September 6, 2016

The premise is elegant in its simplicity: The more information you have about a surgical patient’s biology, the greater your ability to tailor anesthesia medication appropriately for that patient and lower their risk of an adverse drug reaction (ADR), longer hospital stay or hospital readmission, and the better and more cost-effective the overall quality and safety of your anesthesia care.

It’s an approach that clinicians, scientists and President Obama, through his administration’s Precision Medicine Initiative, hope can be used routinely one day to spare surgical patients from unnecessary risks and complications. A personalized approach to anesthesia care such as this could also enable anesthesiologists to add value to their institutions and practices as perioperativists, yielding benefits for health systems, payers and, ultimately, society as a whole.

Pharmacogenomics, a cornerstone of medical science’s movement toward personalized medicine, uses genetic data to guide drug development and testing and help physicians select the proper medication or therapy at the proper dose or regimen. Pharmacogenetic testing can help identify patients who are at greater risk of side effects, or are more likely to experience severe side effects at relatively low doses, require a higher dose to achieve a therapeutic effect or receive no benefit from the medication. As explained in The Lancet in 2000:

Polymorphisms in the genes that code for drug-metabolising enzymes, drug transporters, drug receptors, and ion channels can affect an individual's risk of having an adverse drug reaction, or can alter the efficacy of drug treatment in that individual. Mutant alleles at a single gene locus are the best studied individual risk factors for adverse drug reactions, and include many genes coding for drug-metabolising enzymes. These genetic polymorphisms of drug metabolism produce the phenotypes of “poor metabolisers” or “ultrarapid metabolisers” of numerous drugs. Together, such phenotypes make up a substantial proportion of the population. Pharmacogenomic techniques allow efficient analysis of these risk factors, and genotyping tests have the potential to optimise drug therapy in the future.

Applications in Anesthesiology

The ability to personalize anesthesia care in this manner is more than an idea. Pharmacogenetic testing is now available to help anesthesiologists risk-stratify patients and tailor treatment. A growing number of laboratories are helping anesthesiologists personalize care using pharmacogenetic testing as a tool to predict a patient’s response to postoperative opioid therapy, treatment for postoperative nausea and vomiting with various anti-emetics, and perioperative risk of thrombosis. These predictions can help anesthesiologists choose the appropriate medications for patients whose genetic profiles indicate that they are likely to react poorly to certain drugs, such as opioids, or to metabolize them too quickly.

A preoperative behavioral and medical risk assessment conducted by a nurse, followed by pharmacogenetic testing in patients identified as being at risk of developing opioid dependence or having opioid-related complications that could unnecessarily lengthen their hospital stay or increase their risk of an ADR and re-hospitalization, can alert anesthesiologists to the need to alter treatment or prescribe multi-modal therapy as an alternative to opioids. Patients can also keep this valuable information about their genetic composition and share it with other physicians who treat them.

The use of pharmacogenomic testing is not yet widespread, but its future looks bright. According to the National Human Genome Research Institute, “Doctors are starting to use pharmacogenetic information to prescribe drugs, but such tests are routine for only a few health problems. However, given the field’s rapid growth, pharmacogenomics is soon expected to lead to better ways of using drugs to manage heart disease, cancer, asthma, depression and many other common diseases.”

That is already happening. For example, pharmacogenetic research has shown that patients with a reduced-function CYP2C19 allele have significantly lower levels of the active metabolite of clopidogrel (Plavix), diminished platelet inhibition and a higher rate of major adverse cardiovascular events, including stent thrombosis. Pharmacogenetic testing to identify patients who are poor, ultra-rapid, extensive or intermediate metabolizers of clopidogrel is now often used to guide therapy and is recommended in package inserts. Approximately 100 Food and Drug Administration (FDA)-approved medications now carry such pharmacogenetic testing recommendations on package inserts.

Opioids and ADRs

One look at the sobering data on ADRs and it is easy to see how predictive pharmacogenomics could be used to tackle a serious public health problem as well as the instrumental role anesthesiologists could play in this regard.

According to some estimates, 6.7 percent of hospitalized patients have a serious ADR with a fatality rate of 0.32 percent. That translates into 2.2 million serious ADRs in hospitalized patients and 106,000 deaths each year, and makes ADRs the fourth leading cause of death—ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents and automobile deaths. ADRs account for an estimated one third of hospital adverse events and approximately 280,000 hospital admissions annually, the Health and Human Services Office of Disease Prevention and Health Promotion reports in its National Action Plan for Adverse Drug Event Prevention.¹

Of particular relevance to anesthesiologists is the fact that opioids are one of three groups of drugs targeted in the Action Plan because they are one of the most common causes of ADRs and the cause of more than 75 percent of pharmaceutical overdose deaths. From 1999-2010, the number of prescription opioid overdose deaths in the United States quadrupled.

An editorial in the March 2016 issue of Population Health cited research indicating that 1 in 15 of the more than 95 percent of patients who receive opioids following the approximately 53 million inpatient and 57 million outpatient procedures performed in the U.S. each year will become long-term opioid users. The ability of anesthesiologists as perioperativists to identify patients at risk of opioid addiction preoperatively through risk stratification and pharmacogenetic testing could help mitigate a problem that has reached epidemic scale.

