PLACEBO

"He that cannot reason is s a fool. He that will not is a bigot. He that dare not is a slave." ~ Andrew Carnegie

Do you know what a placebo is? Of course you do. It is that sugar locked up in the form of a pill or a saline solution in a syringe mocking the pharmaceutical realm of a parenteral agent for improving health. The question that arises then is why do we have a placebo when we have such wonderful medicines available today that can lower blood pressure, lower the sugar in the blood, eat, chew and spit out the cancer cells, thin the blood and thicken it, make more blood, or make less, diminish an element/chemical or raise it in the serum, cleanse the kidneys and also the liver, give brain food for thought and sex up the food of love, I mean we’ve got it all. This is modern day society. Something hurts and a pill will make it go away. Something doesn’t feel right and we make it harmonize. We can get rid of infections, hot flashes, cold sweats, feeling alarmed or feeling nothing at all. We can take the body temperature down and raise the awareness of the mind, or raise the threshold for alarm and drop the bar on fright. So then, you might ask if we can do all that, what is this placebo and why do we need it?

The human body has a built in system of controls. It is a remarkable piece of machinery. It truly is. I mean, where else would you come across this wonderment of trillions of pieces that fit together in such awesome and perfect harmony to create a masterpiece called the human body. Imagine creating multi-terabytes of memory that can be parallel processed into a decision that changes the course of human history. A heart that can beat for 3 billion times in a 80 year human lifetime, an eye that can spot a color from miles away, a nose that can differentiate between a filet mignon and a fried chicken, an arm that can lift hundreds of kilos and a leg that can outrun most animals. You get the drift, don’t you? Well in this wonderful contraption wouldn’t you think there would be a mechanism to fix any potential harm that might come about? Your guess is correct, it does! Given the complexity of this prudent concoction of diverse cellular automata there are mechanisms available to rid the “self” of any harm.

Let us see how that would be so. Imagine when you were a kid, a real kid and you might still be if you are lucky, when the world was large and the trees outside looked like a forest, the staircase never ended and the tiny hill you climb with a few steps seemed to loom large, it was your personal Everest, that kind of kid. Now remember if you do, that you had a fever from acquiring the rotten virus from another of your ilk. You may have shared an ice cream float gazing into that someone’s eyes or bitten off a chocolate bar or even heavens forbid, kissed someone whose blue eyes rattled your hormonal sense of existence. That virus, she or he gave you now flourished inside unbeknownst to you until one day it had overtaken your body’s mechanism of self-preservation temporarily. You got a fever, a headache and chills to boot. You stayed away from school and developed the art of communicating via telephone without using your hands. Your mother brought you some cold moist towels as you milked the system for some more entitled sympathy and made her promise to allow you to do things that would under normal circumstances be considered taboo. And a day later the fever was all gone, the headache dissipated and the chills no longer lingered. You felt a little tired but all in all, almost back into the adolescent race of “that one is mine, this one is yours.”

What happened in that 24-hour period? That is the wonder of the human body’s genius. Upon being attacked by the virus, the immune surveillance found out about the invader. It liberated agents into the blood stream called interferons to destroy the virus. The Interferons also have the innate ability to raise the body temperature and all the while the defensive white cells marched and devoured the virus wherever it had been multiplying. The immune cells also took an imprint of the virus and stored it in its memory-banks so that should the virus ever attack again, it would harness the soldiers immediately and prevent breaches in the first line of defense. So while your mother or grandmother crushed leaves and mint to inhale and loaded you up with pills that were essentially ineffective against the virus, taking them fulfilled the prophecy that doing something actually did something. But really it did not. She might as well have given you a sugar pill at that and taken the victory lap in her mind. But let us not disappoint such loving care and desire to do good with such careless remarks. Your body did all that, minus the interfering pills that assuaged the fearful, concerned and troubled minds. By the way, on a side bar, the entire vaccination concept for infectious disease and to extent in cancer is based on exploiting the immune cellular network to the attenuated, dead or live virus or cancer cell antigen in measured doses so that the immune surveillance can develop a memory for the same and ward off future attacks. So even though the attempt was to rid the viral infection with a pill, the effort was more of nebulous thought of efficacy rather than efficacy itself. The pill that your mother/doctor prescribed for your cold was a placebo, a sugar pill! She still swears by it many years later. She claims she saw the concoction in some reputable magazine.

