In randomized, placebo-controlled drug trials, reports of adverse events (AE) are common. 40% or more of patients report such side effects, and in both the drug and placebo arms of the study; serious adverse events often lead to trial discontinuation. But since neither the doctor nor the patient knows — at this stage — who receives the drug and who receives the placebo, why is it that these AE also can occur after taking placebos?
In principle, this question is the same than the one we have asked before with respect to symptom improvement: How do we explain when patients report feeling better after taking a placebo pill for days, weeks, or months? Such symptom improvements have been named placebo effects, while symptom worsening has recently been labeled the “nocebo effect” (1). Predicting such nocebo effects remains an unsolved puzzle (2), as is predicting the placebo response (3). For now, the explanation for both phenomena is the same; the underlying mechanisms are similar, if not identical. These will be a topic for another story at another time.
We have also already elaborated that placebo effects occur inevitably in daily medicine, with every treatment and clinical trial, even when no placebo is given at all. These placebo effects were the subject of many experimental studies. For nocebo effects in medical routines, the situation is far less clear. It is probably easiest to explain a situation that does (hopefully) not occur too often in medicine: A patient receives a false and fatal diagnosis — or misunderstands a correct diagnosis as fatal — and subsequently develops symptoms of the presumed disease until the error is corrected (4). There are not many documented cases in medicine of such a nocebo effect, but the simplest explanation, in this case, may be that anxiety, stress, and emotions produce the symptoms that are erroneously attributed to the disease. Anxiety has been shown to be strongly associated with such nocebo effects.
The situation becomes much more complex with the report of AE in daily medical routine when a real drug is given but the reported side effects are unlikely the consequence of this drug. In this paper, we will illustrate the occurrence of such nocebo effects with four situations that are quite common in medicine but have not yet been the subject of many research efforts. Typically, many such AE are rather global and unspecific symptoms that are responsive to nervous system input, “stress,” in a rather broad sense, and are regulated by the autonomous nervous system: muscle pain and tension, headaches, cardiac hyperactivity, sweating, dry mouth, nausea, stomach awareness, bladder or bowel urges, and so on.
Possibly, a patient may have an underlying medical condition whose natural history produces some symptoms that the patient misattributes to a drug taken for another reason. Even more widespread, however, is the situation where a patient believes to have a clinical condition, e.g. milk (lactose) intolerance, gluten sensitivity, or “food allergies”, without an immunologic background, and where he/she follow self-managed nutritional advice and diet. In this case, it is likely that all symptoms occurring for whatever reason are attributed to the drug taken or to the food ingested.
Four situations where nocebo effects may occur for different reasons
1) The patient may have been warned about AE in patient information sheets, e.g. in drug leaflets, and this negative expectation could then produce the event. How can this occur? Again, the patient may experience a symptom (say, a headache) for other reasons (weather sensitivity, alcohol consumption, stress, otherwise) and attribute the symptom to the drug taken. The mechanisms behind this possibility are difficult to explore (5).
2) The patient may have consulted the internet and other electronic sources to search for the available and most appropriate therapy for his/her condition and may have received conflicting information or contradictory evidence about the safety and AE of a prescribed drug. We will present below one such example that is currently widely discussed among experts and non-experts, namely the use of statins for lowering cholesterol levels in patients with high blood pressure and the risk for cardiac infarction.
3) The nocebo effects were induced by medical information and decisions after a switch from a branded to a generic drug for non-medical, e.g. economic reasons, especially when the current therapy was successful. If such a switch is discussed in popular media and criticized by key opinion leaders (media stars, such as actors) this will dramatically increase the number of AE reported and will last from weeks to months before this effect ceases (6). Below we will discuss another current example: the switch from a biologic to a biosimilar drug in chronic inflammatory conditions (chronic arthritis, inflammatory bowel diseases).
4) The patient may have a relative or friend with a similar condition who has experienced AE with the same or a similar drug — this effect is called “placebo by proxy” and can also induce nocebo effects (7). It has so far mainly been investigated in children and their parents but is related to all patients that have experienced diseases and their treatment in their immediate environment, with family and friends. Placebo-by-proxy will be a topic of a story of its own at another time.
