Pain is the most common symptom reported by parents of children with severe neurological impairments (SNI), but when children can’t tell us where it hurts, parents and healthcare providers rely on interpretation of nonspecific pain-like behaviours to detect the presence of pain. These signs are challenging to evaluate and cannot always be attributed to a specific cause. Moreover, in children with complex neurological conditions, pain-like behaviours are not always due to disease or injury (nociceptive-inflammatory, or nociceptive), but instead may be due to generalized irritability of the central nervous system (nociplastic). When we cannot determine the origin of the sensation we call it Pain and Irritability of Unknown Origin (PIUO). This presentation will provide a description of a specific patient population of children with SNI who experience unexplained pain. Our newest research provides answers to common issues in treating these children. What we add in this seminar are timely findings around possible pain sources, a new clinical pathway for treatment and support for parents, and a medication to address neuroirritability if the clinical pathway fails.