CHOP Researchers Discover Postsurgical Pain Gene Variants

In the first genome-wide analysis of postsurgical pain in children, pediatric researchers identified variations in genes that affect a child’s need for pain-control drugs. The findings suggest that at some point physicians may calibrate pain-medication dosages according to a child’s individual genetic makeup.

“Although this research is only a first step for our team, it provides tremendous new insight into the biological mechanisms and brings us a little closer to personalizing medicine for pain control,” said Scott D. Cook-Sather, MD, a pediatric anesthesiologist at The Children’s Hospital of Philadelphia. Dr. Cook-Sather and colleagues — including Hakon Hakonarson, MD, PhD, the director of the Center for Applied Genomics — published the study recently in the journal Pain.

The study team performed a genome-wide association study (GWAS) of more than 600 children between ages 4 and 18 who had tonsils and adenoids removed in day long surgery procedures. The retrospective study analyzed whether gene variants were associated with the need for higher or lower than average dosages of morphine for pain control. The researchers also analyzed genetic links to postoperative pain scores. The GWAS identified one gene location linked to increased morphine requirement.

“While scientists already know that morphine works by binding to specific opioid receptors in the nervous system,” added Dr. Cook-Sather, “we don’t know exactly why there is, in this setting, a tenfold variation in how much morphine patients require for pain relief.” The study team found that two single-base gene variants at the TAOK3 locus were associated with approximately 8 percent of that tenfold variance in morphine requirement, comparable to that portion of the variance associated with age, body mass and overall health status combined.

Dr. Cook-Sather explained that multiple genes are assumed to contribute to these analgesic effects, and that further investigations, with larger numbers of patients, are needed to understand and prioritize the full array of genes that modify morphine response.

Within their initial sample of 617 children, the researchers found that the association between the variants in TAOK3 and the morphine dose needed for pain relief held up for children of European ancestry but not for African-American children. In both groups, however, the gene variants correlated with increased postoperative pain. “Future investigations,” said Dr. Cook-Sather, “may help us predict which patients will need more pain medicine than the standard dose. We could customize an appropriate dose while the child is still under anesthesia in order to minimize the pain when the child regains consciousness.”

“We have identified a novel biological pain target, and even though the variants we identified in this study explain only about 8 percent of the difference in pain sensation between individuals, they give us a strong lead in developing new therapies,” said Hakonarson. “This proof-of-concept study may advance the process of individualizing pain therapy in children.”