A genetic variation in a regulatory protein may predispose children to side effects from opioids – a finding that may change how pain meds are prescribed.

Opioids – morphine, hydromorphone and fentanyl – are among the most commonly used medications for post-surgical pain, yet the side effects from these powerful analgesics vary greatly from child to child.

Inquiry Pain Management Jiminez 220x130

A recent study by anesthesiologist Dr. Nathalia Jimenez found an association between a genetic variation in the gene for the beta-arrestin-2 regulatory protein and side effects (including nausea, vomiting, pruritus and respiratory depression) from opioid pain medications in children. The beta-arrestin-2 protein is encoded by the ARRB2 gene and helps regulate the mu-opioid receptor – the main target for opioid analgesics.

Though the ARRB2 gene has been studied in connection to opioid addiction, Jimenez was the first to study its connection to morphine response in acute pain management. Her novel inquiry started more than a decade ago while she practiced medicine at a pediatric hospital in Bogota.

“In Colombia, we used U.S. textbooks to reference how much analgesic we should give kids, but we always cut the suggested amount of opioids in half,” she recalls. "It was just an unofficial rule that everyone followed.” When she began her anesthesiology fellowship at Seattle Children’s, Jimenez was quite surprised by the amount of opioid analgesics children required after surgery.

Are side effects related to ethnicity?

To explore whether the divergent dosing requirements had something to do with ethnicity, Jimenez completed a retrospective study to see if there were differences in the way Hispanic and Caucasian children were treated for pain.

Her subjects, all healthy kids who had outpatient surgery to remove tonsils or adenoids, received opioid analgesics intravenously. The Hispanic kids not only received less medication, but the strength of the medication they received was also lower. The finding was intriguing, but it left many cultural and behavioral questions unanswered: Do Hispanic kids have a different pain threshold? Do they experience more side effects that necessitate a switch to a lower dosage of opioid or a less powerful pain medication? Do language barriers prevent their pain needs from being addressed properly?

The answer may be in the genes

Jimenez's hunch – that Hispanic kids receive less opioid because they have more side effects – led to a second study. Patients were given the same type and amount of opioid analgesic and asked to self-report their own pain scores on a scale from 1 to 10, as well as any side effects. She also measured blood levels of the medication and its metabolites to determine if there were any differences in the way some children metabolized the drug.

She recruited 35 Hispanic and 35 Caucasian patients who were all healthy and had the same outpatient procedure as the first study. While both groups reported similar pain scores and metabolized the drug in the same way, the group of Hispanic patients had experienced three times more side effects – and more severe ones – than the Caucasian patients.

Jimenez then began investigating pharmacodynamics – the way opioids interact with opioid receptors to provide analgesia and produce side effects. She found that the children — whether Hispanic or Caucasian — who had a variation in the beta-arrestin-2 intracellular protein experienced more side effects from opioids than children who did not have this variation.

Does ancestry increase the likelihood of variation?

While Jimenez’s finding associated side effects with a genetic variation in the regulatory protein, the results still didn’t answer why Hispanic children had more side effects that were more severe. Her hypothesis is that kids with more indigenous ancestry (like Hispanic children) are more prone to opioid side effects because they are more likely to have the genetic variation in beta-arrestin-2. She’ll test it in her next study at the Hospital San Jose, Universidad del Rosario in Bogota, where she plans to follow a cohort of 100 Hispanic children.

In addition to doing a genotyping check of the ancestry of each child, Jimenez will continue to study the link between the variant of the beta-arrestin-2 intracellular protein and increased side effects, as well as whether this variant is more frequent in a larger Hispanic population.

The study, one of the first international research collaborations to be done in Bogota, is due to start in Colombia in summer 2013 and wrap up in spring 2015.

Children, whether Hispanic or Caucasian, who had a variation in the beta-arrestin-2 intracellular protein experienced more side effects from opioids than those who didn’t.