Mind games in dentistry: confounded evidence suggests a substantial nocebo response in dental impaction pain model

A systematic review and metaanalysis of randomized clinical trials (RCTs).

Electronic search was conducted in PubMed, Embase, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL), on 22 May 2021.

Eligibility criteria included parallel-group placebo-controlled RCTs assessing analgesics after third molar (M3) surgery in healthy patients, reporting the number of patients with at least one drug-related adverse event (AE), and being published in English.

Two reviewers independently screened all identified articles against the eligibility criteria, and performed quality assessment and data extraction. Any disagreements were resolved by discussion involving a third reviewer. The primary outcome was the pooled rate of drug-related AEs in placebo and active arms of RCTs assessing analgesic treatment following M3 surgery. Secondary outcome was the drug-related dropout rates in the same setting.

A total of 50 RCTs in 47 articles were included in the analyses. The pooled rates of patients with AE ≥ 1 in the placebo and active arms were 22.8% and 20.6%, respectively. The pooled drug-related dropout rates in the placebo and active arms were 0.24% and 0.08%, respectively. There were no significant risk differences in patients with AE ≥ 1 and drug-related dropouts (p = 0.61 and p = 0.94; respectively). High statistical heterogeneity was found for the proportion of patients with AE ≥ 1 (I² = 79.7%, p < 0.001), but not for drug-related dropout rates (I² = 0%, p = 1.00).

Patients in the placebo arm reported AEs at a similar frequency as patients receiving active treatment, suggesting that most analgesic-related AEs after M3 surgery may be attributed to the nocebo phenomenon.