The magnitude of nocebo effects in pain: A meta-analysis

The investigation of nocebo effects is evolving, and a few literature reviews have emerged, although so far 33 without quantifying such effects. This meta-analysis investigated nocebo effects in pain.We searched the 34 databases PubMed, EMBASE, Scopus, and the Cochrane Controlled Trial Register with the term ‘‘nocebo.’’ 35 Only studies that investigated nocebo effects as the effects that followed the administration of an inert 36 treatment along with verbal suggestions of symptom worsening and that included a no-treatment con- 37 trol condition were eligible. Ten studies fulfilled the selection criteria. The effect sizes were calculated 38 using Cohen’s d and Hedges’ g. The overall magnitude of the nocebo effect was moderate to large (lowest 39 Q2 g = 0.62 [0.24–1.01] and highest g = 1.03 [0.63–1.43]) and highly variable (range of g = 0.43 to 4.05). The 40 magnitudes and range of effect sizes was similar to those of placebo effects (d = 0.81) in mechanistic stud- 41 ies. In studies in which nocebo effects were induced by a combination of verbal suggestions and condi- 42 tioning, the effect size was larger (lowest g = 0.76 [0.39–1.14] and highest g = 1.17 [0.52–1.81]) than in 43 studies in which nocebo effects were induced by verbal suggestions alone (lowest g = 0.64 [0.25 to 44 1.53] and highest g = 0.87 [0.40–1.34]). These findings are similar to those in the placebo literature. As 45 the magnitude of the nocebo effect is variable and sometimes large, this meta-analysis demonstrates 46 the importance of minimizing nocebo effects in clinical practice.