Drs. Catrina Loucks (left) and Colin Ross (right) are recipients of the 2021/2022 Precision Health Catalyst Grant award for this project entitled “Uncovering patient-specific genetic factors that can be used to optimize morphine-based pain relief while avoiding harm”.
Read a summary of the project here.
“We have conducted preliminary analyses assessing known genetic variants that impact how morphine is processed inside a child’s body and how morphine acts upon a child’s pain”
Can you tell us about the precision health research in childhood health you’re collaborating on?
Our precision health research aims to answer the following question: Why are some children unable to get pain relief from morphine while others experience excessive sedation or toxicity?
Morphine is a common painkiller that is widely used to treat pain in children. While the drug is generally very effective and safe, some individuals carry genetic changes that make them dangerously sensitive to morphine or make the drug ineffective. Our goal is to discover clinically-relevant genetic factors that predict which children are at risk of adverse effects to morphine and which children are unlikely to benefit from morphine, and to use that information to maximize the safe and effective use of morphine for pediatric pain relief.
To do this, we are recruiting children with extreme responses to morphine defined as:
- children without pain relief despite high doses of morphine
- children with excessive sedation or other toxicities at low morphine doses
**We are actively recruiting patients. If you know of potential patients and/or would like to collaborate, please contact us (Catrina Loucks: cloucks@popi.ubc.ca)**
What results have you seen so far?
To date, we have identified 50 children with suspected morphine-related extreme responses (e.g., pruritis/rash/allergic reaction, agitation, hallucinations, decreased breathing rate, prolonged sedation, inadequate/no pain relief). As might be expected if morphine pain relief is an inherited trait, we remarkably found that 3 of the children with severely inadequate pain relief from morphine also had parents who exhibited inadequate pain relief from morphine.
We have conducted preliminary analyses assessing known genetic variants that impact how morphine is processed inside a child’s body (i.e., genetic variation contributing to variable drug exposure) and how morphine acts upon a child’s pain (i.e., genetic variation contributing to variable drug responses). These analyses revealed that the frequency of UGT1A6 rs17863783 (*4) was over 2-fold higher in children with extreme morphine responses (0.038) compared to morphine-treated children without any extreme morphine responses recorded (0.016). The UGT1A6 gene encodes a drug metabolizing enzyme that is critical for the processing of morphine, and thus, genetic variation impacting its function may lead to the accumulation of morphine and/or potentially toxic byproducts. Importantly, the UGT1A6 rs17863783 genetic variant was previously implicated in long-term internalizing behaviours (i.e., anxiety and depressive symptoms) in children who had greater morphine exposure as infants.
We are grateful to have received a Precision Health Catalyst Grant. This funding made it possible for Dr. Erika Scott, a postdoctoral fellow co-supervised by Drs. Ruth Grunau and Catrina Loucks, to obtain an International Association for the Study of Pain (IASP) John J. Bonica Postdoctoral Fellowship to extend this work. Additionally, it enabled Jia He (Janet) Zhang, Dr. Loucks’ MSc student, to obtain a CIHR Canada Graduate Scholarship to validate the biological relevance of genetic discoveries from this work using a pain management model developed in the simple nematode model organism Caenorhabditis elegans.
From your perspective, what do you think is exciting about the future direction of precision health?
In children, ongoing pain can interfere with brain development, disrupt behaviour, and increase the risk of chronic pain. Therefore, providing adequate pain treatment for children is critical, yet it remains challenging to predict how children will respond to prescribed opioids. This is especially difficult in infants and young children who cannot articulate their level of pain, limiting their ability to receive appropriate relief without harm. Pharmacogenomics-based precision health approaches offer a way to customize pain management strategies, where individual genetic differences can help clinicians select analgesics most likely to be safe and effective. More broadly, this approach has the power to combat the opioid crisis, where opioid-based pain management can be restricted to patients most likely to benefit without experiencing life-threatening toxicity.
About Dr. Catrina Loucks
Dr. Catrina Loucks is an Assistant Professor at the University of British Columbia (Departments of Pediatrics and Anesthesiology, Pharmacology & Therapeutics) and an Investigator at the BC Children’s Hospital Research Institute. She has experience uncovering genetic causes for rare disorders from her MSc work at the University of Calgary, under the supervision of Drs. Micheil Innes and Jillian Parboosingh. She then sought to explore functional impacts of uncovered genetic mutations by pursuing a PhD under the supervision of Dr. Michel Leroux at Simon Fraser University, using the simple roundworm, Caenorhabditis elegans, as a model. As a postdoctoral fellow at the University of British Columbia, Catrina worked with Dr. Bruce Carleton and the Canadian Pharmacogenomics Network for Drug Safety to understand how genetic variation contributes to variable responses to medication. Her current research program, the CFI-JELF funded Loucks Pain Management Pharmacogenomics Lab, is developing a pipeline from genetic discoveries to predictive genetic testing to help select the safest and most effective pain relievers for children, where her work has been recognized by a CIHR Drug Safety and Effectiveness Cross-Disciplinary Training (DSECT) Alumni Recognition Award.
About Dr. Colin Ross
Dr. Colin Ross is a Professor and the interim Associate Dean of Research in UBC’s Faculty of Pharmaceutical Sciences, and a scientist at B.C. Children’s Hospital Research Institute. His research aims to develop safer and more precise treatments of cancer and genetic diseases. One approach is to sequence the genomes of cancer patients to identify genetic factors that predispose some patients to develop severe and potentially fatal adverse reactions to their chemotherapy. Another approach is to improve the diagnosis and treatment of patients with genetic diseases using genome sequencing and developing new targeted therapies.