Nocebo Effect From Drug Intake: Is It Worse Than Placebo?
Every year, with efficacy and safety, research and development efforts tirelessly conceive new drugs and other medical treatments to benefit patients. However, in some instances, prescribed drugs do not provide the therapeutic effect that regulators approved it for.
The placebo effect is likely a remarkably familiar medical term. Concisely, it is the phenomenon of patients starting to feel better once they believe they are receiving a treatment (e.g., taking a drug) even if the treatment has not taken effect yet. This effect often occurs in clinical trials where the research team doesn’t tell patients whether they are taking the study’s drug (the treatment group) or if they are taking pills composed only of inactive ingredients such as carbohydrates (the placebo group).
The placebo’s positive effect on patients has a dark opposite — the nocebo effect, also called nocebo hyperalgesia. When you tell your patients the potential adverse effects of a drug, they can start exhibiting those adverse effects. This article will explore nocebo responses to help you manage your patients’ health.
Nocebo Hyperalgesia: Overview
Because of its potentially dangerous effects on patients, researchers are studying the nocebo effect more deeply to help medical professionals avoid it.
The nocebo effect occurs when the patients inadvertently experience the adverse effects of a given treatment even though the available evidence indicates the risk of experiencing it is relatively small. It is wrong to underestimate the power of words and suggestions to patients.
However, this also opens an ethical dilemma. When a physician does not inform about all the risks, besides implying ethical problems, it can even be grounds for lawsuits due to violation of informed-consent medicine. Informing your patients of all the possible scenarios with their treatment is essential to keeping them aware of what would happen to their bodies. Therefore, nocebo hyperalgesia is a delicate topic that medical professionals must understand.
Definitions, Etymology, and Adverse Reactions
Nocebo hyperalgesia is a scenario in which a patient exhibits adverse reactions to a new drug because of their belief that this novel intervention will cause them harm. The word nocebo owes its origin to Walter Kennedy, who coined it as a counterpart to the term “placebo.” Nocebo came from the Latin word nocere, which can be translated as “to harm.”
The nocebo effect is centered on the patient’s response, not on the pharmacology of the drug. Therefore, it is mainly inherent in the patient. As emphasized by Kennedy, this makes the nocebo effect more dangerous than it first seems — the adverse reactions from the nocebo effect experienced by patients manifest physical symptoms that, despite their psychosomatic origins, can be clinically diagnosed.
A major unresolved issue with the nocebo effect is that health professionals often don’t account for its existence. As a result, medical professionals often underestimate nocebo hyperalgesia and the importance of understanding its mechanisms to help them prevent it in their patients or clinical trials of drugs.
Differences Between Placebo and Nocebo
When a patient comes to your clinic, you need to inform them of their medications’ main benefits and most relevant risks. The nocebo effect occurs when the patient’s negative expectations of the treatment eventually cause them to feel such adverse effects that would not have happened otherwise.
Seneca, an ancient Roman philosopher, once said:
“We are more often frightened than hurt, and we suffer more from imagination than from reality.”
This (perhaps emotionally charged) anticipation is the central concept of the nocebo response.
The contrasting response to the nocebo effect is the placebo effect. Placebo comes from the Latin phrase placēbō, meaning “I will please”.
The placebo effect relates to beneficial impacts — the patient gets a positive outcome, such as resolving symptoms or recovering faster, because of their positive expectations about an inert medication. In clinical trials, placebo groups are given an inactive substance while the medical technicians convey that it is supposed to be beneficial to their current health.
Nocebo and placebo are both assumed to be caused by psychogenic factors –the psychological impact of the administered medications induces a physical and measurable change in the body.
Common Scenarios Exhibiting the Nocebo Effect
Regardless of the nocebo effect, you must inform your patient about the possible adverse reactions to the pills you prescribed to them. According to studies, merely telling your patients of potentially active drug side effects is enough to induce real symptoms.
Currently, there is a hazy understanding of the nocebo effect. Given nocebo responses from patients are common in medical scenarios, it is important to know in what instances are they likely to be experienced.
Researchers speculate it to be due to Pavlovian conditioning combined with other psychological mechanisms.
A typical example of the nocebo effect is during clinical trials of novel medications. Novel drugs crucially require a clinical trial to understand them sufficiently so they can enter the market. Pharmacoepidemiology and drug safety precludes any mass production of medicine.
However, clinical trials may face inaccurate data collection because of the nocebo effect. Researchers might record adverse reactions due to psychogenic phenomena, not the drug itself.
Other common examples of nocebo hyperalgesia include patients feeling nauseous when they enter a clinic to receive chemotherapy or experiencing increased pain once a doctor tells them that they will undergo a painful procedure.
