Nocebo as a source of bias in the assessment of treatment effect

The term nocebo refers to the worse outcomes or side effects experienced by patients as a result of their negative expectations regarding a treatment. It may distort estimates of treatment effectiveness and safety in both clinical trials and clinical practice; moreover, it may cause discontinuation of therapy or drop out from a trial. Nocebo effect is evoked by the information given to patients during a clinical consultation or during enrolment into a study, but information available from the media or the Internet may also play an important role. In research settings, a trial design may introduce bias from the nocebo effect. For example, if the non-treatment group is unblinded and aware that they are not receiving any treatment, their treatment expectations are not met, which results in worse outcomes, and subsequently, the problems that the trial was supposed to investigate may be enhanced in the non-treatment arm. Nocebo effect is common, and its magnitude may be large, but it receives less attention and research focus than the placebo effect. Unlike the placebo effect, which is usually taken into consideration while interpreting treatment results and controlled for in clinical trials, the nocebo effect is under-recognised by clinical researchers as well as clinicians. It is important to recognise and any potential nocebo effect must be considered while assessing the effect of treatment and should be minimised through careful choice and phrasing of treatment-related information given to the patients.