What are adverse effects – and how are they related to our expectations?

Undesirable effects, also known as adverse effects, are effects of a drug or therapy that are not intended. Whether and to what extent they occur has a lot to do with our expectations.

Positive and negative expectations influence the effects and side effects of medications.

Side effects, or adverse effects, are any unintended effects of a drug or treatment. However, as an old saying goes: There are no effects without side effects. In other words, active substances always have the potential to cause undesired effects on organ systems. However, the likelihood and extent of such effects varies greatly from drug to drug and from patient to patient.

Before a new drug is approved, clinical trials have to be carried out to prove its efficacy and demonstrate that it has no worrying side effects. But the more severe a disease is, the higher the authorities’ tolerance to accept even serious, though extremely rare, side effects. When a doctor prescribes a drug to treat a disease, the risk-benefit ratio must always be carefully weighed. Please also read the text: „What a doctor needs to know about me".

Prof. Ulrike Bingel, Director of the Interdisciplinary Center for Pain Medicine at the University Hospital Essen, advises patients to seek clarification from a trusted practitioner and to ask the following questions in this order:

• Why should I take the medication?
• What are the benefits for me?
• What experience have you as a doctor had with this treatment?
• What possible alternatives are there
• What adverse effects might occur, and what should I do if I experience any?

Side effects are rarely inevitable. Their frequency and severity depend on characteristics of the patient (e.g. age, sex, concomitant diseases, genetic factors) and on the drug itself (how it’s administered, duration of treatment, dosage, bioavailability).

Drug side effects can occur through various mechanisms:

• Allergic reactions or hypersensitivity to the active substance or carrier substances are also possible.
• Not every organism reacts in the same way. Each individual has their own dose-dependent tolerance of the active substance, i.e. how much of it a person can tolerate. This also depends on weight, previous illnesses and age.
• The active substance may also affect other organ systems as a side effect: for example, antibiotics not only act against disease-causing pathogens but also against some intestinal bacteria that are useful for us.
• An active substance can even be toxic. For example, substances in chemotherapy destroy rapidly dividing cancer cells, but most chemotherapeutic agents act not only on cancer cells but also on other cells, although they do not divide as quickly and are therefore not impacted as strongly by the mechanism of action.

All potential side effects of drugs are mentioned in the package insert of the drug, which must comply with strict drug law regulations. For instance, all side effects that have occurred in clinical studies (see Glossary) are listed in the package insert, even if it has not been verified whether they were really due to the drug. For this reason, whole litanies of very common to very rare side effects are listed, even for harmless medications. As an example, the package insert for the popular over-the-counter drug paracetamol, which relieves pain and reduces fever, lists the following as very rare side effects (occurring in less than one in 10,000 people): allergic reactions up to and including allergic shock, severe skin reactions, painkiller-induced asthma, and changes in the blood count. There are an alarming number of warnings about using this drug - especially about its effect on liver and kidney function. But a search for information about the desired effects, the exact mechanism of action, and the individual benefits will be in vain. You can also read the text: „How do I read the package insert in the right way?“.

According to Sven Benson, Professor of Medical Psychology at the University of Duisburg-Essen, the big issue of side effects should already be brought up when the doctor prescribes a medication during the consultation. “Let me prescribe you something”, is not a good enough explanation, in Professor Benson’s view. “You need to explain the impacts, but also the benefits and the mechanisms of action, because patients aren’t always consciously aware of the symptoms of their disease.” High blood pressure is a good example of this, because the patient doesn’t notice any difference whether they’re taking blood pressure medication or not – at least not at first. So here, you need to clearly explain the long-term benefits of the treatment”, he advises his colleagues. Placebo and nocebo effects already start here. (You can find explanations on this here). If a patient then reads the package insert alone at home, without having the opportunity to ask questions and receive competent answers, they might feel deterred and unsure. This is entirely understandable, and all patients will have experienced this at some point.

