Pharmacogenetic testing (PGT) has the potential to help clinicians improve outcomes for injured workers and reduce costs for payers. While research showing the clinical value of PGT continues to grow rapidly, evidence of the return on investment in the workers’ comp space is just beginning to emerge. Practitioners can benefit from the technology without falling victim to the hype of some proponents by becoming better educated about PGT and those providing it.
Because the use of PGT in the workers’ comp population is relatively uncommon, practitioners may find it challenging to realize the true value of the tests. “A few of our customers are trying PGT on select claimants,” said Dianne Tharp, pharmacist and executive clinical liaison for pharmacy benefit manager Healthcare Solutions, an Optum company. “This is a complex area; everything is evolving. It’s relatively new for the industry, and we are all still learning.”
One growing area of interest is in genetic tests that can identify injured workers most at risk for addiction and abuse. However, there are many challenges with such tests, including uncertainty about their predictive performance in clinical settings, which must be overcome before clinicians can use them to help identify whether an injured worker may misuse or abuse a prescribed opioid. While PGT could be a welcome tool, the science is not yet at a level where clinical application is appropriate.
“On the other hand, pharmacogenetic testing for drug response is often more — and in some cases highly — predictive,” said Naissan Hussainzada, senior director of genetics strategy and commercialization at Millennium Health. “For example, certain genetic variations can change how an individual metabolizes some opioid medications. Using this information, clinicians can identify patients at higher risk for medication failure and/or side effects, which may help them make more informed and tailored treatment decisions.”
Injured workers with preexisting conditions or those who develop comorbid conditions post-injury may especially benefit from PGT — as they may be receiving multiple medications that could potentially elevate their risk for drug-drug and gene-drug interactions. PGT information could also help the clinician better understand whether drugs prescribed for comorbid conditions will be effective.
“In the workers’ comp space, PGT could be used to help the clinician optimize medication prescribing and avoid trial and error,” Hussainzada said. “This has the potential to translate to faster recovery, less time away from work and shorter claim duration for the injured worker.”
Multiple medication regimens and comorbid conditions are frequently present in workers who are injured on the job. The inability to work and the presence of pain can result in additional comorbidities, especially depression.
Metabolism can play an important role in how patients respond to medications, particularly antidepressants, opioids, certain anticoagulants and cardiovascular medications. Mental health providers, in fact, were among the first to recognize the value of PGT in guiding medication therapy and dosing.
“Mental health disorders are often assessed subjectively, and drug therapy can be lengthy, unpredictable and suboptimal,” Hussainzada said. “It may take several months to stabilize a patient on an effective antidepressant using trial and error.”
PGT can be especially useful for antidepressants. “There are actionable PGT results with good evidence for the antidepressants,” Tharp said. “That would be an instance where PGT may be useful [among injured workers].”
In addition to antidepressants, Tharp said PGT is also being used to help determine a patient’s ability to properly metabolize warfarin, which is used to prevent blood clots.
Individuals metabolize medications differently, partly depending on a person’s genetic makeup and partly on clinical factors, such as hepatic (liver) disease, lifestyle factors and administration of other medications. For example, introducing a new medication may change how existing drugs are metabolized, which can change their effectiveness or tolerability. Conversely, an existing medication may have an impact on the metabolism of a new medication.
“There are well-documented drug-drug interactions between opioid analgesics and certain antidepressants,” Hussainzada said. “This is because some antidepressants can inhibit or ‘turn off’ the enzymes responsible for metabolizing opioids. This can lead to the opioid becoming less effective, or in some cases, intolerable or potentially toxic. Making matters more challenging, there are some individuals that carry certain genetic variations that can make them more susceptible to a phenomenon called ‘phenoconversion,’ which can elevate their risk for certain types of drug-drug interactions. For injured workers receiving polypharmacy, PGT may help clinicians identify these higher-risk individuals and help mitigate some of the risks of phenoconversion.”
There are four categories of metabolizer type that correspond to how individuals may metabolize certain medications via hepatic enzymes. Individuals classified as “extensive” metabolizers possess fully functional enzymes and are able to metabolize medications normally. However, some individuals carry genetic variations that lead to reduced or significantly reduced enzyme function, and are classified as “intermediate” or “poor” metabolizers. Finally, some people may have genetic variations that lead to significantly increased enzyme function and are classified as “ultra-rapid” metabolizers. What that means is: Two people taking the same drug at the same dose can have very different responses because of their metabolizer status.
