**Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development**

**Camila R. Ferraz 1, Thacyana T. Carvalho 1, Marília F. Manchope 1, Nayara A. Artero 1, Fernanda S. Rasquel-Oliveira 1, Victor Fattori 1, Rubia Casagrande 2,\* and Waldiceu A. Verri Jr. 1,\***


Academic Editor: Derek J. McPhee

Received: 26 December 2019; Accepted: 7 February 2020; Published: 10 February 2020

**Abstract:** Pathological pain can be initiated after inflammation and/or peripheral nerve injury. It is a consequence of the pathological functioning of the nervous system rather than only a symptom. In fact, pain is a significant social, health, and economic burden worldwide. Flavonoids are plant derivative compounds easily found in several fruits and vegetables and consumed in the daily food intake. Flavonoids vary in terms of classes, and while structurally unique, they share a basic structure formed by three rings, known as the flavan nucleus. Structural differences can be found in the pattern of substitution in one of these rings. The hydroxyl group (–OH) position in one of the rings determines the mechanisms of action of the flavonoids and reveals a complex multifunctional activity. Flavonoids have been widely used for their antioxidant, analgesic, and anti-inflammatory effects along with safe preclinical and clinical profiles. In this review, we discuss the preclinical and clinical evidence on the analgesic and anti-inflammatory proprieties of flavonoids. We also focus on how the development of formulations containing flavonoids, along with the understanding of their structure-activity relationship, can be harnessed to identify novel flavonoid-based therapies to treat pathological pain and inflammation.

**Keywords:** clinical trials; natural products; hyperalgesia; allodynia; analgesia; flavonoid; hypersensitivity; inflammation; cytokines; NF-kB
