CME for family medicine

Understanding Placebo

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On this week’s episode of the Psychiatry and Psychotherapy podcast, I interview Mark Ard, M.D., a third year psychiatry resident at Loma Linda University. On the state level, he works towards developing means of access to care, in-patient psychiatric care, affordability of care, and further access to mental health.

Mark is also the person who encouraged me to start pursuing weight training through Starting Strength, which we will link in this article.

Link to show on: iTunes, Google Play, Stitcher, Overcast, PlayerFM, PodBean, TuneIn, Podtail, Blubrry, Podfanatic

Understanding Placebo

David Puder, M.D., Mikyla Cho, Mark Ard, M.D.

What is placebo?

The original meaning of the word placebo is, “I will please.” That statement comes from a time when doctors didn’t have our modern code of ethics, and they would prescribe whatever would make the person feel better. They probably had the best intentions, but they also would have known that whatever they were prescribing might not have been a real medication for the symptoms the patient was experiencing.

Doctors, even then, knew that suggestion was powerful, sometimes more powerful than the medicine they were prescribing.

Laypeople who hear the word “placebo” automatically think of sugar pills. They may think only that it’s something a doctor gives to placate and make people feel better when they aren’t getting the active medication. Placebos have long been used as a comparison arm for clinical trials. Usually it is in the form of an inert sugar pill or sham-procedure. Researchers can observe a psychobiological response known as the placebo effect.

But when thinking about the word “placebo,” we must think of the entire effect of it, and it is perhaps better termed “the meaning effect.” As I discussed in last week’s episode of the podcast, the meaning we give something creates belief, and belief is a potent change mechanism, even when it comes to our physical health. It is especially potent when it comes to mental health.

The placebo effect encompasses the therapeutic alliance, expectations, natural healing of the body and mind, and the environment of therapy. It involves the power of suggestion, mood, and the beliefs behind even one positive or negative interaction with a doctor. It also, as we will see, involves studies involving heavy-hitting medication.

When there is an increased ritual, there is an increased placebo effect. During a hospital stay, the surgery preparation, meetings with doctors, nurses and therapists can have an incredibly therapeutic effect on a patient. It is possible to see biological mechanisms triggered by psychosocial context and attribute it to a placebo effect.

What is the power of suggestion, the meaning effect, placebo effect, and how do we use it or avoid it in our practices and when testing new medical treatments?

Why do we study placebo?

We study placebos because we need to understand how meaning works, how belief works, and on the other side, if a medicine actually works.

As doctors, we need to be able to read studies critically, with an eye for placebo. We need to see what actually works and what the study was controlling the treatment group to. We also need to know if there parts of the treatment that are working only because of the placebo effect, and if so, how do we use that to heal people.

How does the placebo effect work?

The efficacy of the placebo goes up because of the expectation and meaning we give to placebo.

In one study, half of the patients got the actual medication, half got the placebo. In the same study, in another group, 25% of the patients got the placebo, and 75% of them got the actual medication. In both of these studies, the participants were told the percentage chance they would get the real medication. In the study where only 25% of patients received the placebo, more people experienced positive changes from the treatment, whether they received the placebo or not. Most people believed, because of hearing the percentages, that they would probably get the medicine. That belief increased the placebo effect.

In groups with lower percentages receiving the actual medication, the response is lower, even with real medication.

Researchers think placebo effect works because of expectation and classical conditioning mechanisms. Such understanding may be an oversimplification of a very complex phenomenon but it provides a useful framework. Expectation is how much the patient believes in the therapy. Higher expectation leads to hope and positive outlook, which results in better outcomes. Exactly how this works is still under investigation. There are multiple theories as to the underlying mechanism, but overall, we can say that there is a bidirectional interaction between expectations and emotions, and we respond better when expectations are high and our mood is good.

Classical conditioning contributes to the placebo effect by modulating conscious expectation and non-conscious learning. The white coat effect is a classic example of how our body responds to a conditioned stimulus. Also, when a patient feels better after taking a pill, it becomes a conditioned stimulus, and the body may respond positively even after taking a placebo medication because of its conditioned response.