The list of side effects discourages some patients from taking a medication that could help them. In 2012, a German study of 2,500 representatively selected adults concluded that 33 to 50 percent of respondents either didn’t take a prescribed medication at all or didn’t take it correctly. One of the main reasons for this lack of treatment adherence was the fear or experience of side effects.

Reports of serious side effects also put the brakes on the just-launched broad vaccination campaign against COVID-19 in 2021. Cerebral venous thrombosis in younger women affected only one to two out of every 100,000 persons vaccinated. Similarly, myocarditis in young men was much less likely to occur as a result of vaccination than as a result of COVID itself. But the fear of possible side effects had lodged itself permanently in the minds of many people, and remained greater than the fear of the disease.

This is where a specific feature of side effects comes into play, which is also addressed in the research of the Collaborative Research Centre "Treatment Expectation". Whether and to what extent adverse effects occur during a treatment depends to a large degree on the patient's expectations. A person who has studied the package insert in detail is actually more likely to develop side effects than a person who trusts the information provided by their doctor and feels positive about taking the medication.

Even the doctor’s way of communicating can contribute to you developing positive expectations as a patient in concrete situations. Good information from your doctor should hopefully dispel any doubts you might have. For instance, he or she can explain to you that a "large study has recently confirmed the safety" of a prescribed medication. Your doctor won't hide the possible side effects from you but will emphasize the desired effects of a drug by telling you that "90 percent of patients tolerate the drug very well and without problems, and only 10 percent experience side effects." And because your doctor may have frequently prescribed this medication in the past and received feedback from patients, he or she can tell you about other patients’ experiences with it. Feel free to ask your doctor about this.

Very important: Of course, if you experience any side effects, you must tell your doctor, as they might be adverse effects. However, you should also be aware of the nocebo effect.

Just as positive expectations can improve the effect of a treatment (placebo effect), negative expectations can increase undesired side effects (nocebo effect). Just knowing that possible effects can occur might lead us to perceive that we are experiencing them ourselves. This has been demonstrated in various studies that compared real treatments with sham treatments. Here are three examples:

• A recent study on COVID-19 vaccination demonstrated this phenomenon particularly impressively. The study evaluated international investigations of COVID-19 vaccinations and found that the nocebo effect is likely responsible for about three quarters of all side effects reported after the first vaccination. People’s expectation of experiencing headaches and fatigue shortly after receiving a vaccination led to a strong occurrence of precisely these side effects. What is more, even in the group that received a sham vaccination, around 35 percent complained of these symptoms.

  Winfried Rief, Professor of Clinical Psychology at the University of Marburg, who was involved in the study, would like to see the population more informed about the nocebo effect. He emphasizes that the nocebo effect is particularly unfortunate in the context of COVID-19 vaccination, as it fosters fears and concerns about getting vaccinated.

• A study in 2020 showed that muscle pain when taking cholesterol-lowering statins, which many people complain of, is also influenced by the nocebo effect. 90% of patients who received a placebo instead of statins reported muscle pain, but only if they had previously reported this pain when taking medication.
• A nocebo effect might also be at work in the dreaded Long COVID: 10 to 15 percent of patients continue to suffer from fatigue, breathing difficulties, aching limbs or difficulties concentrating for weeks to months after COVID-19 infection. However, a French study found that almost as many people show these symptoms when they only think they have been infected, leading medics to conclude that one's own expectations probably also play a role in the development of Long COVID.

Being aware of the nocebo effect won’t make side effects and adverse effects disappear into thin air - but it can give you a greater feeling of confidence when talking to your doctor and reading package inserts. It’s important for everyone to realistically assess the risk of an adverse effect, and as a patient, you should definitely bring this aspect up with your doctor.

Tell us your personal story about placebo and nocebo effects! Medicine is also shaped by people’s stories. This is why we’re gathering patients’ diverse experiences regarding their own expectations for the Collaborative Research Centre “Treatment Expectation”. You can find out more here.