Natural products for orofacial nociception in pre-clinical studies: A systematic review

•Pharmacological treatment of orofacial pain usually causes serious adverse effects.•Natural products tested in pre-clinical models of orofacial nociception were reviewed.•Fifty natural products compared to placebo reduced orofacial nociception in rodents.•Terpenes were the most studied class of compounds in models of orofacial nociception.•Considerations for future studies were proposed to minimize the risk of bias. The aim of this systematic review was to summarize the use of natural products (NP) in the treatment of orofacial nociception in animal models. Pre-clinical studies that have evaluated the efficacy of NPs in experimental orofacial nociception were sought in the Medline, Web of Science, Scopus, Embase, SciELO, LILACS and Scholar databases in January 2020, covering the period since the inception of each one. Two reviewers independently selected the studies, extracted the data and evaluated the risk of bias of the included studies. We included 41 records in qualitative synthesis. Fifty different NPs were investigated. All studies presented positive results for at least one orofacial nociception test. Regarding the risk of bias, most studies presented poor experimental design, mainly lack of randomization and blinding. The main class of isolated compounds tested was terpenes, of which monoterpenes were investigated in the majority of the studies. These results indicate that NPs are effective in treating experimental orofacial nociception and highlight some of these NPs, mainly terpenes, suggesting their potential for translational research.