Expectation can be shaped by many factors. Broadly, these factors can be grouped into patient effect, clinician effect and study design effect. Patient effect refers to patient characteristics such as beliefs, values, cultures, and the meanings associated with the illness and the treatment.

In a study of IBS patients, Vase et al found that expected pain levels and desire for pain relief accounted for up to 81% in the variance in visceral pain intensity. There is also a greater dopamine release in patients who had higher expectation. (De la Fuente-Fernández). Conversely, pessimists were more likely to have negative side effects (when compared to optimists’ responses) when told a placebo would make them feel bad.(Geers)

How a patient interprets and generates meaning in a given treatment condition is widely variable and difficult to control for. A similarity in demographic characteristics would not account for all of them. Direct-to-consumer (DTC) advertising of antidepressants is an example of how a society can shape one’s view and expectation of the illness and the treatment. The promotion of antidepressants inherently depends on the biological model of depression. By simplifying depression as serotonin deficiency, antidepressants were promoted as a simple solution to a complicated problem. These advertisements are designed to convey that “psychopharmaceuticals have an obvious, objective, and scientific relationship to the symptoms they are supposed to treat”(Greenslit, 2012). The reality is more complex and difficult to understand than the advertising, but the narrative is believed and shapes decision making.   

An interaction with a clinician can shape the expectation of outcomes as well, especially if there is a strong alliance. Warmth, empathy, duration of interaction, and communication of positive expectation may significantly affect clinical outcome (Kaptchuk).  

One article (Verhulst et al., 2013) deconstructed the correlation between the medical alliance and placebo. The placebo effect encompasses the beliefs, values, and expectations that patients have about a treatment. We can help shape a patient’s belief and expectations by giving realistic illustrations of the treatment, which are more valuable than false hopes; this is the medical alliance that we as healthcare providers can utilize. Part of the medical alliance is the idea of concordance between the physician and patient. There is both narrative concordance, the shared understanding of the patient’s condition, and the relational concordance, the shared relationship structured based on scripts, boundaries, and interactional rules. Ultimately, by utilizing the idea of concordance and a strong alliance with the patient we can influence how they view a treatment and better the outcomes via the placebo effect.

Study design can also change expectation. Having a higher chance of being assigned to the treatment group and having a choice (Rose 2012) increases the expectation. The degree to which placebo resembles the treatment is another important consideration, because unblinding can lead to decreased expectation. (Some studies utilize active placebo to make unblinding more difficult.) In pharmacological studies, active placebo usually contains some real medication that contains some of the expected side effects to imitate the expected treatment.  

The mechanisms that control placebo effect:

  • Opioid system

This system bolsters a lot of the evidence for pain relievers—you have more of a placebo effect on the patient if they know they're getting the medication than if it’s snuck into an IV. The opioid system in the brain begins to work as a pain reliever before any actual medication sets in, if it’s even administered.

  • Dopamine system

Dopamine signaling is involved in expectation and response. Our brains will respond as if something is happening if it believes it will happen. This pathway is also involved in habit formation and novelty seeking. The brain lights up in the same way to a placebo as it does to an active intervention. There is a fascinating link between dopamine deficiency and Parkinson’s disease; placebos can induce dopamine release, leading to improvement in Parkinson’s disease motor dysfunction.

In another study, people were told they were getting either a cheap medication or an expensive medication. Even though they both received placebos, the group who was told they were getting the more expensive medication experienced a greater placebo effect.

Even the color of medication can affect a person’s response. Brand names can affect a person’s response. A person who is told they are receiving an anti anxiety medication will calm down, even if it’s a placebo.

  • Prefrontal cortex

The third “system” is prefrontal cortex, which is involved in associations and meaning. This is also one of the main areas involved in improvement of depression (Murray, 2013).


What is the effect of placebos on the medical profession?

Is placebo testing accurate?

Some industries fail to examine things with an accurate and rigorous placebo. For example, in a recent study on Botox used for depression, ¾ of the subjects knew if they had received the placebo or not (Finzi & Rosenthal, 2014). Some studies also neglected that placebos can actually change brain chemistry, and activate or deactivate different areas of the brain.

