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What Happens When a Sugar Pill Turns Sour?

How the nocebo effect is tacking itself onto to the list of side-effects associated with countless medical treatments.

Just as Anakin Skywalker revealed his dark side when he shifted into the galactically feared super-villain Darth Vader, the well-known and well-regarded placebo possesses a rather dark side as well.

Throughout the past decade, society has become increasingly familiar with the concept of a placebo and its common mode delivery as a sugar pill that can provide patients with relief from a number of negative symptoms they may be experiencing. The healing powers associated with this sugar pill have been linked to an individual’s expectations surrounding a positive reward. These learned preconceptions we process surrounding the delivery of a medical treatment can quickly become somewhat of a double-edged sword when this perspective begins to morph into an expectation or fear that something bad is going to happen following the delivery of a medication or treatment. This phenomenon is known as the nocebo effect, or more casually, the placebo’s evil twin.

The nocebo effect has been formally defined as a harmless substance or treatment that when taken by a patient elicits negative side effects or symptoms due to the patient having expectations surrounding its results. Although the concept of a sugar pill causing sour side effects may seem rather far-fetched, a significant number of scientific studies have provided a wealth of supporting evidence indicating the legitimacy of the nocebo effect.

Like a Jedi using the force to control the mind of another, the nocebo will often use the words of a physician or care-provider to provide it with its mild altering abilities. It has long been thought that the best way to properly prepare a patient for experiencing pain is by using terms such as “this might hurt quite a bit” or “brace yourself for a pinch”, however, studies have recently revealed that these well-intended words are inflicting a form of pain on their own regardless of if a medical treatment is present or not. One experiment in particular analyzed a patient’s perception of pain after being injected with a radiographic substance by determining how their sensation varied depending on the phrases the doctor used prior to delivering the injection. They found that the more frequently the doctor used words such as “sting”, “burn”, or “hurt”, the greater the degree of discomfort was felt by the patient.

In 2012, researchers from the Technical University of Munich produced an in-depth review of 31 empirical studies that focused on the clinical applications of a nocebo. Follow this review, they concluded that not only does the nocebo effect exist, but it has been silently leaching its way into doctors’ offices and pharmacies around the world for years.

The researchers conducting this review set out on a mission to portray an accurate representation of the neurobiological mechanisms that influence the strength of a nocebo. They questioned its relatedness to the more widely studied placebo effect, and if the nocebo is caused by the same type of learning and conditioning as what has been deemed to be the source of the placebo.

A number of these studies provided direct evidence that the nocebo effect can elicit a physical response in a patient’s perception of pain. Like the placebo effect, a few central chemical messengers, including dopamine and endogenous opiates, have been linked to the intensity of the experienced nocebo effect. Where the brain of the patient delivered a placebo will display an increased level of these neurotransmitters, a patient’s brain following the delivery of a nocebo will exhibit a sharp decrease in the internal levels of these same chemicals. This is an extremely logical finding as a release of dopamine in the brain is normally associated with a decrease in anxiety and pain levels, both of which are elevated when a patient is delivered a negative nocebo treatment.

One experimental study put the nocebo effect to the test by randomly dividing 50 individuals with chronic back pain into two groups prior to a preforming repetitive leg flexions. One group was told that the test would cause a slight increase in pain whereas the other group was told there would be no increase in pain. The group provided with the negative information reported a significantly higher level of pain than those given the neutral information and preformed fewer leg flexions as a result. This showed researchers that the physicians’ words alone had enough power to cause a physiological response in the patient’s response.

Similar to how a Jedi uses the Force to control the mind of their target, the nocebo will often use the words of a doctor or a care provider as its main source of power. It has long been thought that that proper way to prepare a patient for experiencing any pain, the care provider must describe a treatment using phrases such as “this might hurt quite a bit” in order to invoke anxiety so they know what to expect. One study in particular showed that these well-intended words of a doctors are actually inflicting a form of pain on their own even regardless of if a medical treatment is present or not. This experiment analyzed a patient’s perception of pain after being injected with a radiographic substance and how their level of discomfort varyied depending on the phrases that doctor used before delivering the injection. They found that the more frequently words such as “sting”, “burn”, or “hurt” were used, the greater the degree of discomfort the patient felt. However, if a care-provider neglects to disclose the slew of side-effects accompanying a given treatment, they may be at risk of being accused of malpractice or in the most extreme cases, getting sued for mistreatment.