Now where else have I heard this song before? Oh, I know, I know, you raise your hand. In the various medical journals! You say. You would be right, because most well thought of studies have usually undergone the rigor of experimentation. By that, let me explain, I mean the medicine being developed for a certain disease is compared to a placebo so as to evaluate the real benefit of the medicine. Why placebo? You ask. Why does one have to compare to a sugar pill? Good question. Remember if your mother had done nothing for your viral fever and your body fixed the problem wouldn’t that suggest that the body would take care of the malady? Yes of course it would. So the innate ability of the body to fix is a self-fulfilling prophecy. Adding to that the mother lode of the mind now furthers the “cause-celebre”. Remember mind over matter. And what is even more intriguing and well documented is the fact that if you were to choose a pill or an injection, both placebos, the injection has a better impact in relieving the pain. Funny how our mind and body plays tricks. Your mind tells your body what to do all the time. It is a subjective process. So now lets venture into another thought experiment, to differentiate the efficacy between a “blue” pill and a “red” pill, knowing the color of the pill would change your perceptions towards the benefits of that pill, especially if you had heard that red was better than blue or vice versa. 

Morpheus in Matrix with the red and blue pills

Knowing the potential benefit between two sets of criteria, color the thinking so much as to yield a potential benefit of up to 14% in a statistical modeling. And this statistical modeling renders results in “p-values” of probable significance. In other words, knowing the end result changes everything. This placebo effect is an internal bias of the human body to fix itself. If either the experimenter or the person being tested knows the color of the pill, the bias thus built in the experiment can yield results to suit and confirm the premise undertaken. By that I mean the system is “Rigged” from the beginning. So both parties have to be blinded for a thorough and clear unbiased experimentation ~ therein lies the concept of the “Double-Blinded” Studies. Here is where the placebos come in. The placebos are contained in exactly the same container and look identical to the experimental drug, so the patient does not know the “color of the pill.” The inherent benefit from placebo is therefore contained on both sides of the experiment, thus negating that particular bias. Everything else would then be considered the real, real result - maybe. The experimenter also does not know which patient is getting what and neither does the patient have any clue. The patient’s own immune system, through the power of his or her mind, is invoking the placebo effect of gaining benefit from the “pill”/therapy and on the other side of the equation, the experimenter being blinded as to which patient is being treated, cannot stack any favors (like, younger patients against older, or more women against men or white against color, or gymnasts against sedentary slobs) on the experimental drug side to arm it with better outcomes. However based on the fact that on both sides, the patients are getting something and thus their mental gymnastics will produce the “placebo-effect” and render any such bias moot. In today’s world, only the computer knows and is un-blinded to the experiment. It fills in the numbers of patients on both sides of the aisle to balance the scales between the experimental medicine and the placebo. So if the result after the study has accrued enough numbers of patients it isthen  un-blinded to the experimenter, the statistics will show the real value or lack thereof! Any untruths by omission or commission are betrayals of the self. There is a part of me that wants to address the Confidence Interval and Probability in Statistics, but maybe save it for another day. Suffice to say that the most commonly used CI (Confidence Interval) is at 95%, which means the measure of success is based on 95% accuracy, or putting it another way that equates to a 2 Standard deviation disregarding the impact of the five-percentages. And to get to a Six Standard Deviation or Six Sigma the numbers of patients to be tested in an experiment would rise to 1,000,000,000 or One Billion and that will test accuracy to a value of 99.7% CI!

Venturing further, if you really wanted to see the “placebo effect,” you could divide one group into receiving a “placebo” pill and the other nothing. At the end of the study you would magically and miraculously prove to your non-believing self that the “placebo” group received some benefit that they imagined while the other group did not. 

Snake Oil Pills

The placebo pill grew more hair, less hair, could see better and farther, hear the high “C-Note” or felt stronger, nimbler and could articulate better. Placebos have been known to benefit many an unsuspecting individual against a slew of maladies in various experiments through time. That is what gave rise to the largest industry of the Snake-Oil Salesmen. Fascinating, don’t you think? That something can be had from almost nothing but from the pure distillation of a thought. Some of those fascinating examples are listed below in references.

