Nocebo response in third molar analgesic trials


In pharmacological trials adverse events (AEs) may occur following the administration of an active agent. However, they may also occur following the administration of a placebo (inactive)agent so these must result from non-pharmacological, non-specific factors and are termed a nocebo response. While the nocebo response has been investigated in medical conditions and treatment there is limited research in the dental field.

The aim of this review was to estimate the nocebo response in dentistry by assessing the AEs prevalence in placebo- and active arms of randomised controlled trials (RCTs) assessing analgesic treatment following third molar (M3) surgery.


A protocol was registered in the PROSPERO database.  Searches were conducted in the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, PubMed, Scopus, and the Web of Science databases. Randomised controlled trials (RCTs) published in English of analgesics for post-operative pain following M3 surgery in patients reporting number of patients who experienced at least one drug-related AE were considered. Two reviewers independently screened and selected studies, extracted data and assessed quality using the Cochrane Risk of Bias Tool 2 (RoB2), any disagreements were resolved with a third reviewer. Pooled rates for patients experiencing AEs and drug-related dropouts were calculated and risk differences (RDs) between the proportion of patients in the placebo and active arms calculated.


  • 47 publications involving 10,909 patients (8,438 active, 2471 placebo) from 50 RCTS were included.
  • The pooled rates of patients experiencing at least one drug-related AE in the placebo arms and drug related dropouts are shown in the table below.
Pooled rate (95%CI)
Placebo Arms Active Arms
At least one drug-related AE 22.8% (21.1 to 24.5) 20.6% (19.8 to 21.5)
Drug-related dropout 0.24% (0.09 to 0.52) 0.08% (0.03, 0.17)
  • Meta-analyses showed: –
    • no significant difference between the active and placebo arms in the proportion of patients experiencing at least one drug-related AE, RD = −0.84% (95%CI: −4.06 to 2.38).
    • no significant difference in drug-related dropout rates, RD = −0.01% (95%CI: −0.37 to 0.34).


The authors concluded: –

…..patients in the placebo arm reported AEs to the same extent as patients receiving active treatment, suggesting that most AEs in analgesic medication following M3 surgery may be attributed to the nocebo phenomenon.


This well conducted review pulls together data from 50 RCTs of placebo-controlled analgesics in third molar surgery finding that AEs were at similar levels in both active and placebo groups.  The reported level of 23% is lower than an average of 49% seen in other areas such a migraine treatments, cardiovascular disease and psychiatric diseases but similar to those for headache treatment studies (18%) and knee-osteoarthritis (27%) supports the existence of nocebo responses in dentistry. The commonest AEs reported were, nausea/vomiting, headache, dizziness/light headedness, sleepiness/drowsiness, flushing/hot/raised temperature, tiredness/fatigue and abdominal pain.


Primary Paper

Watanabe T, Sieg M, Lunde SJ, Persson M, Taneja P, Baad-Hansen L, Pigg M, Vase L. Nocebo response in dentistry: A systematic review and meta-analysis of adverse events in analgesic trials of third molar removal. J Oral Rehabil. 2023 Apr;50(4):332-342. doi: 10.1111/joor.13414. Epub 2023 Jan 24. PMID: 36648379.

Review protocol in PROSPERO

Photo Credits

Photo by Hal Gatewood on Unsplash



Share on Facebook Tweet this on Twitter Share on LinkedIn Share on Google+