A Prescription DNA Test for Risk of Developing Opioid Use Disorder: Do Not Use

In December 2023, the Food and Drug Administration (FDA) approved a DNA (genotyping) test for the risk of developing opioid use disorder (AvertD).[1] The test claims to predict an individual’s risk of developing opioid use disorder after a short course (4-30 days) of an opioid pain relief medication.[2] The rationale is that if an individual was found to be at high risk of developing opioid use disorder, the test result could be used to advise them not to take an opioid pain medication for acute pain, including after a planned surgical procedure.

The FDA’s approval was surprising because in October 2022 the agency convened an advisory panel of outside experts to review the same clinical trial data on which the approval was based.[3],[4] The expert panel voted 11 to 2 that the risks of the test were greater than the benefits.[5] At the advisory committee meeting, Public Citizen’s Health Research Group opposed approval of the test because the pivotal clinical trial was flawed and because the test had high rates of both false negative and false positive results.[6] Now that the test has been approved, we have classified it as Do Not Use. As of this writing, the test is not widely available.

Background on the new DNA test

The new test uses DNA extracted from a buccal (inside the cheek) swab to identify the presence or absence of 15 specific gene polymorphisms (variants).[7] The gene variants map to protein expressions (biosynthesis of enzymes, neurotransmitter receptors and other cellular building blocks) that are linked to a complex set of behaviors including satiability, reward seeking and pleasure perception.[8] The results are interpreted with a proprietary algorithm that assigns the pattern of observed genetic markers to two mutually exclusive categories: “elevated genetic risk” or “non-elevated genetic risk” for future opioid use disorder.[9]

The test is only meant to be used in patients prior to receiving a first prescription of oral opioids for 4-30 days for acute pain. The labeling includes a “black box warning,” the strongest warning that the FDA can require, that opioid-sparing techniques should be used regardless of the test results, that the risk of future opioid use disorder is uncertain and that the test should only be used as part of a fuller clinical evaluation. The test is only for people 18 years or older. It is not for use in patients receiving treatment for chronic pain.

The pivotal clinical trial

The primary clinical trial supporting approval of the DNA test enrolled 812 individuals who were exposed at least one year prior to enrollment to 4-30 days of opioid pain medications. Eventually, 381 were selected for full study participation. Participants had a mean age of 33 years; 92% were White. Standardized clinical interviews classified 174 (46%) of the 381 full participants into those diagnosed with opioid use disorder at some point 1 to 51 years (mean of 10 years) after the 4-30- day opioid use period; the other 207 (54%) full participants were classified as without opioid use disorder.

A positive DNA test matched to 83% of those with opioid use disorder, based on a standardized clinical review not involving DNA analysis. A negative test matched to 79% of those without opioid use disorder. Although these percentages may seem high, they are misleading and unlikely to generalize to the U.S. population. The study population was mostly White, and the prevalence of opioid use disorder was high. Moreover, because persons with opioid use disorder were overrepresented (the prevalence of opioid use disorder is about 3% of the U.S. population over 12 years of age)[10], a coin flip could have successfully classified participants about 50% of the time.

Secondly and most importantly, the results are suspect because separate research adjusting for ancestry — a person’s geographic origins — has shown that a test with 15 gene markers (14 of which are included in the new DNA test) explains away the test’s ability to predict future opioid use disorder.[11] Stated another way, the DNA test appears to have sorted people by geographic origin as much as by risk of opioid use disorder, calling into question its usefulness in individual cases. This confounding flaw was pointed out by several experts in brain genetics in a public comment sent to the FDA in October 2022.[12] The experts also noted that research published in 2021-2022 further found that “even a full genome’s worth of markers (roughly 6,000,000) are not sufficient to predict [opioid use disorder] in a clinically useful way.”

Response to the approval

Use of the new DNA test exposes consumers to two harms. False negative results may give clinicians and patients an inaccurate sense that they can safely use opioids for acute pain with little risk of developing opioid use disorder. On the other hand, false positive results may discourage the use of potentially beneficial opioid pain medication.