Individuals susceptible to phenoconversion can “switch” metabolism type, for example, from an intermediate or extensive metabolizer to a poor metabolizer. The trigger for these conversions is non-genetic extrinsic factors, such as administering a drug that inhibits the enzyme pathway. Certain metabolizer types are associated with higher risk of phenoconversion and risk of drug-drug interactions.
“Intermediate metabolizers may be at higher risk for phenoconversion compared to normal metabolizers,” Hussainzada said. “However, it can be difficult to identify these patients because they may display normal or typical response to a medication, even if they are metabolizing that drug at a reduced rate. However, if an inhibitor of the drug is added to their regimen, this can shift the individual from intermediate to poor metabolism and lead to medication failure and/or potentially serious side effects.”
For some claimants who take medications for pre-existing conditions, adding a pain medication can increase the risk for drug-drug interactions and phenotypic conversion. “So a claimant who has been taking antidepressants for years is now also prescribed an opioid because of his injury,” Hussainzada said. “If he is an intermediate metabolizer for the opioid, the antidepressant may convert him to a poor metabolizer. This could lead to inadequate pain relief, which may delay recovery and increase risk of poor outcomes.”
In another scenario, an injured worker who is taking opioids for his injury and who later develops depressive symptoms may be treated with concomitant antidepressant therapy. “In this case, the opioid may have been initially effective, but certain opioids would lose analgesic potency once the inhibitor, or antidepressant, is added,” Hussainzada said.
PGT can also help a clinician identify patients who may need to be started with atypical or non-standard doses of certain analgesics. One particular enzyme responsible for the metabolism of a large number of medications is cytochrome P450 2D6, or CYP2D6. Claimants who are reduced metabolizers for the pathway may not respond adequately to a standard dose of oxycodone.
“If you are a CYP2D6 poor metabolizer, standard doses of oxycodone or hydrocodone may not effectively control your pain,” Hussainzada said. “However, without knowing this type of genetic information beforehand, it may appear to the clinician that these individuals are drug-seeking if they continue to ask for higher doses.”
Some poor metabolizers may not get any pain relief, even with very high doses of a medication. Identifying these patients through PGT can lead the clinician to prescribe a different pain medication from the start, something that can be critical to getting an injured worker back to function.
According to a recent position paper from Healthcare Solutions, the rates of comorbidity and polypharmacy are on the rise in workers’ comp and can lead to increased medical costs, delayed returns to work and longer claim durations. Clinical depression is a common comorbidity, and the use of antidepressants is prevalent; however, both are associated with poor recoveries and outcomes.
“For patients taking multiple medications, there may be multiple enzymes that are recruited to metabolize and eliminate these drug combinations from the body,” Hussainzada said. “Some recent data indicates that when you look across multiple enzymes, genetic variation is much more common than when you look at a single enzyme. So for the claimant receiving polypharmacy, it may be even more important to understand how their genetics will contribute to their medication response since it is likely that at least one enzyme system may be variant.”
Clinicians can use PGT information at the beginning of a claim to optimize initial prescribing and dosing of opioids and other medications, which may hasten the recovery time. “In workers’ comp, the data are pretty clear: The faster we can facilitate post-injury recovery and get the claimant back to work, the better their overall prognosis,” Hussainzada said. “Particularly with opioid therapy, we want to use these drugs judicially and effectively.
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Researchers and workers’ comp practitioners continue to monitor the clinical evidence for testing in an effort to help clearly identify those injured workers who would benefit most from PGT — in terms of better outcomes and lower costs. For now, there are several types of injured workers who may be good candidates for testing.
“A claimant taking multiple medications from several therapeutic classes, one who has failed several therapies and changing dosages or a patient on ultra-high daily morphine equivalent doses may be a good candidate for PGT,” Healthcare Solutions’ Tharp said.
Ultimately, proponents hope PGT can be a useful tool in getting the right medication at the right dose to each patient. If test interpretations are based on firm clinical evidence, PGT can provide clinicians with a road map for navigating prescribing decisions that can often be complex and subjective. However, providers are advised to become familiar with PGT and, especially, the companies marketing these services.
“Payers, clinicians and patients need to be aware that not all pharmacogenetic testing is equal. Ask questions about the evidence for specific genes and drugs and make sure there are clinical standards in place for how results are interpreted,” Hussainzada advised. “Some tests may not be ready for clinical use, so it’s important to be informed.”