Given such an impressive array of benefits from taking “sugar pills” the charlatans as I just mentioned, never stay far behind. In fact they, unfortunately will cast larger shadows over crystal clear reason and muddy the waters of logical thought by spreading the myth of their latest “wondrous” drug or concoction that can cure such things as cancer. I’ll take you back a few years and maybe you might remember an actor Steve McQueen with his rugged smirk, who developed cancer (Mesothelioma) and decided to spend his waning months trying to recoup life through the use Laetrile manufactured and promoted in Mexico. 

Steve McQueen

Vitamin-17 they called it and touted it’s benefits, saying that modern medicine did not want to use the product because the pharmaceutical industry was heavily vested in promoting their own drugs. They had ginned up testimonials from fictitious patients about their miraculous cure from using Laetrile. Oh what a travesty that was for the many people who were seduced into spending their fortunes finding the elusive nonexistent cures. But those kinds of shenanigans are not limited solely in the purview of snake-oil salesmen. A similar circumstance would be if an industry crafted an “observer-biased” experimental study to promote a product. Don’t hold your breath and gasp, it does go on in today’s world. It would impact a large group of vulnerable patients at the mercy of greed. It is therefore paramount for physicians to understand the experiment performed, the methodology utilized, the statistical manipulations used, the criteria established and whether or not there is a “moving percentage” to qualify for a benefit or not. Some of you might be surprised with that latter statement. But it is true. Let me explain: Previously the definition of a Partial Response or PR in the field of oncology (cancer care) was that the verifiable disease by clinical or radiological evaluation had to have resolved by more then 50% with an experimental drug under study. Simple enough! Then some one decided to change the PR criteria to a resolution of equal or more than 30%. Now what gives? Essentially by changing that criterion the author was able to upstage response number by migrating “minimal responses” (or responders with less than 50% resolution) into partial responders. Here suddenly the drug effect appeared huge. They could not tinker with the “complete response” which means complete disappearance of the disease and thus is not modifiable. So what was left then, was a smaller group of minimal responders tied with “stable disease” and voila the magic of statistics did the rest by enhancing the numbers of partial responders. Not only that they then started lumping the complete responders with the now magnified numbers of partial responders to compare with a previous study that used a different set of rules. So essentially they were comparing data of different drugs that would otherwise be considered non-equivalent and asserting that the new drug was a potential blockbuster drug of the future, since it gave so many more responders. Abominable to say the least! While we are on the subject, let me state quite unequivocally something that most of the oncologists agree upon. The best response criterion in oncology is the overall survival. Really simple! If the drug A makes you live longer then Drug B (previously tested against a placebo without any of the said statistical and marketing manipulation) then you may have a better product. Using Progression Free Survivals, Disease Free Survival, Time to Progression and all such terminologies indicate a sub-par benefit to the patient, especially if any morbidity is associated with the product in use. We must critically read and learn to understand the nuances of all scientific “experimental-studies,” teach ourselves the techniques to understand the difference between a good and a not so good scientific study and then come to our own conclusion. A snake-oil salesman will sell you his wares if you have the unsuspecting and an incurious mind.

White cells and Red Cells (EM)

So how does “placebo” really work? Using inferences from various studies it appears that positive imagery leads to an up-regulated immune systems that drives the mechanics of white cells (Lymphocytes: T, B, Dendritic and Macrophage cells) into interacting with the invading agent; such as a virus, bacterium or even cancer cell and render them impotent. 

Dendritic Cell

In addition a much slower mechanism is also in place for example Sickle Cell Anemia is a genetic mutation in the African community as a mode of preservation against Malaria. Since there is a prevalence of the Anopheles Mosquitoes that is ubiquitous to the region the population has the predilection for the red cell genetic mutation to prevent itself from being hijacked by the (Malaria) disease. In essence the evolutionary forces forced a gene mutation to create a circumstance that prevents falling prey to a deadly disease. And another issue that you may be familiar with is “Spontaneous Resolution.” Spontaneous resolution does occur in cancer and the mechanism is believed to be also via the immune pathway. Placebo, it is believed works through a similar mechanism of positive imagery that is used as a rallying cry against the “non-self” enemy. In the end, the human body remains the ingenious enterprise, crafty, plastic and changeably protective of self.