Statins and their potency to induce nocebo effects
Statins are therapy-of-choice for many patients with high blood pressure and cholesterol levels, since their first proof they could lower blood lipid levels in the late 1970s. Statins have common AE (headache, dizziness, abdominal pain, dyspepsia, diarrhea, constipation, nausea, fatigue, muscle pain) that are also quite common in the general population, as well as a few rare AE such as myopathy (muscle inflammation), diabetes, and stroke. Following long-term prescription, discontinuation rates due to AE in placebo arms of different trials are rather high and vary between 5 and 25% (8), which is of great concern because of the increased risk of cardiovascular events.
Increased AE, specifically muscle pains, that lead to medication discontinuation were significantly more often reported in unblinded studies and in clinical practice, while the evidence for increased muscle pain as AE in blinded, placebo-controlled trials is not supportive (9). Clearly, this calls for an influence of public media on the AE reports via internet forums and chat rooms on the nocebo effect (10).
To investigate this further, Khan et al. (11) correlated the number of webpages discussing statins and statin-associated AE with the reported incidence of AE across 13 countries worldwide, divided between different language areas (Dutch, English, French, German, Italian, Japanese, Polish, Portuguese, Spanish, Swedish). They found a positive and significant correlation between both, and while we know that correlations cannot be interpreted as causal, this supports the notion that increased incidences of AE following statin prescription is driven by public information available, predominantly in English-speaking countries (UK, US, Canada).
Biologics versus biosimilars: The switch may induce nocebo effects
Biologics are medications extracted (or semi-synthesized) from biological sources, in comparison to totally synthesized pharmaceuticals, and involve recombinant DNA technology using hormones, antibodies, or proteins. A classic example is Humira (adalimumab), a monoclonal antibody acting as an antagonist against Tumour Necrosis Factor (TNF), used as therapeutic of rheumatoid arthritis, inflammatory bowel diseases, and other chronic inflammation-associated diseases. First developed biologics (also called originators) are extremely expensive (with annual therapy costs of 20,000 USD/Euro or more) (12) for lifelong therapy; therefore, subsequently developed “biosimilars” receive support from health care providers for their ability to substantially cut these costs (13, 14). This encourages hospitals, doctors, health insurance plans, and health agencies and authorities to use biosimilars in newly-diagnosed patients and to propose a switch from biological to biosimilars wherever possible in previously-treated patients.
Biosimilars have to prove their therapeutic equivalence before approval and usually do not provoke more AE than the originators in randomized, controlled trials. As with statins (see above), more EA are reported with an open label switch than with a switch under double-blinded conditions, especially when the initial therapy with the biologic was successful (15-17). This mimics effects seen with the switch from a branded to a generic drug (3). It has been shown that different health care systems require different solutions to prepare and accompany a patient for such a switch for economic reasons, (e.g. (13, 18, 19).
These nocebo effects cannot be attributed completely to the patients’ unwillingness to change from a successful treatment. It has been shown that the doctor’s knowledge of the equivalence of biosimilars to biologics is limited (20), and this may co-determine the patient’s acceptance of the switch. A further limitation — that applies to all statistical estimates of the likelihood of experiencing AE with all drugs — is the divergent interpretation of global indicators of AE occurrence (e.g. very likely, likely, seldom, rarely, etc.) by different health care providers (doctors, pharmacists, nurses, medical students) (21) and patients (22). As long as doctors understand the likelihood of AE different from patients, an agreement may be difficult to reach and may require a change in the doctor-patient communication beforehand.
Why we cannot tell a patient that he/she shows nocebo effects
Why is it advisable, not only in these but also in other cases of presumed nocebo effects, to not label such expectancy-induced effects “nocebo effects” for and in front of the individual patient? Different from nocebo effects in placebo-controlled trials (see above), AE experienced after taking a “real” drug can always, even if extremely unlikely, be the consequence of the drug and not of the expectation to experience AE, and these two can rarely be separated in individual cases — nocebo effects occur only as group means across many patients. This is why:
Labelling AE symptoms as “nocebo effects” is violating the autonomy of the patient and undermining a trustworthy doctor-patient relationship (1). But this will be the topic of another story.
This is part 7 of a series covering “placebo” provided by Paul Enck and Sibylle Klosterhalfen from the Tübingen University Hospital. Continuous updates on placebo research can be found at www.jips.online.
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- Gupta A, Thompson D, Whitehouse A, Collier T, Dahlof B, Poulter N, et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. The Lancet. 2017;389:2473-81
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- Stolshek BS, Wade S, Mutebi A, De AP, Wade RL, Yeaw J. Two-year adherence and costs for biologic therapy for rheumatoid arthritis. The American journal of managed care. 2018;24:Sp315-sp21.
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