Significance Chronic pain represents a massive therapeutic challenge that requires understanding of underlying mechanisms to develop novel treatments. We show that genetic deletion of the Rap1 guanine-nucleotide exchange factor Epac1 protects against chronic inflammatory mechanical hyperalgesia. Moreover, an orally active Epac inhibitor reverses existing inflammatory pain without affecting normal pain sensitivity. Epac1-mediated pain is controlled by G protein kinase 2 (GRK2) through inhibition of Epac1-to-Rap1 signaling and inhibition of sensitization of mechanocurrents mediated by Piezo2. Molecularly, GRK2 controls Epac1-to-Rap1 signaling by phosphorylating Epac1 at Ser-108 to inhibit plasma membrane accumulation of Epac1. Our findings provide further insights into the molecular pathways regulating Epac1 activity, demonstrate its key role in chronic pain, and identify Epac1 as a potential target for treatment of chronic pain.