P2X3 and P2X2/3 receptors inhibition produces a consistent analgesic efficacy: A systematic review and meta-analysis of preclinical studies

BACKGROUND: P2X3 and P2X2/3 receptors are promising therapeutic targets for pain treatment and selective inhibitors are under evaluation in ongoing clinical trials. Here we aim to consolidate and quantitatively evaluate the preclinical evidence on P2X3 and P2X2/3 receptors inhibitors for pain treatment. METHODS: A literature search was conducted in PubMed, Scopus and Web-of-Science on August 5, 2023. Data was extracted and meta-analyzed using a random-effects model to estimate the analgesic efficacy of the intervention; then several subgroup analyses were performed. RESULTS: 67 articles were included. The intervention induced a consistent pain reduction (66.5 [CI95% = 58.5, 74.5]; p < 0.0001), which was highest for visceral pain (114.3), followed by muscle (79.8) and neuropathic pain (71.1), but lower for cancer (64.1), joint (57.5) and inflammatory pain (49.0). Further analysis showed a greater effect for mechanical hypersensitivity (70.4) compared to heat hypersensitivity (64.5) and pain-related behavior (54.1). Sex (male or female) or interspecies (mice or rats) differences were not appreciated (p > 0.05). The most used molecule was A-317491, but other such as gefapixant or eliapixant were also effective (p < 0.0001 for all). The analgesic effect was higher for systemic or peripheral administration than for intrathecal administration. Conversely, intracerebroventricular administration was not analgesic, but potentiated pain. CONCLUSION: P2X3 and P2X2/3 receptor inhibitors showed a good analgesic efficacy in preclinical studies, which was dependent on the pain etiology, pain outcome measured, the drug used and its route of administration. Further research is needed to assess the clinical utility of these preclinical findings. PROTOCOL REGISTRATION: PROSPERO ID CRD42023450685.