Nocebo in Headache Treatment

Nocebo refers to adverse events (AEs) related to negative expectations that medical treatment will likely harm instead of heal and affects significantly adherence and treatment outcome. It varies considerably among neurological conditions but can be assessed in placebo-controlled clinical trials (RCTs) by investigating the AEs observed in patients treated with placebo. In clinical practice nocebo can be predicted by applying the Q-No questionnaire. Clinically relevant outcomes for nocebo in RCTs include the percentage of patients treated with placebo who experienced any AE (nocebo AE) and the percentage of patients who discontinued treatment due to AEs although treated with placebo (nocebo withdrawal). Meta-analyses of RCTs for migraine prevention estimated that nocebo AE and withdrawal rise up to 42.78% (95% CI 34.73–51.36%) and 4.75% (95% CI 3.28–6.45%) of placebo-treated patients. In studies for symptomatic treatment for migraine, the nocebo AE and withdrawal frequencies were 18.45% (95% CI 14.90–22.23%) and 0.33% (95% CI 0.19–0.53%), respectively. In trials for prevention of tension-type headache (TTH), nocebo and dropout frequencies were 23.99% (95% CI 4.61–52.20%) and 5.44% (95% CI 1.32–12.12%). For symptomatic treatment of cluster headache, the nocebo AE frequency was 18.67% (95% CI 10.65–28.33%; insufficient data were gathered to calculate the nocebo withdrawal). In clinical practice nocebo can be predicted by using the Q-No questionnaire, a four-item (rating range 4–20) self-fulfilled questionnaire. Using a cutoff at score 15, the Q-No predicts nocebo with 71.7% specificity, 67.5% sensitivity, and 42.5% positive predictive value. Almost 57% of headache sufferers score more than 15 indicating potential nocebo behaviors that contributed significantly in their therapy choices, as well as in treatment adherence. These data indicate that nocebo plays a severe role in headache therapeutics requiring major attention and appropriate management, although it remains largely unknown and underappreciated.