Lets raise a glass to that best of the best in defense against all humans being scourges. For in that defense lies our superiority against illness and disease. In that defense lies the virtue of our being!

I think a small dose of what makes the “placebo-effect” tick would be in order, don’t you think? How can we marshal such defenses? Simple really!

1. Imagine good health! (A corollary in baseball would be for a batter to concentrate on the gaps between the fielders rather than the fielders themselves if he/she wishes to enhance his/her hitting percentage.)

2. Incorporate the wellness you feel from exercise on a daily basis. If you can sit, don’t lie down. If you can stand, don’t sit, if you can walk don’t stand and if you can run don’t walk. Amplify your behavior. The Endorphins released in your brain through exercise will enhance the sense of “Well-being.” A healthy body nourishes a healthier mind and thus creates a positive “feed-back loop.”

3. Eat to live and not live to eat. Excess food is stored as fat and forms the bases of diminished activity as a result and ultimately leads to limited activity that leads to less endorphin release and neuro-psychochemical induced depression. The feeling of lack of wellbeing ensues and that ultimately hurts the so-called viable “placebo-effect.” Depression can also lead to chronic disease as a self-fulfilling prophecy.

4. Limit Stress!

5. Take time to enjoy little things in life.

Okay, enough proselytizing the demons out of our existence for now.

Placebo is music for outsiders, by outsiders and our gigs are like conventions of outcasts, which is cool~ Brian Molko ~ Placebo (Musical Group)

References:

Benedetti F, Pollo A, Lopiano L, et al. Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses. J Neurosci. 2003;23(10):4315-23.

Boström H. Placebo -- the forgotten drug. Scand J Work Environ Health. 1997;23 Suppl 3:53-7.

Haour, F. Mechanisms of the placebo effect and of conditioning. Neuroimmunomodulation. 2005;12:195-200

Hrobjartsson A, Gotzsche PC. Is the placebo powerless? Systematic review with 52 new randomized trials comparing placebo with no treatment. Journal of Internal Medicine. 2005;257:394-396.

Kaptchuk TJ. The placebo effect in alternative medicine: Can the performance of a healing ritual have clinical significance? Ann Intern Med. 2002;136:817-825.

Wampold, BE, Minami T, Tierney SC , Baskin TW, Bhati, KS. The placebo is powerful: Estimating placebo effects in medicine and psychotherapy from randomized clinical trials. Journal of Clinical Psychology. 2005;61:835-854.

Wager TD, Rilling JK, Smith EE, et al. Placebo-induced changes in fMRI in the anticipation and experience of pain. Science. 2004;303:1162-1167.

Young JH. Laetrile in historical perspective. In Merkle GE, Petersen JC, editors. Politics, Science, and Cancer: The Laetrile Phenomenon. Boulder, CO: Westview Press, 1980.

Relman A. Closing the books on Laetrile. New England Journal of Medicine 306:236, 1982.

Friedman MJ. 1978. Erythrocytic mechanism of sickle cell resistance to malaria. Proc Natl Acad Sci U S A 75: 1994-1997.

Fleming AF, Storey J, Molineaux L, Iroko EAm, Attai ED. 1979. Abnormal haemoglobins in the Sudan savanna of Nigeria. I. Prevalence of haemoglobins and relationships between sickle cell trait, malaria and survival. Ann Trop Med Parasitol 73:161-172.

Boecker H, Sprenger T, Spilker ME, Henriksen G, Koppenhoefer M, Wagner KJ, Valet M, Berthele A, Tolle TR (February 2008). "The Runner's High: Opioidergic Mechanisms in the Human Brain". Cerebral cortex (New York, N.Y. : 1991) 18 (11): 2523.

Jillian R. Satin, Wolfgang Linden, and Melanie J. Phillips. Depression as a predictor of disease progression and mortality in cancer patients: a meta-analysis. Cancer, 2009