual' treatments.


What is the "Placebo Effect"?


Before long, scientists began to postulate that patients were perceiving changes in symptoms in response to these inert placebos. In 1953, Beecher et. al were studying the effects of pain relievers. They used placebos in their control groups. Some of the control patients exhibited significant pain relief. The researchers called such patients "placebo reactors".
 
After removing the "placebo reactors" from the study, the researchers could actually measure a difference between the treatment and the control groups. So it seems that some patients - but not all - can experience pain relief with inert sugar pills comparable to narcotics.

In 1955, H.K. Beecher published a paper in JAMA called The Powerful Placebo. He concluded that up to 35% of the perceived effect of a treatment may be due to the placebo effect.

Since then, many have observed effects - presumably from placebos - in studies designed to test treatments for asthma, depression, anxiety, pain, high blood pressure and others. The effect resulting from taking a placebo is known as the "placebo effect". Moerman and Jonas pointed out that this is a bit of a circular definition, and is thus without substance. Yet, a significant percentage of patients seem to persist in feeling better after taking inert treatments, as long as they think that they are real.    

The term "placebo effect" is often misunderstood. In terms of pain, there may be a physiologic response to the psychological thought of taking a treatment. Mostly, the "effect" is limited to subjective improvements rather than objective measures of disease improvements. Sometimes, the "effect" is not an effect at all, but rather the natural course of disease and symptoms.

Peter Lipson, MD, described it this way: "What we've learned about so-called placebos over the years is that "placebo" is not an intervention like a medication or a surgery.  It is an artifact of observation.  A certain amount of change can be expected any time you study a group of people.  "Placebo (effect)" is simply all of the change that can't be explained by the primary intervention".


Is it Real?


Is it real? Well, it depends on what one means. A systematic review of the literature in 2001 suggested that placebos have not been found to produce measurable effects, with the possible exception of pain management.  

Self-limited conditions, such as the common cold and acute back pain, progress over time with respect to symptoms in recognized patterns. After onset, symptoms reach a peak and then decline back to baseline. It is reasonable to expect that patients will seek care at or near the peak of symptoms. At that point, any advice or "treatment" will appear to work as the symptoms decline.

When studies are done to investigate such treatments, they must be compared to a placebo "treatment" to determine if the effect is real. If the improvement in the treatment arm in the study is not superior to the improvement in the placebo arm, then the treatment is deemed ineffective. The perceived effectiveness of the treatment is often called "the placebo effect". However, this is simply the natural progression of the condition and an incorrect assumption on the part of the practitioner and the patient.

Other conditions are not self-limiting, but go through natural swings in symptoms around a baseline 'mean'. Again, treatment is often sought at the peak of symptom severity, and the symptoms will then naturally "regress to the mean". Again, this appears to simply give false credit to an ineffective treatment (see Regressive Fallacy).

Some argue that perceived responses to inert treatments are due to classical conditioning. We learn to associate real treatments with feeling better. When given a fake treatment, we tend to have a subjective feeling of being better just as Pavlov's dog learned to salivate at the sound of a bell.

However, when it comes to pain management, the belief in the treatment may actually cause a biochemical response that reduces pain. Benedetti et. al discussed such a response and show that it can be reversed with the drug naloxone, just as with actual narcotics. The effect can be potentiated by administering the cholecystokinin. In a related study, they also showed that patients can become conditioned to different placebo responses based on their cognitive awareness of how different actual pain medications work. For instance, when patients thought they were given a non-narcotic pain reliever, the effect was not reversible with naloxone.

The release of pain-reducing biochemicals did not occur in patients that were unaware that a placebo was being administered, as demonstrated by Sinclair et al. Post-operative patients did not respond biochemically to intravenous 'placebo' pain-reducers while they were still asleep. The real pain reduction response of an inert substance appears to depend on the patient's awareness of the substance being administered and their belief that it works.

So, there appears to be at least two things going on here. A 'perceived' placebo effect and a 'true' placebo effect.


Perceived and True Placebo Effects


Edzard Ernst distinguished the "perceived" from the "true" placebo effect. The entirety of the perceived placebo effect is composed of a potential true effect and other elements. He points out that if a true placebo effect is present, then it should be distinguishable from all of the other non-specific effects that contribute to the perception of value in an inert treatment. 