The moral obligation surrounding a physician’s duty to inform their patients of any adverse effects that may be associated with a given medication, chemotherapy, or psychological treatment causes them to walk a fine line in order to avoid adding ‘bad-vibes’ to the list of negative side effects of a treatment. If a patient believes that they will experience harm because of a prescribed treatment, they may transform this notion into a self-fulfilling prophecy. Alternatively, some individuals may talk themselves out of taking their medication following an overly detailed review of the ill effects associated with it. This put physicians in a tough spot in terms of deciding how they will deliver a pre-treatment script to a patient without making a rather symptom laden bed for their patient to rest in.

Thankfully, this review also provided several tips and tricks for physicians attempting to avoid the nocebo effect, one of which emphasizes the importance placing any potential side effects under a more tolerable light. Using this strategy, a physician will attempt to phrase any possible adverse effects more positively by stating “most patients tolerate this treatment very well”, instead of “5% of patients report…”. The effectiveness of this tactic was highlighted in a study on the importance of briefing a patient prior to the delivery of an influenza vaccine. If the care-provider isn’t as keen to perform the literary work of Shakespeare on a side-effects list, they can instead directly ask the patient if they would like to hear the information regarding the mild side effects of a treatment or not. Although the patient must still be informed of any serious implications associated with this treatment, filtering out the overwhelming “what if’s” and “maybes” can steer them away from entering a spiral of anxious thoughts regarding the treatment they are about to receive.

Figure 1: A patient’s reported pain level after being administered an influenza vaccine based on the words and phrases used by the physician prior to its delivery.

Figuring out how to communicate effectively to handle a patient’s fears and anxieties surrounding a medical treatment appears to be almost as challenging for physicians as fighting the illness itself. Ironically, the best weapon for a physician to bring to a battle against a nocebo is their words, or in some cases with the permission of the patient, the lack thereof. This review, along with several additional studies centred around the mind controlling power of the nocebo, emphasize the harsh reality of the phrase “the less you know the better” and that sometimes being left in the dark may be more beneficial than you may think.

Reference Article

Häuser, W., Hansen, E., & Enck, P. (2012). Nocebo Phenomena in Medicine. Deutsches Ärzteblatt International. https://doi.org/10.3238/arztebl.2012.0459

For more information on the Nocebo effect check out these links:

https://www.smithsonianmag.com/science-nature/what-is-the-nocebo-effect-5451823/

https://www.webmd.com/balance/features/is-the-nocebo-effect-hurting-your-health

Until next time,

-Kalli

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“Here, let me write you a prescription for a sugar pill”

A brief glimpse into how science is starting to uncover the way a placebo can manipulate the brain of patient diagnosed with Parkinson’s disease.

  One can only imagine the eerie silence that must have washed over the de la Fuente-Fernández lab as the image captured from the brain of a patient suffering from Parkinson’s disease flashed onto the screen. A silence instantly broken by an entire team of researchers flocking like a heard of hungry geese over to the PET machine in awe of what was being displayed before them. Collectively, they knew that this image would change the way this uncurable disease was treated and, if they were lucky, change the lives of people diagnosed with Parkinson’s disease forever. This excitement invoking image captured nothing more than a brain containing lots and lots of dopamine.

  To the untrained eye this abundance of dopamine may have seemed insignificant but to the researchers, this meant something astonishing was occurring in the brain of these patients. It told them that the neurological pathway that experiences the most damage in people living with this disease was surprisingly alert and functioning relatively smoothly. What made this moment so significant was that this spike in dopamine wasn’t caused by any pill or medication as previously would’ve been assumed. This increase in dopamine was caused by the Parkinson’s patient being administer a hefty dose of absolutely nothing at all.

  Speaking scientifically, “absolutely nothing” is defined in a more professional sense as a placebo. Placebos have been a common occurrence in the realm of science for centuries.  They are required to prove if the effects of any medical treatment, procedure or experiment can be classified as significant when they are compared to a ‘control condition’ of receiving no treatment at all. It hasn’t been until recently that these experimental controls were looked at from a completely different angle of having the ability to inflict their own impacts on the results of an experiment.

   Many recent clinical studies have produced a plethora of evidence suggesting that a placebo treatment can provide a higher level of personalized care to an individual suffering from a variety of conditions. When the effects of a placebo are leveraged properly, they have the capability of reducing the symptoms associated with chronic pain, depression, and multiple sclerosis. These are just a few examples of when the effects of this ‘control’ treatment have shocked the scientific community, leaving them to ponder exactly why the brain responds this way to something that isn’t a medical treatment at all.