Another study has shown that the doctor’s choice of words before injecting a radiographic solution influenced the patient’s response to pain. Patients report more discomfort when the doctor uses terms like “hurt,” “sting,” or “bad” pain.
Nocebo effects are real and clinically diagnosable. Common nocebo symptoms include depression, nausea, loss of appetite, hypotension, sleep problems, and itching.
Nocebo Effect and COVID-19 Vaccinations: Are They Related?
The massive impact of the COVID-19 pandemic on the medical world has demanded prompt attention to developing treatment and vaccines. As a result, several COVID-19 vaccines have been designed, tested, manufactured, and administered in an extraordinarily brief amount of time. For instance, regulatory bodies have cleared vaccine types such as the Moderna mRNA-1273 SARS-CoV-2 vaccine and the Novavax NVX-CoV2373 COVID-19 vaccine.
Vaccination against this novel virus has been largely successful as more people are getting protected from severe and fatal forms of the disease. However, a substantial amount of the population worldwide remains hesitant to get vaccinated, and the nocebo effect might (at least partly) explain this.
People tend to be vigilant of the vaccine’s adverse effects, leading to hesitancy. Findings in a COVID-19 vaccine trial reported that placebo patients received fewer adverse effects, but the patients acquired adverse effects after receiving the second dose of the placebo. An exploratory analysis has speculated that nocebo responses may provide adverse effects, almost as severe as those receiving the first dose of the vaccine.
Better communication strategies to the patient are encouraged to address this hesitancy regarding the COVID-19 vaccine. Further, informing the public about the possibilities of a nocebo effect could also be helpful.
How Powerful Is the Nocebo Effect?
Surprisingly, nocebo hyperalgesia experienced by patients is more potent than expected. For example, one case study recorded an individual who attempted suicide by swallowing placebo tablets that they believe were medication. Specifically, the individual tried to end their life by ingesting 26 placebo sugar pills with no active ingredients. Aside from the psychological impact, the individual also manifested severe hypotension and needed supportive management.
As soon as the individual realized that the pills were merely a placebo, all symptoms alleviated immediately. The researchers reported that the individual was initially confident that overdosing on those “drugs” would be fatal. And they were almost correct — the magnitude of the effect of the nocebo hyperalgesia on this individual proved that it is powerful enough to endanger a person’s life.
While this incident showing the nocebo effect’s potency was recorded, there are almost certainly many more unrecorded incidents. Therefore, with more and more drugs needing clinical trials, medical professionals should always consider the nocebo effect in conducting research.
Nocebo’s Ambiguity in the Medical World
Placebo and nocebo are contrasting terms that may ultimately be counterproductive in healthcare. The two terms are opposites and seem easy to tell apart, but these can be ambiguous terms when used in practice.
Researchers argue that there is no benefit from labeling placebo as unconditionally desirable and nocebo as invariably undesirable because it only leads to confusion. Also, researchers need ample evidence regarding the desirable and undesirable drug effects, which requires administering and following the patients, which usually takes months before enough data is available to arrive at a conclusion.
One example is that analgesia is usually correlated with the placebo effect, while hyperalgesia is usually connected to the nocebo effect.
Another example is that immunosuppression is a desirable effect for patients with an autoimmune disorder, but it is undesirable for most healthy people. Therefore, immunosuppression can be both a positive and a negative, depending on whom or how it arises. So, it is ambiguous whether it should be called a placebo or a nocebo effect.
Lastly, the placebo-nocebo labeling of drug effects leads to a false dichotomy. There is no solid black-and-white scenario where the drug only gives two different outcomes — whether an effect is either desirable or undesirable depends on the context.
Nocebo’s Ambiguity in Anthropological Usage
Modern medicine is not the only school of thought regarding healing. Anthropological perspectives have brought rituals, faith healing, and other traditional means to heal or cure people, like how people use conventional treatments (approved for the market after clinical trials). Anthropologists have also extended the placebo and nocebo labels into anthropological medicine.
However, ambiguity and complexity are still a problem here. There are still rituals that can be both a placebo and a nocebo. For example, some rituals are considered placebo rituals when they are performed to heal people while at other times, they are performed to injure people and so are nocebo. But the same complexity is a problem.
Negative Expectations and Suggestibility as the Main Drivers of Nocebo Effect
Research studies have associated nocebo responses with several psychological factors. For example, studies have linked negative expectations and suggestibility as one way for patients to manifest the nocebo response.
Personality factors also work together with psychological factors in increasing or decreasing pain experienced. These factors are optimism, empathy, and fear of pain. So, when medical professionals agitate anxiety and negative expectations, the nocebo effect is more likely to occur.
