Studying Pain and Irritability of Unknown Origin (PIUO)

Optimizing the Management of Pain and Irritability

in Children with Severe Neurological Impairment 


Our study in a nutshell

Children with diseases affecting the nervous system often experience pain and irritability due to unknown causes. Sometimes the source of pain and irritability can be identified through careful physical examination, lab tests and imaging. Many times, however, examination reveals no obviously correctable source for pain and irritability. At that stage, various therapies are attempted to reduce pain, irritability and agitation. Unfortunately, there is no common approach to treating these problems. 

Our international team of researchers is currently conducting a patient-oriented study called "Optimizing the Management of Pain and Irritability in Children with Severe Neurological Impairment," which is funded by the CHILD-BRIGHT Network under CIHR's Strategy for Patient Oriented Research. The purpose of this project is to develop, test, and disseminate a new approach to reducing and resolving pain in children with Severe Neurological Impairments (SNI). It focuses on the problem of ongoing, unexplained, and difficult-to-treat pain and irritability that many children with SNI, and their families, experience.



Our team of researchers would like to see how useful it is for your healthcare team to use standardized clinical guidelines when treating your child. When doctors and nurses follow standardized guidelines, we sometimes call it a clinical pathway. In this study children with unexplained pain and irritability follow a pathway of known tests and treatments in order to find the cause and resolve the pain.

Our goal is to improve the management of Pain and Irritability of an Unknown Origin (PIUO) beyond what has been accomplished by the child's usual clinical teams. In a small pilot study of the PIUO Pathway we reduced or resolved pain and irritability for 63% of participants. The primary outcome of our study is better pain control for non-verbal children with SNI. We also hope to decrease pain severity for our participants, improve family quality of life and ensure that the PIUO Pathway can be easily implemented by clinicians in the future. 

With this study, we hope to:

1. Develop Guidelines

If the PIUO Pathway helps us to successfully reduce or resolve pain for children with PIUO, we can make it the standard approach to managing PIUO. New practice guidelines for clinicians will achieve early detection, effective interventions (personalized medicine) and ultimately prevention for persistent complex pain in a highly vulnerable population of children.

2. Increase Consistency

When the PIUO Pathway is the clinical standard for managing PIUO, we can create training programs that ensure consistency in the approach practitioners take to assessing and treating PIUO. A consistent approach will increase the confidence in our clinical ability to help families who experience great stress in the face of PIUO.


Ability to help children across the province to obtain care in the community, which means fewer clinic visits and emergency room visits, fewer days for inpatient care and thereby overall savings to the health care system


We know that for some children, even a careful search for a cause will not reveal a source for their pain and irritability. For those kids a number of medications have proven to help, but no-one knows what the mot effective medications might be or what the best sequence of medications is. Through a clinical trial of 4 commonly used medications for PIUO, we aim to determine the best medication sequence for children experiencing inexplicable pain.


“This study helped by acknowledging that pain has been an ongoing issue since my son was born. The study helps medical teams to better understand the unexplained pain within your child. This is very valuable, especially when the child is non-verbal and cannot express how or where it hurts.”

— Parent Participant in the PIUO Study


We developed the PIUO Pathway based on best evidence from existing literature. We also performed a pilot observational study in 10 non-verbal children with Severe Neurological Impairments (SNI).

The children ranged in age from 5 to 17 years and their SNI had a wide variety of causes, with high degrees of medical complexity and communication impairment. The children were recruited from community pediatric practices and all were followed by hospital sub-specialists. Our results were surprising: while it might be assumed that evaluation for pain and irritability would be thorough and revealing, just the opposite occurred in these children (. . .)

If your child is experiencing pain and you don't know why, you might be eligible to participate in the PIUO Study.

We are looking for children between 6 months and 18 years with neurological problems, who cannot communicate verbally about their pain and continue to have unexplained pain. The pain must not be due to accidents, injury or to medical procedures, and must not have responded to treatments in the past.


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