For example, according to an FDA learning module on adverse drug reactions sponsored by the Agency for Healthcare Research and Quality:

The absence of cytochrome P450 2D6 in 7% of Caucasians means that these individuals cannot metabolize codeine to the active metabolite, morphine, and therefore will get little, if any, pain relief from codeine.¹ However, they will experience codeine’s adverse effects, particularly if the dose is increased in the futile attempt to obtain pain relief.

Thirty percent of Ethiopians studied had multiple copies of the 2D6 gene (up to13) and increased eynzyme activity resulting in ultrarapid metabolism.² Ultra-rapid metabolism results in lower blood levels following a standard dose of any drug metabolized by this enzyme. Therefore these patients may have an inadequate response to standard dosages of ß-blockers, narcotic analgesics, or antidepressants and may require higher dosages for clinical effectiveness.

A 2013 review of the evidence for the clinical utility of pharmacogenetic testing notes that package inserts for approved drugs and newly approved versions of drugs containing codeine as a major component now include information about ultra-rapid metabolizers of CYP2D6.

Evidence of pharmacogenetic testing’s utility in chronic pain management is also beginning to accumulate. A late-breaking poster presented at the 2016 American Academy of Pain Medicine Annual Meeting reported the successful use of pharmacogenetic testing in a chronic pain patient who had been taking morphine extended-release tablets at a dose of 100 mg up to three times daily with escalating doses over four years with little pain relief. Pharmacogenetic testing showed the patient to be an ultra-rapid metabolizer of CYP2D6. His physician added gabapentin (Gralise, Depomed), an anticonvulsant, and low-dose methadone, which is metabolized by CYP3A4 and CYP2B6. Within three visits, the patient’s pain score dropped from 10 to 4.

Roadblocks Ahead

Despite these signs of promise, questions need to be answered before pharmacogenetic testing becomes mainstream in medicine. According to Stuart A. Scott, PhD, of Mt. Sinai School of Medicine writing in Genetics in Medicine (Personalizing medicine with clinical pharmacogenetics):

. . . interindividual drug response variability has only recently become available to help clinicians guide pharmacotherapy, in part due to US Food and Drug Administration-mediated product insert revisions that include pharmacogenetic information for selected drugs. However, despite pharmacogenetic associations with adverse outcomes, physician uptake of clinical pharmacogenetic testing has been slow. Compared with testing for Mendelian diseases, pharmacogenetic testing for certain indications can have a lower positive predictive value, which is one reason for underutilization. A number of other barriers remain with implementing clinical pharmacogenetics, including clinical utility, professional education, and regulatory and reimbursement issues, among others.

Reimbursement presents an ongoing challenge. Last year, Medicare discontinued payment for some pharmacogenetic testing. “This decision is designed to save money at the expense of patient care,” says John Logan Black, III, MD, co-director of Mayo Clinic’s Personalized Genomics Laboratory. “It comes down to dollars and cents and not really what patients need. Medicare officials are trying to control costs by saying they haven’t seen enough benefit from these tests. However, it has long been considered that pharmacogenomic testing is the low-hanging fruit from the Human Genome Project, because these tests give us a lot of personalized information about patients. But now critics say it’s too hard to implement or insurers say they’re worried about the costs to implement this testing.”

Others point to a lack of scientific evidence supporting pharmacogenetic testing’s benefits in randomized controlled trials. However, as Felix W. Frueh, PhD, of the FDA states in Pharmacogenomics:

Personalized medicine refers to an approach of clinical practice where a particular treatment is not chosen based on the ‘average patient’, but on characteristics of an individual patient, for example, a genetic profile that may vary from one patient to another, and therefore, allows to ‘personalize’ the treatment to a patient’s individual needs. While the call for prospective randomized controlled trials to assess the effective use of such measurement may make sense in some cases, it is, when applied without distinction, hindering the implementation of personalized medicine. Important evidence for the validity and clinical effectiveness of using biomarkers, for example, a patient’s genetic profile, can be gained from alternative approaches, including case–control and cohort studies, and retrospective analyses of data. Hence, we need to re-focus on approaches that are neither new nor unproven, but have been ignored over the last few decades.

Despite these obstacles, pharmacogenomics is unlikely to disappear and anesthesiologists would be wise to keep it on their radars. In the not too distant future, we would expect that clinical application software including anesthesia information systems will incorporate more pharmacogenomic data and decision support. As healthcare marketing specialist Daphne Swancutt stated it in KevinMD, “The future is in personalized medicine. Pharmacogenetics is on a wave that is only going to become stronger. Genetic testing and targeted therapies will change the way patients are treated, customizing their care and reducing the likelihood of ineffective—and possibly toxic—treatments. We have to get the ball rolling faster and support the kind of research that can make this happen. It’s good medicine.”

ABC clients: Reimbursement for pharmacogenetic testing varies. Please contact your ABC Client Service Executive if you have any questions.

With best wishes,

Tony Mira
President and CEO

¹U.S. Department of Health and Human Services, Office of Disease Prevention and Health Promotion, National Action Plan for Adverse Drug Event Prevention, 2014, p. iii.