Bartels D, van Laarhoven A, Stroo M, et al. Minimizing nocebo effects by conditioning with verbal suggestions: a randomized clinical trial in healthy humans. Plos One. 2017;12(9):e0182959.
To find out if nocebo effects can be reduced by inducing positive expectations from electrical and histaminic itch stimuli.
Randomized controlled multiarm, parallel-group, single-blind trial
One hundred twenty-nine participants of Dutch nationality aged 18 and over, with mean age 20.25±2.46 years; 78.7% were women. Exclusion criteria included severe physical morbidity, psychiatric disorders, chronic itch or pain complains, histamine hypersensitivity, regular use of prescription medications in the past 3 months, use of pacemaker, and color blindness.
Study Parameters Assessed
Effect of conditioning, counterconditioning, and verbal suggestion on nocebo effects from electrical and histaminic itch stimuli; effect of psychological characteristics on nocebo effects.
Primary Outcome Measures
Level of itch verbally reported by participants; psychological characteristics/personality traits assessed through self-report questionnaires.
Nocebo effects were significantly smaller, and even reversed, in the group that had positive expectation induction. Psychological characteristics of the participants did not affect the outcomes.
The study included only healthy volunteers, used only a single session to test the reversal of the nocebo effect, had a small study population size, and included mostly women.
Nocebo effects are adverse effects from treatments that are induced by patients’ negative expectations. It is a well-known phenomenon in randomized clinical trials: Patients in the placebo group may experience not just the benefits (placebo effect) but also the same treatment side effects as patients in the groups who receive active treatment.1 Negative expectations can also affect patients who receive active treatment: patients may not get expected reduction of pain.2
Nocebo effects may influence a wide range of symptoms, including perception of pain, fatigue, nausea, allergic symptoms, and itch. Therefore, knowing how to change nocebo effects can be a very useful clinical tool.
As clinicians, we have a responsibility to inform our patients of possible adverse effects, yet informed consent can inadvertently lead to negative expectations related to proposed treatment intervention.
Nocebo and placebo effects have been studied widely. In psychology, 2 expectation induction procedures are frequently used: verbal suggestion and conditioning. Verbal suggestion provides verbal or written information about potential benefits and side effects. Conditioning uses an unrelated neutral stimulus (eg, color or sound) coupled with an active stimulus (eg, induction of pain or itch). With time, coupled neutral stimulus (seeing a particular color or hearing the sound) can cause increased perception of pain or itching even in the absence of the active stimulus. The present study used both verbal suggestion and conditioning procedures.
The results of the study showed that nocebo effects can be diminished or even reversed by positive expectation induction. This is a significant clinical finding, given that many patients come to their providers with expectations, often negative, about how they might respond to the treatments. Understanding the sources of patients’ expectations can guide clinicians as they help people adhere to their treatment regimens and can, in turn, improve treatment outcomes. Such sources include informed consent, past patients’ experiences, pre-existing conditions, and nonclinical influences coming from media and friends.3,4
It is interesting that psychological characteristics of the participants in this study did not affect the outcomes. Another study came to a similar conclusion: personality factors (anxiety, fear) had no direct effect on the level of expectation related to pain.5 A systematic review of the literature on the nocebo effect showed that people’s expectations mainly affected the placebo response,6 thus placing more emphasis on the role of the healthcare provider in influencing the expectations and nocebo and placebo effects.
The docere (doctor as teacher) principle is at the core naturopathic physicians' practice. We try to educate our patients and also help them take responsibility for their health. As clinicians, we have a responsibility to inform our patients of possible adverse effects, yet informed consent can inadvertently lead to negative expectations related to proposed treatment intervention.
How do we give informed consent effectively?
Research suggests that the way we deliver information to our patients makes a difference. In a 2017 study by Howe et al, positive expectations (placebo effect) were intensified when providers were warm and confident.7
Other studies have shown that authentic communication style, providing adequate information, feedback, and assessment of patients’ anxieties, concerns, and prescriptions, help minimize nocebo effects of medications,8,9 and explaining procedures and intervention in simple language and educating the patient can be protective against unwanted side effects.10-12
Such approaches ultimately lead to improved patient outcomes, therefore highlighting the importance of establishing positive rapport and empowering our patients on their road to better health.
- Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA. 2002;287(5):622-627.
- Bingel U, Wanigasekera V, Wiech K, et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med. 2011;3(70):70ra14.
- Reicherts P, Gerdes AB, Pauli P, Wieser M. Psychological placebo and nocebo effects on pain rely on expectation and previous experience. J Pain. 2016;17(2):203-214.
- Colloca L, Miller F. The nocebo effect and its relevance for clinical practice. Psychosom Med. 2011;73(7):598-603.
- Corsi N, Colloca L. Placebo and nocebo effects: the advantage of measuring expectations and psychological factors. Front Psychol. 2017;8:308.Go to:
- Horing B, Weimer K, Muth E, Enck P. Prediction of placebo responses: a systematic review of literature. Front Psychol. 2014;5:1079.
- Howe LC, Goyer JP, Crum AJ. Harnessing the placebo effect: exploring the influence of physician characteristics on placebo response. Health Psychol. 2017;36(11):1074-1082.
- Bingel U. Avoiding nocebo effects to optimize treatment outcome. JAMA. 2014;312(7):693-694.
- Petrie KJ, Cameron LD, Ellis CJ, Buick D, Weinman J. Changing illness perceptions after myocardial infarction: an early intervention randomized controlled trial. Psychosom Med. 2002;64(4):580-586.
- Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA. 2002;287:622-627.
- Colloca L, Finniss D. Nocebo effects, patient-clinician communication, and therapeutic outcomes. JAMA. 2012;307:567-568.
- Lawrence D, Egbert, MD, Battit GE, Welch CE, Barlett MK. Reduction of postoperative pain by encouragement and instruction of patients – a study of doctor-patient rapport. N Engl J Med. 1964;270:825-827.