We often think that the patient who is administered a placebo, in taking the medication, thinks it is real and thus the whole placebo response is merely from taking the pill. But in those results we neglect the human factors that come into play when a person meets with a psychiatrist that is doing the patient interview, and how it could be the therapeutic alliance and feeling cared for that influences outcomes and spontaneous remission of symptoms.

For the medical field to determine that it’s not only the placebo effect taking place, that the medicine or treatment actually works, many factors come into play.


Discussing negative side effects with patients

How do you talk about medication as a doctor without scaring the patients with a side effect list? Studies show that by listing side effects, people are more likely to experience the side effects.

I usually discuss the side effects with patients if they occur in more than 1% of patients or if the side effect is life threatening. Also, if the patient feels like they need to stop the medication, I tell them to call or email me. Even knowing they can reach out of they are experiencing problems gives patients a sense of peace, and could decrease negative placebo effects of the medicine, and increase positive effects of it.

In medical education at large, there seems to be a loss of the science of connection and a focus on medicine rather than being able to emotionally connect to people, and mental health is part of the human experience.


Therapy and the placebo effect

Placebo and psychiatry have an interesting and complicated relationship—both are concerned with the mind-body connection. Using placebo in psychiatriatric research is, therefore, more challenging. It is more difficult to tease out the true effect of a treatment since mental illnesses have significant psychosocial components.

Higher therapeutic alliance, higher empathy, and higher interpersonal skills all have better outcomes. Beyond the model of therapy, each therapist’s kind of connection to their patients deeply affects a patient's’ response.

The value of the therapeutic alliance can be as powerful as medication, and also bolster the effectiveness as the medication itself.

In their paper Wampold, Frost, and Yulish (2016) reviewed the history of how placebo was used in randomized control trials for testing the efficacy of psychotherapies. They found that when poorly designed placebo therapies were used as controls, the psychotherapy treatment group had superior results. It is difficult to have a truly controlled placebo. For example, it can be obvious whether a therapy is a placebo or a true psychotherapy and the providers administering the treatments would also know which was the true treatment. People have advocated that different psychotherapies are beneficial because of their common factors such as the therapeutic alliance, discussing expectations, and instilling hope. These and other factors common to the variety of psychotherapies can also be found in the placebo effect, which facilitates the argument that placebo psychotherapies are not inert. Therefore when we look at studies that compare psychotherapies to a placebo therapy, we must be aware that the comparisons may not be completely accurate.

In therapy practice there are no effective placebos to be given to compare, so effect size with therapy is very different than effect size with medication vs placebo. A broader and more nuanced understanding of the placebo effect is important in two ways. First, it allows a clinician to critically evaluate studies that compare the treatment with placebo. Placebo should be evaluated within the framework of mental illnesses. Secondly, understanding placebo allows a clinician to maximize the clinical outcome by focusing on factors such as alliance. Placebo teaches us about the complexity of the mind body connection, and calls for a more integrated approach in treating mental illnesses.

The effect size in double blind studies, however, does not tell the whole story of the effectiveness of the psychiatric relationship, because it does not take into account the part of the placebo response that actually came from a psychiatrist’s relationship with the patient.

Even since the beginning of psychopharmacology, in the 1940’s, placebo effect has increased. In part, I believe that’s because we’ve reduced mental illness to a few symptoms and then say those can be helped or fixed by a pill. For example, there is commonly believed language around depression that says it’s a serotonin deficiency. So, patients take medicines to boost their serotonin (SSRI medication). That is not the only thing going on in depression, and it’s not necessarily true. So SSRI medications have a large placebo effect.

Further, different psychiatrists will have different effectiveness with patients (McKay, 2006). The authors analyzed data from the Treatment of Depression Collaborative Research Program (TDCRP) that compared imipramine hydrochloride with clinical management vs. placebo with clinical management and found that 7% to 9% of outcome variabilities depended on the psychiatrist providing the treatment. When using BDI, the results were statistically significant (p < 0.05) and when using the HAM-D the results were marginally significant (p = 0.053). Therefore the authors concluded that the psychiatrist effect was at least equal to or greater than the treatment effects. The effectiveness of a psychiatrist is also critical in proving optimal treatment.  


