Many infants, children and youth with rare diseases and complex conditions affecting the central nervous system often experience pain and irritability. Sometimes the pain is due to medical procedures such as scoliosis repairs, or due to chronic conditions such as muscle spasms. There are, however, many times when it is difficult to find a source as these children often have severe language delays. Pain specialists may call this Pain & Irritability of Unknown Origin (PIUO). Clinicians often do not agree on the best approach for determining the cause of this pain. The lack of a common treatment pathway results in inefficient and inconsistent care. In addition, a child is cared for by up to 10 specialist teams and communication among clinicians can make treating pain difficult. The PIUO Clinical Pathway is a guideline developed to standardized approaches to assessing and treating PIUO using history, physical, diagnostic tests and screens to rule out unknown causes of indeterminate pain. The pathway also provides support and connection for parents of these children.