 

Ernst then points out that it follows that if a treatment has a true effect - beyond any placebo effect - then it must be above and beyond the entire perceived placebo effect. 

 



True placebo effects seem to mainly be present in treatments for subjective conditions such as pain, fatigue, depression and anxiety.


Oxytocin (the "love hormone") may be a major player in true placebo effects. Oxytocin is a hormone that is released from the pituitary gland during empathetic and emotionally engaging interactions between people. It is speculated that oxytocin is released during empathetic interactions between a caregiver and a patient. It is fair to speculate that interactions that are perceived as warmer and more caring (especially those involving the caregiver putting the patient in a relaxed setting and touching the patient in some way) may lead to higher oxytocin release from the patient's pituitary gland.

A 2013 study in JAMA demonstrated that intranasal oxytocin, when given with a sham pain reliever, led to a statistically significant increase in the perception of pain relief from the intervention. The study was well controlled to rule out a possible direct analgesic effect from the oxytocin itself. This likely does not explain the whole story, but it provides at least one possible biochemical pathway to explain true placebo effects.



Different Effects for Different Placebos


We saw above, that patients tended to respond to placebo pain treatments in a way consistent with their knowledge of how the actual drugs work. It turns out that a person's biases regarding a drug's cost, route of administration, dosing frequency, pill size, commercial origin and even color influence the perception of effectiveness. 

The following is a list of such placebo effects:

- trusted brand-name drugs work better than others

- expensive treatments work better than cheaper ones

- green pills may be better for phobias and anxiety

- red and yellow pills may work better for depression

- sham devices may work better for pain than pills

- treatments work better if administered by a practitioner perceived as being kind, warm and caring.

- in general, invasive treatments (eg. surgery, injections, procedures) seem to work better than less invasive ones


User Dilemma


We learned in the Science and Philosophy section that Science is concerned with "is" questions (the actual nature of things). Philosophy is concerned with "ought" questions (decisions and actions we ought to take). Science can tell us if a treatment has an actual effect or just a perceived one. We must decide if we ought, or ought not, to use placebo-based treatments.

Placebos are often necessary to conduct proper studies. To not employ them in research when appropriate would result in unreliable results due to biases. One can argue that the use of placebos is ethical when conducting clinical research. Such an argument is made by Franklin Miller, Ph.D. at the National Institute of Health. However, when a treatment has already been proven effective, new treatments should be compared to the standard, not a placebo. Informed consent must be obtained by patients participating in any trial and they must understand the nature of a blinded clinical trial. The ethics of human research has been hashed out at length in the World Health Organization's Declaration of Helsinki.

The 'placebo effect' requires, for the most part, the patient to believe in the treatment's effectiveness. A doctor that is aware of the ineffectiveness of a particular treatment, yet promotes the treatment anyway for the 'placebo effect', is literally being dishonest. The doctor must present the treatment as useful and effective to harness the 'effect'. Outside of clinical trials, the promotion of placebo treatments requires dishonesty.

The skeptical doctor must come to terms with the ethical dilemma presented by this fundamentally dishonest practice. Is it always unethical to be dishonest? After all, about half of doctors surveyed admit to using placebos in clinical practice. This is a question that the practitioner must consider. Science will not help us here.

Kaptchuk et al. published a small study in PLoS ONE looking at the effectiveness of the placebo effect for irritable bowel syndrome when the patient was presumably made aware that the treatment was a placebo. Their conclusion was that the placebo treatments still exhibited an effect. If so, this could allow doctors to get around the ethical issue by allowing them to be honest about the treatment's lack of biologic effect. However, upon close examination (as blogged about here and here), their conclusion may not be warranted. It still seems that the patient must be deceived for the effect to work, whether deceived by the physician, or perhaps themselves.

In addition to the issue of dishonesty is another question. Is it ethical to use the 'placebo effect' to make a patient feel better, when treating them with proven medicine actually modifies their disease? In other words, is it enough to just make people feel better when legitimate therapy is available?

