Testing for specific genes may prevent opioid-related deaths

By Liz Meszaros, MDLinx
Published June 28, 2017

Key Takeaways

Researchers have identified 10 genes that may predict how patients with respond to opioid pain medications, and may, in the future, help clinicians more effectively tailor opioid prescribing for individual patients, to optimize treatment and reduce fatalities caused by overdose, according to a review published in the American Association for Clinical Chemistry’s journal, Clinical Chemistry.

In 2015, over 17,500 people died from prescription opioid overdose in the United States, a number that is four times the number of deaths from this cause in 1999. Doses needed to alleviate pain in those patients with severe pain, and therefore a legitimate need for opioids, varies greatly and clinicians have no recourse by trial and error to determine the correct opioid and the correct dosage that will help such patients. This can put some at risk for life-threatening side effects, including respiratory depression, while others are left undertreated and still in pain.

Previous research has identified a number of genes that may guide clinicians to safer and more effective opioid treatment, but treatment guidelines have been developed based on only one of these genes—CYP2D6.

Lead researcher Ron H.N. Van Schaik, PhD, Erasmus University Medical Center, Rotterdam, the Netherlands, and fellow researchers conducted a systematic review of 4,257 studies on opioid genetics, and determined the usefulness of each gene based on the following factors:

  • The gene’s effect on patient opioid response as confirmed by several independent studies;
  • A high enough gene frequency in Caucasians to use in screening.

Thus, they identified 10 genes with the highest potential of refining opioid prescription patterns, which included:

  • cytochrome P450 family 2 subfamily D member 6 (CYP2D6),
  • cytochrome P450 family 3 subfamily A member 4 (CYP3A4),
  • cytochrome P450 family 3 subfamily A member 5 (CYP3A5),
  • UDP glucuronosyltransferase family 2 member B7 (UGT2B7),
  • ATP binding cassette subfamily B member 1 (ABCB1),
  • ATP binding cassette subfamily C member 3 (ABCC3),
  • solute carrier family 22 member 1 (SLC22A1),
  • opioid receptor kappa 1 (OPRM1),
  • catechol-O-methyltransferase (COMT), and
  • potassium voltage-gated channel subfamily J member 6 (KCNJ6).

Dr. van Schaik and fellow researchers found that the presence of two inactive SLC22A1 genes can lead to high blood concentrations of the active metabolite in tramadol, and in children, can lead to a significantly decreased clearance of morphine. Patients with these mutations may be at an increased risk, therefore, of overdosing from tramadol and morphine, especially with the presence of certain CYP2D6 mutations.

Conversely, in patients with the OPRMI 118A>G variant, a higher dose of opioids may be necessary, although they are at risk for adverse events.

Finally, they found that certain COMT mutations were associated with lower opioid requirement and fewer side effects, while others were linked to highest pain scores and highest opioid consumption in surgical patients.

“The most solid evidence of a clinically relevant pharmacogenetics effect on the analgesic treatment with opioids is available for genetic variation in CYP2D6, COMT, SLC22A1, and the genetic variant OPRM1 118A>G,” said Dr. van Schaik.

“As clinical guidelines for codeine and CYP2D6 genotyping have been formulated and CYP2D6 genotyping has been successfully implemented in pediatric clinical practice…the application of pharmacogenetics in the management of pain with opioids certainly has the potential to improve therapy,” he concluded.

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