Non-therapeutic medical fields and doctor-patient relationships

Even the awareness that the placebo effect exists should make medical workers understand that we need to consider people’s outside lives, not just the psychopharmacological effects of the medication. If little things have a placebo effect, and that is directly related to meaning and belief, what are the patients experiencing outside of the medical office that is influencing them?

Conclusion

Our brains were made to create meaning out of things, and this meaning can change the very nature of the brain. When we understand placebo we become better guides to our patients, steering them away from things that don’t do anything, and towards things like having a connected relationship with a caring person, which can be the treatment itself. We also look not only at how powerful a medication was compared to the placebo, but also if the patients thought they were taking the real medication or not. We also learn that belief is powerful and can understand how people get swayed into cults and taking things which have been proven to only be harmful.  

Therapeutic Alliance Part 2: Meaning and Viktor Frankl’s Logotherapy

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In this week’s episode of the podcast, I’m going to be emphasizing the meaning that I, as a therapist, can help draw out of other people’s experience through a therapeutic alliance.

David Puder, M.D., Kristen Bishop, Brooke Haubenstricker, Mikyla Cho

In the celebrated book Man’s Search for Meaning, author Viktor Frankl wrote about his intimate and horrific Holocaust experience. He found that meaning often came from the prisoners’ small choices—to maintain belief in human dignity in the midst of being tortured and starved and bravely face these hardships together.

“The way in which a man accepts his fate and all the suffering it entails, the way in which he takes up his cross, gives him ample opportunity—even under the most difficult circumstances—to add a deeper meaning to his life. It may remain brave, dignified and unselfish. Or in the bitter fight for self-preservation he may forget his human dignity and become no more than an animal.” - Viktor Frankl

“We who lived in concentration camps can remember the men who walked through the huts comforting others, giving away their last piece of bread. They may have been few in number, but they offer sufficient proof that everything can be taken from a man but one thing: the last of the human freedoms—to choose one’s attitude in any given set of circumstances, to choose one’s own way.” - Viktor Frankl

Frankl argued that the ultimate human drive is the “will to meaning,” which could be described as the meaning to be found in the present and in the future. For example, I have had patients who are suicidal, yet they would not kill themselves, despite part of them desiring death, because they would not get to see their grandkids grow up. The meaning of the future moments and being able to help their grandkids in some small way empowers them to keep going to treatment.

People’s meaning keeps them going, even when other drives, like sex or desire for power, are completely gone. In this way, Frankl noted, “Focus on the future, that is on the meaning to be fulfilled by the patient in his future…I speak of a will to meaning in contrast to the pleasure principle (or, as we could speak also term it, the will to pleasure) on which Freudian psychoanalysis is centered, as well as in contrast to the will to power on which Adlerian psychology, using the term ‘striving for superiority,’ is focused.”

This idea led to the beginning of a new type of therapy—logotherapy.

Helping a patient find meaning

Being unable to find personal meaning in our lives can lead to depression, hopelessness, anxiety, and suicidality. As a physician, I see this often, and I try to help my patients find meaning in their lives. However, the approach I have learned from Dr. Tarr (my mentor), and from my studies, is different than the normal approach of just asking people, “What is your purpose?” or, “What is your vision for the future?” The technique I use is based on another principle called “psychic determinism,” which means that everything has meaning. There is nothing that a person says, no flash of emotion, no change in body posture that is meaningless.

When you believe this, you view the patients’ words differently. The meaning may not be readily apparent; it may be expressed in primary process mentations and have an unconscious-type meaning like dreams, which may be difficult to understand. Suffice to know at this point that the mindset we have when we approach people is that everything they say has meaning; every sequence of thoughts that they say is deep and valuable.

We start from small moments of meaning that are coming from their words, their body language, their microexpressions, your experience of them in the moment, and we take those small moments of meaningfulness and start to verbalize what we find meaningful. Listening to our patients and helping them to understand the hidden meaning in their lives, even in the midst of work or difficult times, can help them withstand trauma, stress, and hardships.

No rambling is random

Sometimes patients will talk for awhile, changing subjects rapidly, and we may think it is random, but it isn’t. Even when schizophrenic patients talk, there is meaning behind what they’re saying. When we allow for free association, we can derive a sense of meaning from the commonalities in topics that come up.