  Unfortunately, it is still too soon to run to your local CVS pharmacy to pick up a pack of placebo. That being said, trying to stop the mind of curious scientist is like trying to stop a moving train and this motivation for discovery is evident in the amount of research that is currently being conducted on the neurological impacts of a placebo. Recent studies have demonstrated that these impacts appear to be exaggerated in the motor pathways of the brain in individuals diagnosed with Parkinson’s disease. Parkinson’s (PD) is an uncurable illness that is caused by a significant loss of nerve cells in a region of the brain known as the substantia nigra (see Figure 1). When this region becomes compromised, it triggers a dramatic reduction in dopamine levels. We produce most of the neuromodulator dopamine internally, however, we can increase levels ‘artificially’ through the consumption of alcohol, nicotine, and opioids. Unless medically prescribed, the activation of dopamine pathways through consumption of these external products is short lived and can quickly lead to long-term reliance and addiction. This is just one of many reasons why it is so important to ensure that these regions of the brain are functioning smoothly and can produce sufficient and healthy amounts of dopamine.

Figure 1: Purple highlighted areas represent regions of the brain impacted by the release of the neuromodulator dopamine. Substantia nigra is labelled to indicate the specific location of the area that experiences the most nerve cell loss in patients suffering from Parkinson disease.

  PD is characterized by 3 main symptoms: involuntary shaking of specific body parts, slow movement, and stiff muscles. The effects of PD are not limited to physical ailments as many psychological impacts also leech their way into the brains of patients suffering from this disease. Some of these include depression, anxiety, problems sleeping and memory loss.

  Aside from making us feel happy, dopamine also plays a vital role in regulating simple body movements therefore, many of the trademark symptoms of PD directly reflect low dopamine levels. Unfortunately, attempting to determine the root cause of this dramatic drop is comparable to trying to find a needle in a dozen haystacks. Clinical trials have emphasized the importance of locating specific biological markers that reflect these changes, but the exact cause is still unclear. Based on the current, published research, most experts hypothesize that it is due to a combination of genetic and environmental factors. Queue the nature vs nurture debate.

  The discovery of the impact a placebo has on a patient suffering from PD opened somewhat of a pandoras box within the scientific world. The placebo treatments given to these patients delivered a shockingly high degree of symptom relief compared to most other placebo-illness combos.  One of the first attempt to unearth the neurological mechanisms underpinning how the brain of a Parkinson’s patient responds to a placebo was made in 2001 by de la Fuente-Fernandez and his colleagues. The research done by his team was the first to provide a clear a pathway into the brain of PD patients when they showed how a placebo injection of nothing other than saline can trigger the release of dopamine in the striatal nuclei which is a critical component of the motor and reward systems.

  So how did they know that this excess dopamine was caused by the placebo and not from daydreaming about cute pictures of puppies? Thankfully, these scientists showed us that it takes more to earn that title than just wearing a fancy white coat as they accounted for the experimental ‘noise’ by including a control other than just a placebo. Following this internationally agreed upon guideline, they performed a PET scan on 6 PD patients to measure the binding of dopamine to receptors located within their brains. This served as an indication of dopamine activity. Each test took place on two different days. On the first day, each patient underwent a brain scan in 3 different conditions. Condition 1 was the placebo; condition 2 was a after receiving a small amount of a drug that causes more free dopamine to be present in the brain, and condition 3 was a slightly higher dose of the same free dopamine inducing drug. On day 2, every patient underwent another scan without any of these conditions to provide the oh so important baseline control values. Since the drug administered to the PD patients is known to increase dopamine levels, it was no surprise that conditions 2 and 3 showed an increase in dopamine activity compared to baseline levels. What took the scientists off guard was that the brain scans following the delivery of the placebo showed higher dopamine levels than all other conditions including the increased amount of the drug. The brain of these patients was so reliant on the expectancy of improvement that the administration of nothing besides a hearty dose of placebo outpowered the medical magic of a free dopamine inducing drug.

    Further research in this area has enhanced the findings of the de la Fuente-Fernandez team specifically emphasizing the importance of the patient’s expectations of reward. However, this improvement seen in the brain of PD patients in response to a placebo appears to be entirely dependent on the element of surprise. The patient must be completely unaware that they are receiving a fake treatment instead of a real treatment or else there is unlikely to be any response at all. Additional studies have shown that the neural pathways underlying this response can be tuned by previous learning which will impact the degree to which a placebo triggers any biological changes. Therefore, it is still safe to assume that we are still smarter than a sugar pill, at least for now.

  There is still an overwhelming amount of ground for scientists to cover before they can fully map out how the brain of a PD patient reacts when administered a placebo. What needs to be shown with a greater clarity is how, when and where the expectation of reward interacts with the primary motor systems of the brain. Do these lines of communication made between brain regions function in a predictive way? If so, how can modern medicine harness the power of a placebo to provide a more sustained and effective treatment of Parkinson’s disease? A placebo’s role in shaping modern medicine is only just beginning as high levels of speculation and controversy surrounding their use as a legitimate medical treatment remain. Thankfully, this isn’t stopping researchers from continuing to search for unique ways to unite placebos and medicine to deliver the best patient care possible.