In April 2024, Public Citizen’s Health Research Group joined with other experts in genetics, addiction, psychiatry and public health to urge the FDA to rescind approval of the new DNA test and, in parallel, to urge the Centers for Medicare & Medicaid Services not to cover the test for Medicare beneficiaries.[13]

What You Can Do

Opioids should be used sparingly for acute pain, with careful medical monitoring and only after other pain therapies are tried.[14] When opioids are used, regardless of any purported genetic risk of opioid use disorder, they should be prescribed at the lowest effective dose, for a limited time and with a plan to gradually taper patients off their maximal dose to minimize withdrawal symptoms.

If you are experiencing acute pain and are considering an opioid prescription, do not use the new DNA test. Work closely with your clinician to minimize your risk of becoming dependent on these powerful and risky medications.
 

References

[1] Food and Drug Administration. Press release. FDA approves first test to help identify elevated risk of developing opioid use disorder. December 19, 2023. https://www.fda.gov/medical-devices/medical-devices-news-and-events/fda-approves-first-test-help-identify-elevated-risk-developing-opioid-use-disorder. Accessed May 4, 2024.

[2] Food and Drug Administration. Summary of safety and effectiveness data: AvertD. December 19, 2023. https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230032B.pdf. Accessed May 4, 2024.

[3] Food and Drug Administration. Summary of safety and effectiveness data: AvertD. December 19, 2023. https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230032B.pdf. Accessed May 4, 2024.

[4] Food and Drug Administration. FDA executive summary. Prepared for the October 20, 2022, meeting of the Clinical Chemistry and Clinical Toxicology Devices Panel. DENxxx, AvertD, SOLVD Health. https://www.fda.gov/media/162373/download. Accessed May 4, 2024.

[5] Food and Drug Administration. Summary minutes: Center for Devices and Radiological Health, Medical Devices Advisory Committee, General and Plastic Surgery Devices Panel re. AvertD test. October 20, 2022. https://www.fda.gov/media/162982/download. Accessed May 4, 2024.

[6] Public Citizen. Testimony before the FDA’s Clinical Chemistry and Clinical Toxicology Devices Panel opposing marketing authorization of the AvertD genetic test to predict the risk of opioid use disorder. October 20, 2022. https://www.citizen.org/article/testimony-before-the-fdas-clinical-chemistry-and-clinical-toxicology-devices-panel-opposing-marketing-authorization-of-the-avertd-genetic-test-to-predict-the-risk-of-opioid-use-disorder/. Accessed May 4, 2024.

[7] Food and Drug Administration. Summary of safety and effectiveness data: AvertD. December 19, 2023. https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230032B.pdf. Accessed May 4, 2024.

[8] Food and Drug Administration. FDA executive summary. Prepared for the October 20, 2022, meeting of the Clinical Chemistry and Clinical Toxicology Devices Panel. DENxxx, AvertD, SOLVD Health. https://www.fda.gov/media/162373/download. Accessed May 4, 2024.

[9] Food and Drug Administration. Summary of safety and effectiveness data: AvertD. December 19, 2023. https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230032B.pdf. Accessed May 4, 2024.

[10] Substance Abuse and Mental Health Services Administration. 2023. Key substance use and mental health indicators in the United States: Results from the 2022 National Survey on Drug Use and Health (HHS Publication No. PEP23-07-01-006, NSDUH Series H-58). https://www.samhsa.gov/data/report/2022-nsduh-annual-national-report. Accessed May 4, 2024.

[11] Hatoum AS, Wendt FR, Galimberti M, et al. Ancestry may confound genetic machine learning: Candidate-gene prediction of opioid use disorder as an example. Drug Alcohol Depend. 2021;229(Pt B):109115.

[12] Hatoum AS, Agrawal A, Edenberg HJ, Gelernter J. Comments to the FDA Clinical Chemistry and Clinical Toxicology Devices Panel, Re: AvertD genetic test for OUD risk, from SOLVD Health. https://www.fda.gov/media/162374/download. Accessed May 8, 2024.

[13] PROP joins prominent geneticists and scientists to oppose new OUD risk genetic test. April 4, 2024. https://www.supportprop.org/opioid-news/prop-oppose-oud-risk-genetic-test/. Accessed May 4, 2024.

[14] Pino CA, Wakeman SE, Weiner SG. Management of acute pain in opioid naïve adults in the ambulatory setting. UpToDate. April 2024.