However, pain is multidimensional in the clinical setting, where it differs from individual to individual. Therefore, studies that correlate negative expectations and suggestibility to the nocebo effect can only guide the interpretations of patients’ feelings and experiences of pain and adverse effects.
Misattribution of Negative Symptoms
The misattribution by medical professionals of patients’ negative psychosomatic experiences as being symptoms of a particular medical treatment is a potential effect of the nocebo effect. For example, in a study on 50 people with chronic back pain, researchers aimed at studying the usefulness of a flexibility test. The study team split the participants into two groups. In one group were participants who researchers told would feel “some pain” when undergoing the test and then administered the test. In the other group, researchers just administered the test. The researchers found that participants who, before the test, were told the test involves “some pain” reported feeling more pain than in the other group.
Another study with a pattern of nocebo involved participants who needed finasteride for their prostate disease relief. It has erectile dysfunction as a possible adverse side effect. Researchers only mentioned the side effects to half of the participants. At the end of the experiment, 40% of the aware group experienced the side effect, while only 15% were affected in the unaware group.
The media can sometimes disseminate information about an adverse reaction to medicine in a hyperbolic fashion. This widespread dissemination of adverse medical reactions causes even more people to report their negative reactions, leading to a media storm. This can induce a more prominent nocebo effect as it increases the number of people who know about potential negative effects to their treatment and can therefore experience them psychosomatically.
Many studies point to a consistent outcome in nocebo responses. However, if many researchers and health professionals are unaware of the nocebo effect, the adverse reactions reported by patients during the administration of a drug or treatment could be misattributed to the medical treatment itself. Therefore, it is best to exercise prudence and watch for the nocebo and placebo effects.
How Do I Prevent the Nocebo Effect on My Patients?
Both verbal and non-verbal communication triggers the nocebo effect. Therefore, enhancing your communication skills can improve your patients’ overall experience. These “soft skills” are the most effective way to combat the nocebo effect, as proven by the previous studies cited in this article.
Moreover, knowing which groups of patients are more likely to develop nocebo hyperalgesia can also help you. For example, patients struggling with anxiety and depression or those who are generally pessimistic or high in neuroticism are more strongly influenced by their external environment. So, expect the inadvertent nocebo effect to manifest more commonly in these individuals.
The best tip to prevent nocebo responses is maintaining a good balance when telling patients about a treatment’s beneficial and harmful side effects. Take your time explaining these concepts and make follow-up questions to confirm that your patient understands you
Finally, the chance for nocebo effects to occur is said to decrease if you frame your statements positively. For example, rather than focusing on the side effect by saying “5% experiences this side effect,” it is better to frame it as “most people who took this treatment did not feel any side effects.”
How Can You Reduce Your Patients’ Nocebo Effect?
Clinical trials are only effective if they gather accurate data and arrive at unbiased conclusions. Therefore, you can opt to administer a clinical assessment tool in the clinical setting. Such a tool can help you assess and manage your patients’ expectations and minimize or completely get rid of nocebo effects. Tools such as the Perceived Sensitivity to Medicines (PSM) scale or the Revised Illness Perceptions Questionnaire (IPQ-R) are some tools you can use.
Another effective nocebo hyperalgesia reduction method is a two-step strategy. You first initiate the therapy at doses below the recommended therapeutic dose. This cautious approach will help gauge your patient’s ideas and response to the medication. Then, for the second step, you increase the dose to the correct amount for the required clinical effect. You can use what you learned in the first step as a baseline for monitoring their health.
Are There Drugs to Help Minimize the Nocebo Effect?
Pain’s neural pathways are one of the explanations for the nocebo effect. For example, two pain pathways activate when nocebo-inducing suggestions are said to the patient. One of the pathways consists of the hypothalamus-pituitary-adrenal axis, which controls the stress reaction. Administration of diazepam reduces the activation of this pain axis.
Similarly, the cholecystokinin system is another anxiety-inducing mechanism. So, if the patient takes proglumide, it blocks this pathway, and the nocebo hyperalgesia is moderated.
By understanding the pathways of pain and anxiety, participants can prescribe patients drugs to modulate the nocebo effect.
In Conclusion
The nocebo effect has always existed in medical settings. As you have read in this article, the nocebo effect occurs when patients acquire adverse effects from treatment because they have learned about it from somewhere, for example, if a medical professional emphasized a possible adverse effect or they heard about it on TV.
As a health professional, you have to be aware of this and work around it to provide your patients with the best treatment and care. However, there is much more to learn about nocebo effects in your clinical practice. Countering the nocebo effect can only be effective if you know your patient’s response to treatment. You can get in touch with Hyfe to help you track your patient’s response to treatment. Hyfe tracks your patients’ symptoms efficiently so you can combat the nocebo effect.
