Nocebo in headaches: implications for clinical practice and trial design

The term nocebo refers to a harmful, unpleasant or undesirable adverse event a subject manifests after receiving an inert dummy drug or placebo. This reaction is originating by the patients fear and negative expectation that medical treatment most likely will produce unfavorable consequences instead of healing. Like placebo, nocebo shares key functions in pain conditions. Two recent systemic meta-analyses searched for nocebo in trials for prevention of migraine and tension-type headache and revealed that 1 out of 20 patients treated with placebo withdraw treatment due to adverse effects. Additionally, adverse events in placebo groups mirrored the adverse events expected of the active medication studied, confirming that pretrial suggestions induce the adverse events in placebo-treated patients. Therefore, nocebo reduces the study population by 10% and limits the treatment outcomes in randomized controlled trials for primary headaches. The potential implications of this substantial nocebo effect for both trial designing and clinical practice are discussed in this article.