For example, a patient might be talking about how they are angry at their significant other, then immediately report that when they were young their mother would often yell at their father, and their father would cower in his room in silence. How is their current anger related to how they felt as a child watching this drama? How might the two be linked? What about the microexpression of disgust that flashed as they reported both topics.  

As you look deeper, the meaning becomes more evident. In this particular situation, the disgust or revulsion they experience recollecting their father’s cowardice magnified the disgust they felt toward their significant other. Understanding the link and the uncovered meaning helped them tolerate the intensity of that negative feeling, and helped them develop new meanings about their current and past experiences.

Even hallucinations and delusions generated by some mental illnesses have meaning. When I’ve given patients antipsychotics and they’ve adapted to the medicine, we explored their hallucinations and they were able to see why they wanted to believe in an alternate reality—it gave them a sense of power or control, or related to a deep underlying fear in some way. As we developed meaning in their real lives, they felt more comfortable in their actual reality.

When we sincerely believe that everything the patients say has meaning, the patients themselves feel meaningful. Ascribing meaning enhances the patient’s esteem tremendously and makes them feel safe enough to continue to freely associate. Incredible progress can be made with patients in this way.

To get people to free associate, you need to reduce the shame enough to get people to feel safe enough to be able to share their uncensored thoughts and feelings.

Empathize with the meaning

“Men are not moved by events but by their interpretations.” - Stoic Epictetus

Relationships can allow for deeper understanding and meaning to develop in life. To strengthen our relationship with our patients, we must understand what they’re saying and then empathize with that meaning.

We often think in the context of our own lives, and as therapists or physicians we need to allow people to be the experts of their own lives. A word or phrase may mean something completely different to our patients than it does to us, so we must ask the patients to help us understand their interpretations and the meanings they assign to the events they’ve experienced. It is important that the patient communicates their meanings and that assumptions aren’t made. Misunderstandings can cause feelings of isolation, leading to strains or ruptures in the relationship. If this happens, try to reconnect, as this conveys respect.

Try to deeply connect with the patient emotionally through empathy and listening. Listen to what is said, what is not said, and what makes the patient defensive. We can listen to the rhythm, the sound, their vocal cadence, and watch their face for emotional cues.

Even if we believe the patient isn’t entitled to the emotions they are experiencing, we have to search for the meaning they’ve assigned to their pain. That meaning is what we can empathize with, no matter the circumstance. When we empathize, we can join them in their distress or enjoyment, and we can develop a deeper therapeutic alliance that is patient-centered and emotion-centered.  

“To feel with a patient and share distress and hopelessness and mistrust of the future, is therapy. You are an observer in taking history, but you’re a participant as a therapist. To share together, is therapy.” - Dr. Tarr

Meaning develops emotional endurance

People who have chronic pain who believe they are enduring it for a deeper meaning report feeling far less physical pain compared to those who do not report a deeper meaning. Even in birthing units, women report the highest amount of pain, but also often the highest amount of satisfaction. The child being born gives meaning to the pain, and this meaning is so powerful that some women choose to endure the pain instead of accepting medication.

Help patients find meaning in their symptoms. Most symptoms are adaptive, even eating disorders, cutting, and other harmful behaviors. These things have helped people cope with the realities of their lives in some way. We don’t want them to judge their symptoms, but we want them to identify what the meaning behind them.

To really connect with a patient, we must convey to them through our words and actions that they mean something to us, and that we empathize with the meanings they’ve assigned to their lives.

Here are a few phrases I like to use that convey to the patient that I want to connect with them:

  • “What we are talking about together is meaningful.”

  • “We want to make sure we are understanding each other.”

  • “I think I know what you mean. Please tell me if ______ is what you meant. I want to make sure I am understanding you and that we are in tune with each other.”

  • “If you feel I misunderstood you, please tell me right away so we can clear it up as soon as possible.”

  • “We will know together, find out together…”

  • “Could you give an example, elaborate on that, I want to be sure I understand what you are sharing with me.”

  • “I can understand in part how that interaction would make you feel that way.”

Logotherapy, created by Viktor Frankl, helps patients understand and develop meaning in their lives.