Another small study published in the New England Journal of Medicine compared the effectiveness of Albuterol therapy for acute asthma exacerbations with two different placebo treatments. The objective measure of lung function was the forced expiratory volume after blowing into a tube for one second (FEV1). The study also recorded how the patients felt after treatment. The conclusion was..."Although albuterol, but not the two placebo interventions, improved FEV1 in these patients with asthma, albuterol provided no incremental benefit with respect to the self-reported outcomes." 

Arguments ensued over the implications of this study. Is there a real difference in the treatments if the patients all felt equally better? It hardly has to be pointed out that the albuterol group not only felt as good as the placebo groups, but they actually were better. In conditions such as asthma, objective outcomes do matter. Admittedly, acute treatment with albuterol does not do much to promote long-term outcomes in asthmatics. However, other treatments, such as inhaled steroids, have true positive effects on long-term outcomes. If the long-term overall health of the patient is important, then it would be unethical to simply focus on the short-term by only using Albuterol. 

Either way, promoting short term "feel good" treatments while ignoring underlying pathology would lead to poor long-term outcomes. This would be unethical. In the short run, we still have the dishonesty question to deal with. Albuterol actually works. Placebo treatments give the illusion of an effect, but only if the patient is deceived by the practitioner, themselves or both.


Is it Ethical?


In philosophy, ethics can be considered from different perspectives.

In Consequentialism, the consequences of an action determine its ethics. In Deontology, the ethics of an act is determined if it is carried out according to one's duty to society. In Virtue Ethics, an act is ethical if it is carried out due to one's fundamental moral character, or virtue. We can consider the ethics of promoting fake treatments as if they are true in terms of the ethics of dishonesty and lying.

The A.M.A.'s position on the use of placebos outside of research states: "In the clinical setting, the use of a placebo without the patient’s knowledge may undermine trust, compromise the patient-physician relationship, and result in medical harm to the patient." This appeals to Consequentialism by pointing out the negative consequences. Another negative consequence is the enforcement of false beliefs.

The father of Deontology, Immanual Kant, felt that lying was always unethical as it requires the violation of duty.
"By a lie, a man...annihilates his dignity as a man." Others feel that this is too restrictive and that there may be situations where civic duty calls for lying. However, it is hard to imagine a situation in which this applies to health care.

Tim C. Mazur, Chief Operating Officer, Ethics and Compliance Officer Association (ECOA) states, "Though the nature of virtue ethics makes it difficult to assess the morality of individual acts, those who advocate this theory generally consider lying wrong because it opposes the virtue of honesty." 


** Is it ethical? Once a doctor is aware of the ineffectiveness of a treatment, the use of the treatment for a placebo effect requires deception.  Barring rare exceptions, when considering ethics from a consequential, duty or virtue standpoint, deception is ethically wrong



John Byrne,  M.D.


References and Links

Straus JL, von Ammon Cavanaugh S, Psychosomatics. 1996 Jul-Aug; 37(4):315-26.
<http://www.ncbi.nlm.nih.gov/pubmed/8701009/>

Pepper, O.H.P. A note on the placebo. Trans. Stud. Coll. Physicians Phila.
13, 81–82 (1945)

"Opinion 8.083 - Placebo Use in Clinical Practice - American Medical ..." 2011. 
<http://www.ama-assn.org/ama/pub/physician-resources/medical-ethics/code-medical-ethics/opinion8083.page>

Beecher, Henry K et al. "The effectiveness of oral analgesics (morphine, codeine, acetylsalicylic acid) and the problem of placebo" reactors" and" non-reactors"." Journal of Pharmacology and Experimental Therapeutics 109.4 (1953): 393-400.

