Could Genetic Markers Help Identify Patients at Risk of Opioid Overdose?

Researchers at Erasmus University Medical Center in the Netherlands have identified 10 genes which may help healthcare providers predict which patients could respond poorly to opioid medications. The details of these genetic markers and their effects on opioid metabolism were published in the journal, Clinical Chemistry.

Prescription opioid overdoses contributed to the death of over 17,500 people in the US in 2015. This number is a four-fold increase over the number of opioid-related deaths in 1999.

While an increase in the incidence of prescription opioid abuse has contributed to the rising death toll, clinicians have found that even appropriate use of these painkillers can have risks. Since each patient metabolizes the drug differently, doctors may need to try different opioids at escalating concentrations before the optimal dosage can be established.

Throughout the course of this trial and error approach, some patients may be left with insufficient pain relief, while others could be overdosed leading to a potentially life-threating condition known as respiratory depression. While previous research has identified genes that could offer some clinical utility at predicting the patients’ response to opioids, only one – CYP2D6 – has been included in pharmacogenetics guidelines for medical practice.

To identify the genes with the most potential, the researchers reviewed over 4,200 published studies on opioid pharmacogenetics. The study authors used two measures to assess whether a gene could be used as a marker: whether the gene’s effect on opioid metabolism was confirmed in several different studies; whether the gene occurred frequently enough in the Caucasian population to warrant its use as a genetic marker.

Just 10 genes met this criteria and showed the strongest potential of guiding healthcare providers in their prescribing decisions on opioids. The previously established CYP2D6 was among those identified, along with the SLC22A1, OPRM1 variant 118A>G, and COMT.

“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 senior study author Dr. Ron H.N.van Schaik, of Erasmus University Medical Center. “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.”

In the case of one of these genes, patients with two inactive copies of SLC22A1 show higher blood concentrations of the active metabolite of the opioid, tramadol. This gene is also a marker for decreased morphine clearance in children, suggesting that patients with this genotype may be at higher risk of opioid overdose.

Interestingly, patients with the OPRM1 118A>G variant have a lower risk of side effects but require higher doses of opioids to manage their pain. Some genes even show different responses to opioids, depending on the variant; some COMT variants are linked with lower required opioid doses while others are associated with high opioid consumption due to elevated pain scores.

Pharmacogenetics is a growing area in pain management which has the potential to help reduce the risk of serious opioid-related adverse events. The implementation of further genotypic prescreening before patients are prescribed opioids could go a long way to preventing overdose-related deaths.