Viktor Frankl’s book not only chronicles how the principles of logotherapy helped Frankl survive the Holocaust, it also recounts his observations of how others used meaning to retain their human dignity during times of great suffering. So what is this “logotherapy” that helped people survive?

Essentially, logotherapy is a meaning-centered approach to psychotherapy. Frankl first published his ideas on logotherapy in 1938, and it is now known as the “Third Viennese School of Psychotherapy.”

The Viktor Frankl Institute lists the three principles that are the basis for logotherapy:

  1. Freedom of will

  2. Will to meaning

  3. Meaning in life

The core tenants can also be elaborated in another way, as done by the Viktor Frankl Institute of Logotherapy in Texas:

  1. Life has meaning in all circumstances, even the most miserable ones.

  2. Our main motivation for living is our will to find meaning in life.

  3. We have freedom to find meaning in what we do, and what we experience, or at least in the stand we take when faced with a situation of unchangeable suffering.

Frankl noted that there are a variety of ways in which we can find meaning, such as by our actions, our experiences, our relationships, and our attitude toward suffering. Indeed, logotherapy has been utilized to help treat a variety of psychiatric illnesses, such as anxiety, depression, obsessive-compulsive disorder, and even schizophrenia. Currently, there are several logotherapy institutes around the world in Africa, Asia, Europe, and North America that focus on educating the public about logotherapy and applying it to find meaning in people’s lives.

Here are some studies about logotherapy:

  • One study (May, 2010) found psychological safety and psychological meaningfulness was significantly related to engagement in work. 73% of the variance in engagement in work was able to be explained, with 62% coming from meaningfulness and 42% coming from psychological safety.

  • One study (Mahdizadeh, 2016) of patients after heart surgery found that those receiving logotherapy had improvement in mood. Additionally, this study found that logotherapy did not change the physical capabilities of the patient post surgery. However in the patients who had little to no symptom relief and continued limitation of functions post-op, it still showed an improvement in mood 6 months after the study was completed.

  • Another study (Robatmili, 2014) had the logotherapy group work on describing what was meaningful, setting goals, and then had the group facilitate each other moving towards their goals. In this treatment group, the “meaning of life” scores increased and depression scores decreased. Discovering and pursuing meaning is facilitated by helping through the following steps: (a) establishing the therapeutic relationship; (b) increasing insight regarding identity, values, and goals; (c) reframing meaninglessness and depression; (d) discovering meaning within the meaninglessness and depression; and (e) pursuing the fulfillment of meaning.

  • Once you have some positive attributes, you find other positive attributes—like a snowball effect of developing positive meaning in life. One study (Zhang, 2018) showed this after surveying 1,000 elderly people in Hong Kong. There was a higher level of meaning associated with happiness, health status, and decreased healthcare utilization.

  • Another study (Mahdizadeh, 2016) showed that when educational interventions based on the main concepts of logothearpy were made, it lead to an improvement of the patient’s quality of life after CABG surgery in persons over the age of 35 (specifically, scores in QOL were improved psychologically).

  • In one study (Mosalanejad, 2013), an infertile experimental group that used logotherapy showed significant decreased psychological stress scores.

  • One case review (Southwick, 2006) looked at adding a meaning-based intervention into the treatment of chronic combat-related PTSD showed positive enhancement of outcome when combine with traditional therapies and medications.

  • A study of women with breast cancer (Mohabbat-Bahar, 2014) showed logotherapy to be helpful at reducing anxiety.  

  • I also discussed a study (Thomas, 2014) regarding how structured sessions helped cancer patients improve their sense of meaning in life.  

  • A qualitative interview study on nursing home residents (Drageset, 2017) found that meaning could be found in physical and mental well-being, belonging and recognition, personally treasured activities, and spiritual closeness and connectedness.  This present study also showed a link between well-being of patients’ hope for an improved state of health and are in accordance with previous studies showing significant associations between meaning, hope and well-being among older people in nursing homes.

  • Finally, a study (Leveen, 2017) explored how poetry can be used to increase a sense of meaning in physicians caring for patients.    

Conclusion:

By focusing on what is said by our patients and those we care about and by believing that everything that is said has meaning, we can increase our connectedness with them.  We can also slowly find the deeper sources of meaning and purpose which can help make sense of suffering and physical and emotional pain.






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