I am posting the first chapter of my placebo book “Placebo 3.0” here. Please make sure you are ok with this disclaimer.
Chapter I
Placebo Terminology
Placebo Generations 1 – 2 – 3
Placebo 1.0
The word placebo stems from Latin. It originally meant “I will please.” An early 19th century medical dictionary by Quincy defined a placebo as any medicine that was given “more to please than to benefit the patient.” Until the 1950s medical students learned that placebos were “mere sugar pills that do nothing”. Placebos did not get much attention then. I propose to call this era Placebo Generation 1.0
Placebo 2.0
The possibility of a real therapeutic benefit from placebo was first investigated by Dr. Henry Knowles Beecher (1904–1976), an anesthesiologist at the Massachusetts General Hospital. He noticed that severely injured soldiers in the combat zone were less likely to ask for pain relievers compared to similarly injured soldiers who were at hospitals. He theorized that injured soldiers in the field may be able to bear pain better, because they are relieved or even euphoric to have survived and look forward to being put back together again. This mindset might allow them to tolerate pain better, or might even reduce the intensity of pain. Yet, by the time severely injured soldiers reach the hospital their euphoria has worn off and they are likely to feel more anxious, for example about their financial and social future. This led him to study the mind’s impact on pain control and self-healing and. He wrote a paper in 1955 on “The Powerful Placebo” which was published in the Journal of the American Medical Association (JAMA), claiming that “placebos have a high degree of therapeutic effectiveness in treating subjective responses.”
Since then, research on placebos gradually accelerated. Especially the discovery of the role of natural opioids released by the body was a major break-through in this field. In 1978 a landmark experiment showed how pain relief from placebo actually has a physical effect on our body. Levine et al, used naloxone, a drug that blocks the effects of opiates on patients who had just undergone dental surgery. Levine’s experiment showed that naloxone not only prevented pain relief from opioids, but it also blocked pain relief from placebo. This gave strong support to the hypotheses that taking placebos can trigger the body to employ its own natural opioids (called endorphins).
Opioids
Opioids are the most powerful drugs used for pain relief. This class of drugs is widely prescribed but has resulted in a controversy due to a 4-fold increase in deaths over the first decade of the new millennium.
Naxolone
When the medication Naxolone is given, it blocks the body’s opioid receptors and prevents other substances from binding to these receptors.
Endorphins
Endorphins are powerful and safe opioids that the body produces. Endorphins bind to opioid receptors in the brain. The same receptors are also used by opioid medications.
Recent studies using the brain-imaging technology showed that taking placebos leads to neurobiological patterns in the brain that can also be observed when powerful pain relievers are given. Petrovic et al (2002), demonstrated that the same regions of the brain are activated when patients receive an opioid pain reliever (remifentanil) or when patients take a placebo. Similar brain imaging studies by Zubieta et al (2005) and Eippert et al (2009) also showed that placebos trigger brain responses that ameliorate pain.
For those who are interested in learning more about fascinating field of brain imaging in Neuroscience, the studies described here used two techniques to generate high definition, three dimensional images of brain function:
Positron Emission Tomography (PET)
PET measures metabolism and the flow of blood to different parts of the brain. PET is a non-invasive method that also allows for some movement during the scan, but it does expose patients to radiation from a biologically active tracer molecule.
Functional Magnetic Resonance Imaging (FMRI)
Similar to PET scans, FMRI measures blood-flow in the brain. FMRI has the advantage that a radioactive tracer molecule it not needed. The image resolution of FMRI is also better than PET. However, since patients need to remain still during FMRI scans, this imaging method cannot be used for experiments where, e.g., patients need to read out words during a scan. Redesigned equipment and advancements in computing power are likely to overcome this barrier in the future.
In the 1980’s The US Food and Drug Administration (FDA) started to require the use of placebos to demonstrate the therapeutic effectiveness of new drugs before giving market approval. The basic concept of FDA effectiveness trials is to compare a new drug to be tested to a placebo pill that looks exactly alike but is assumed to do “nothing”. FDA reviewed clinical trials are usually randomized, double blind studies, neither doctor nor patient know if the drug or the placebo are administered. During the initial years of placebo-controlled trials there were many surprises when beneficial therapeutic effects were observed not only from the new drug to be approved, but also from its placebo counterpart. Thanks to the rigorous design of large clinical trials we now have ample evidence that placebos are efficacious. Later in the 90s the National Institutes of Health (NIH) started to fund placebo specific research that provided us more insight into how placebos work.
That being said, up to now there are no therapeutic options available to use pure placebos outside of clinical studies. The use of placebo Generation 2.0 was neither feasible nor considered to be ethical in the regular care of patients. The paradigm of the Placebo 2.0 era states that ‘patient deceit is required for placebos to work’.
For a paradigm shift to occur it is not enough to simply falsify its foundational laws. It also takes a contrarian mind to simply acknowledge observations that contradict a paradigm. Scientific paradigm shifts are typically slow and only seen retrospectively. This was first observed by Thomas Kuhn and described in his book “The Structure of Scientific Revolutions” (1962). The dynamics of such fundamental shifts is also explored in more recent books such as “The Tipping Point” (2000) by Malcom Gladwell.
For more than twenty years after the therapeutic benefits of placebos were demonstrated in clinical trials not a single study questioned the fundamental belief that “placebos can work only with deceit”.
Placebo 3.0
It took a contrarian thinker to pursue the idea that the placebo effect could be reproduced in subjects that knew that they were taking placebos (honest Placebo).
The idea that honest placebos” work was inconceivable for anyone thinking inside the placebo paradigm of the day. Paradigm shifts require observations that are either stumbled upon by accident or are gathered purposely by a contrarian thinker. Ted Kaptchuk, Professor at Harvard’s Center for Placebo Studies, is such a contrarian. Utilizing an ingeniously simple study design that explored honest placebo use, resulted in a paradigm-shifting landmark study that was published in 2008.
Two groups of patients with Irritable Bowel Syndrom (IBS) received standard treatment. One of the groups also received a placebo in addition to their standard treatment. They were told that placebos had shown some beneficial effect in clinical trials. These patients were told that they would receive pure placebo pills and that was not necessary to believe in the placebo effect, but an open mind could be helpful. The pill bottles that patients took home were clearly labeled “Placebo”. The outcome? The group that received a placebo in addition to standard treatment improved significantly more than the group that only received standard treatment. Taking placebos in an honest way made a meaningful clinical difference for these patients.
This study really marks the start of the 3rd generation of Placebo treatment.
Zeebo
Disclaimer:
To shape the 3rd Placebo Generation, I created Zeebo – pure, open, branded placebo, taken in an honest way. Zeebo was designed to create a complete placebo-taking experience. Zeebo pills supported by the Zeebo App provide a showcase of how to deliver a honest placebo effect.
This book is a general introduction to 3rd Generation placebos. Zeebo is only mentioned here and in the chapter on “Placebo Examples”. If you want to know more about Zeebo, please go to: www.zeeboeffect.com
| Placebo | Effective | Honest |
| Generation 1 | ‒ | ‒ |
| Generation 2 | + | ‒ |
| Generation 3 | + | + |