Nocebo effects: more investigation is needed

KEYWORDS:

• Nocebo
• placebo
• expectation
• clinical trials

1. Introduction

Placebo and nocebo effects may represent a problem in drug development [1]. If, on the one hand, large and substantial placebo effects often confound the interpretation of positive outcomes in clinical trials, on the other hand nocebo effects are often responsible for the adverse events observed in the setting of clinical trials. In this latter case, adverse events can take place in both the verum and placebo groups, which indicates that they are not attributable to the drug itself, but rather to nonspecific effects, such as patients’ negative expectations. For example, since large nocebo effects may occur in the placebo arm, this may make it difficult to detect adverse reactions to the drug in the drug arm of a clinical trial. Whereas most of the discussion, literature, and understanding have focused on placebo effects over the past years, much less is known about nocebo effects and much less attention has been paid to nocebo phenomena in clinical trials. Therefore, in this article we want to discuss some key issues related to the nocebo effect and their potential importance in drug development. Nocebo effect in clinical practice has not been studied systematically. We believe that investigating nocebo phenomena from a biological, methodological, and ethical perspective may help answer several unanswered questions both in the setting of clinical trials and in routine medical practice.

2. Possible mechanisms

Many mechanisms may be at work in the nocebo response, including patient-related factors, psychosocial context, and neurobiological factors, such as cholecystokinergic hyperactivity [2]. None the less, the most studied and understood mechanism is related to patients’ negative expectations. This is not surprising after all, as the expectation of an adverse event triggers anticipatory anxiety mechanisms which, in turn, may affect several symptoms, such as pain, nausea, sexual performance, and many others. From a strict mechanistic perspective, although we know much more about the biological underpinnings of placebo effects, some of the mechanisms of the nocebo effect are beginning to be unraveled [2,3]. Much of this knowledge comes from the field of pain, whereby placebo administration along with negative expectations of pain increase have been found to activate cholecystokinin and cyclooxygenase [2], as well as to affect several brain regions [4] and even the spinal cord [5]. This mechanistic approach to the nocebo phenomenon and this new neuroscientific knowledge are important for several reasons. First and foremost, they make us understand that placebo effects and nocebo effects are real biological phenomena; thus they are associated to changes in the patient’s brain and body. Second, this shows that medical practice can be impacted by these effects; in fact, what we want to do in routine clinical practice is to maximize placebo effects while minimizing nocebo effects. Third, the opposite situation is present in clinical trials, in which we want to minimize both placebo and nocebo effects. Therefore, understanding the biological underpinnings of placebo and nocebo phenomena is an important future challenge that may lead to the development of new clinical trial designs.

3. The generation of negative expectations

One of the main sources of negative expectation-generated nocebo effects is the list of adverse events in the informed consent. For example, in analgesic clinical trials, adverse events are reported for the painkiller under evaluation and compared with adverse events in the placebo group. A study compared the rates of adverse events reported in the placebo arms of clinical trials for three classes of anti-migraine drugs: non-steroid anti-inflammatory drugs, triptans, and anticonvulsants [6]. It was found that the rate of adverse events in the drug and placebo arms of trials with anti-migraine drugs was high. In addition, and most interestingly, the adverse events in the placebo arms corresponded to those of the anti-migraine medication against which the placebo was compared. For example, anorexia and memory difficulties, which are typical adverse events of anticonvulsants, were present only in the placebo arm of these trials. These results suggest that the adverse events in placebo arms of clinical trials of anti-migraine medications depend on the adverse events of the active medication against which the placebo is compared. Similar findings were obtained for headache [7], fibromyalgia [8], diabetic peripheral neuropathy [9], and neuropathic pain [10]. The most likely explanation for these effects is that the list of adverse events in the informed consent generates negative expectations, although a crucial point is related to the method through which adverse events are assessed, as also discussed below.

Pain is not a special case. In fact, other conditions, like depression, show the same effects. In a comparison of the rates of adverse effects reported in the placebo arms of tricyclic antidepressant trials and placebo arms of selective serotonin reuptake inhibitor trials, the way in which trials recorded adverse events influenced the rate of adverse effects substantially [11]. A total of 143 placebo-controlled randomized trials and data from 12,742 patients were analyzed. Systematic assessment led to higher rates than less systematic assessment. Far more adverse effects were reported in tricyclic antidepressant placebo groups compared with selective serotonin reuptake inhibitor placebo groups, e.g. dry mouth, drowsiness, constipation, sexual problems. In general, adverse effect profiles were strongly influenced by expectations from investigators and patients, with adverse effect patterns of the drug group closely related to adverse effects of the placebo group.

Sexual function can be affected by nocebos as well. Finasteride, used to treat prostatic hyperplasia, is known to cause sexual side effects such as erectile dysfunction, loss of libido, and ejaculation disorders, with a frequency of 15% after 1 year of treatment. In a study in patients with a diagnosis of benign prostatic hyperplasia [12], a group received finasteride for 1 year and the possible side effects were described to them in detail by the physician; a second group received the same dose of finasteride but was not informed about the possible side effects. The second (non-informed) group reported one or more sexual side effects with a frequency of 15.3%, and the first (informed) group showed a frequency as large as 43.6%. In particular, the incidence of erectile dysfunction, decreased libido, and ejaculation disorders were 9.6%, 7.7%, and 5.7%, respectively, in the non-informed group; they were 30.9%, 23.6%, and 16.3%, respectively, in the informed group. Thus, the patient’s knowledge about the possible side effects of finasteride may have a dramatic negative psychological impact on sexual function.

4. How to identify and mitigate nocebo effects

The first obvious approach to identify nocebo effects is represented by the systematic assessment of adverse effects in placebo groups, and their subsequent comparison with the verum group. Besides the recording of dropouts, careful analysis should make use of a checklist with all the possible side effects. Many clinical trials consider patients’ spontaneous reports of side effects rather than a checklist, and in many trials only dropouts are reported, without any systematic analysis of adverse events. Therefore, future clinical trials should include a careful report of both dropouts and systematically ascertained adverse events both in the verum and in the placebo group.

A second approach is related to the format of the informed consent [13]. For example, the probability of experiencing adverse effects can be communicated ‘negatively’ by focusing on the minority of patients who experience a particular side effect or, alternatively, ‘positively’ by focusing on the majority of patients who do not experience the side effect. Patients who were told the percentage of patients without influenza vaccine side effects (positive communication) showed less side effects than patients who were told the percentage reporting side effects (negative communication) [14]. An authorized concealment has also been proposed, whereby certain information about possible adverse events can be concealed [13]. For example, patients could be asked whether they agree to receive no information about certain types of side effects, with the exception of harmful adverse events.

5. Expert opinion

Much more attention should be paid to nocebo effects in drug development. Their better understanding could be crucial to control and avoid poor compliance and dropouts. A recent example is represented by biosimilars, namely, biologic medical products which are almost an identical copy of an original product that is manufactured by a different company. Indeed, the biosimilar infliximab for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis has resulted in lack of efficacy and increased discontinuation mostly attributable to subjective complaints, with large and robust nocebo effects [15]. As biosimilars represent an alternative treatment option to the more renowned biologics, patients are likely to believe that they would not work as effectively as the originator biologics [16]. We believe that future research should be aimed at better understanding these nocebo phenomena from different perspectives. Whereas the neuroscientific approach will give us information on the biology of nocebo effects, the methodological perspective will help us design better clinical trials, and the ethical perspective will allow us to devise new ways of writing informed consents.

Declaration of interest

No potential conflict of interest was reported by the authors.

Additional information

Funding

This paper has not been funded.