Beecher, HK. "THE POWERFUL PLACEBO." 1955. 
<http://jama.jamanetwork.com/article.aspx?articleid=303530>

Moerman, Daniel E, and Wayne B Jonas. "Deconstructing the placebo effect and finding the meaning response." Ann Intern Med 136.6 (2002): 471-6.
<http://annals.org/article.aspx?articleid=715182#ref-30>

"Shame on you, New England Journal of Medicine ... - Scientopia." 2011. 
<http://scientopia.org/blogs/whitecoatunderground/2011/07/25/shame-on-you-new-england-journal-of-medicine/>

Hróbjartsson, Asbjørn, and Peter C Gøtzsche. "Is the placebo powerless?." New England Journal of Medicine 344.21 (2001): 1594-1602.
http://www.nejm.org/doi/full/10.1056/NEJM200105243442106#t=articleDiscussion

Benedetti, F. "The neurobiology of placebo analgesia: from endogenous opioids to ..." 1997. 
<http://www.ncbi.nlm.nih.gov/pubmed/9185235>

Amanzio, Martina, and Fabrizio Benedetti. "Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems." The Journal of neuroscience 19.1 (1999): 484-494.
<http://www.ncbi.nlm.nih.gov/pubmed/3288007>

Ernst, Edzard, and KL Resch. "Concept of true and perceived placebo effects." BMJ 311.7004 (1995): 551-553.

Simon Kessner; Christian Sprenger, MD; Nathalie Wrobel, MSc; Katja Wiech, PhD; Ulrike Bingel, MD. Effect of Oxytocin on Placebo Analgesia: A Randomized Study.JAMA, October 2013

Branthwaite, A. "Analgesic effects of branding in treatment of headaches. | BMJ." 1981. 
<http://www.bmj.com/content/282/6276/1576>

Waber, Rebecca L et al. "Commercial features of placebo and therapeutic efficacy." JAMA: the journal of the American Medical Association 299.9 (2008): 1016-1017.
<http://jama.jamanetwork.com/article.aspx?articleid=181562>

Kaptchuk, TJ. "PLOS ONE: Placebos without Deception: A Randomized Controlled ..." 2010. 
<http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015591>

Schapira, Kurt et al. "Study on the effects of tablet colour in the treatment of anxiety states." British medical journal 2.5707 (1970): 446.
<http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1700499/>

de Craen, AJ. "Effect of colour of drugs: systematic review of perceived effect of ..." 1996. 
<http://www.ncbi.nlm.nih.gov/pubmed/8991013>

Kaptchuk, Ted J et al. "Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome." Bmj 336.7651 (2008): 999-1003.
<http://www.bmj.com/content/336/7651/999>

Hall, Harriet, Martin Bier, and Stephen Sniderman. "Skeptic: Promoting Science and Critical Thinking." issues 31: 40.
<http://www.skeptic.com/eskeptic/09-05-20/>

Miller, Franklin G. "The ethics of placebo-controlled trials." The Oxford Textbook of Clinical Research Ethics (2008): 2001.
<http://www.bioethics.nih.gov/hsrc/slides/Miller-Placebo-Controlled_Trials.pdf>

"WMA Declaration of Helsinki - Ethical Principles for Medical ..." 2009. 
<http://www.wma.net/en/30publications/10policies/b3/>

Tilburt, Jon C et al. "Prescribing “placebo treatments”: results of national survey of US internists and rheumatologists." BMJ: British Medical Journal 337 (2008).
<http://www.bmj.com/content/337/bmj.a1938>

Kaptchuk, TJ. "PLOS ONE: Placebos without Deception: A Randomized Controlled ..." 2010. 
<http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015591>

"You wouldn't lie to me, would you? | White Coat Underground." 2010. 
<http://scientopia.org/blogs/whitecoatunderground/2010/12/24/you-wouldnt-lie-to-me-would-you/>

Wechsler, Michael E et al. "Active albuterol or placebo, sham acupuncture, or no intervention in asthma." New England Journal of Medicine 365.2 (2011): 119-126.
http://www.nejm.org/doi/full/10.1056/NEJMoa1103319#t=article

"Consequentialism (Stanford Encyclopedia of Philosophy)." 
<http://plato.stanford.edu/entries/consequentialism/>

"Deontological Ethics (Stanford Encyclopedia of Philosophy)." 
<http://plato.stanford.edu/entries/ethics-deontological/>

"Virtue Ethics (Stanford Encyclopedia of Philosophy)." 2003. 
<http://plato.stanford.edu/entries/ethics-virtue/>

"BBC - Ethics - Lying." <http://www.bbc.co.uk/ethics/lying/lying_1.shtml>

"Opinion 8.083 - Placebo Use in Clinical Practice - American Medical ..." 2011.