    To read more about the developments of de la Fuente-Fernandez team, click this link: https://doi.org/10.1002/mds.27438

        Reference article:

  Quattrone, A., Barbagallo, G., Cerasa, A., & Stoessl, A. J. (2018). Neurobiology of placebo effect in Parkinson's disease: What we have learned and where we are going. Movement Disorders, 33(8), 1213-1227. https://doi.org/10.1002/mds.27438

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Trick or Treatment?? - The role genetics play in determining the strength of a placebo

The placebo effect is a phenomenon that has puzzled the minds of the world’s most elite scientists for decades. It is a fantastic example of how powerful the human brain is and its ability to outwit even some of the most advanced modern medicines. Loosely defined, a placebo is a substance or treatment for an illness that is designed to have no medical or therapeutical value. The burning question that remains surrounds scientists’ ability to harness the power of placebo how to use it to enhance existing medical treatments. One way to do this is to look even deeper into the role genetics play in how a person may respond to the placebo treatment they are being administered.

 A team of European researchers have proposed the concept of "The Placebome" to explain the connection between genetics and the effectiveness of a placebo treatment. This is a network of genes that could dramatically alter the degree to which a patient responds to a legitimate medical treatment vs a placebo. Although research is still very 'fresh', there have been several findings that suggest genetic variation in the brain's neurotransmitter pathways can modify the strength of a response to a placebo. As a result, placebo treatments are beginning to emerge as the new “hot medicine” on the scene and are gaining more traction as a potentially efficient way to deliver optimal patient care for individuals suffering from cancer, psychological disorders, and pain management.

 That being said, it is still far too soon to be dumping the contents of your medicine cabinet in the trash bin. Medical drugs have been designed with a purpose and a proven efficiency to treat ailments that the human brain alone would struggle to overcome. However, this research could lead to an abundance of novel treatments for some stubborn illnesses, a few of which we will begin to delve into in this blog in the weeks to come. Stay tuned for more surprising moments in recent science and a glimpse at how proper use of the placebo effect has changed the lives of some individuals forever.

Until next time,

KW

Source: Beth Israel Deaconess Medical Center. (2015, April 13). The placebome: Where genetics and the placebo effect meet. ScienceDaily. Retrieved January 26, 2022 from https://www.sciencedaily.com/releases/2015/04/150413140906.htm

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Une Petite Amuse Bouche

Hello, my name is Inigo Montoya… please prepare to be amazed by a science blog like no other. Kidding, well not about the fantastic blog you are only a mere introductory post away from diving into. Unfortunately, my name is not Indigo Montoya, it is Kalli, or Kallista if you are my mom, a substitute teacher, or a Government Agency. I am a fourth-year science student at the University of New Brunswick studying Biology with a concentration in Environmental Management (now say that 5 times fast). I was born in Halifax, Nova Scotia but spent most of my awkward adolescent years in Victoria, BC with the hopes of finally being able to put an end to timeless ‘west coast best coast’ debate that us North Americans are constantly in the midst of. Let’s just say, I decided to go to university on the East Coast for a reason.

 Enough about me though, let’s talk about the reason you are really here, to indulge in a science blog like no other. My goal for these upcoming posts is to start exploring the relatively uncharted waters of the scientific community and begin unearthing some bizarre research findings that we often don’t stumble across in our daily science news feeds. Throughout university, we spend the majority of our time clustered into boxes moulded to fit a certain area of research. These boxes are then given a label whether it be ecology, virology, microbiology etc. Everything within these boxes aligns perfectly together and aids scientists in forming a clearer picture of the mechanisms powering life on our planet. For my blog, I decided to take a less conventional approach starting with using these categorical ‘boxes’ as kindling to fuel the fire burning inside the mind of curious scientists. No clear predictions, no central topic, and no overarching theme, just a bunch of oddball and interesting corners of recent science research and literature that I believe need to have some light shed on them.

 As it stands, the blog itinerary includes exploring subjects such as the power of the placebo effect, bringing back species through de-extinction, and the discovery of the new mysterious colour known as ultra-black. Due to the crude nature of these topics, the published, peer reviewed literature on them is still few and far between, hence why I have taken it upon myself to help you sort through the rift raft and dig out the real gems in recent research on these mind-boggling topics. You’re welcome.

 So please, put a leg up (or two), sit back, relax, and behold the some of the wonders that the strange science world has to offer.

  Until next time,

-KW