In her article “To treat pain, study people in all their complexity,” Beth Darnall wrote, “In 2016, the Institute of Medicine estimated that up to one-third of the U.S. population lives with ongoing pain. Chronic pain, the main cause of disability, is more prevalent than diabetes or heart disease.”
A 2010 analysis found that one-third of patients taking long-term opioid therapy for nonmalignant chronic pain either experienced the medication to be ineffective or poorly tolerated the treatment. Pain management frequently involves a trial-and-error process over time. But, what if there was a way to choose the right medication AND the right dose for a patient the first time?
The answer, in some cases, may lie in pharmacogenomics, an emerging field of genetic prediction of medication response. Pharmacogenomics shifts our current medical paradigm from reactive to preventive by studying the genetic variations that are among the factors responsible for the wide variability in drug responses that we encounter today.
How do genes affect pain?
It is estimated greater than 90% of the population has some genetic variation which could change how a patient responds to one or more medication. Some form of chronic pain has been reported by 11% of adults in the U.S., which has in turn, contributed to the rise of pain medication use. It has been reported one out of five patients seen by a clinician receives an opioid.
One well-described example of pharmacogenetic variation is of cytochrome P450 (CYP450) enzymes, which are involved in opiate metabolism. One specific example of this is the association of the CYP2D6 genotype and benefits and/or adverse effects of opioid use. There are clinical recommendations provided to help guide therapy of multiple opioids – including codeine, tramadol, oxycodone, and hydrocodone – based on the CYP2D6 genotype, although the level of evidence varies between each medication. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelinesprovide CYP2D6 genotype-based recommendations for codeine use, along with additional recommendations for tramadol, oxycodone and hydrocodone, based on the available clinical evidence. In addition, data is available (although limited) to guide some chronic pain therapy with non-opioids, such as therapies that include tricyclic antidepressants and celecoxib.
In the future, pharmacogenomics testing may lead to safer, faster, and more effective drug therapies, reducing the trial-and-error method of prescribing of these medications, although current evidence is insufficient when it comes to most opioids.
Metabolism
Gene variations can affect the metabolism of a pain medication, such as codeine, resulting in lower or higher drug concentrations. This variability leads to patients being categorized as poor, intermediate, normal, or ultrarapid metabolizers. Approximately 5-10% of patients have been found to have a deletion of the CYP2D6 gene (no activity), and 1-2% of patients have multiple copies, or increased activity.
Opioids are highly correlated with respiratory depression, a harmful and life-threatening adverse effect. It is difficult to tell which patients will respond to higher or lower doses, which is why individualized therapy is needed when prescribing such potent medications. It is also important for clinicians to use pharmacogenomics testing as another tool, combining it with knowledge of the patient’s previous opioid use, renal function, and other prescribed medications to determine the best course of action.
The opioids codeine, tramadol, oxycodone, and hydrocodone are, to varying extents, activated by the CYP2D6 enzyme to a more active form. If a patient is a poor metabolizer, they will likely experience reduced concentrations of active metabolites, possibly resulting in reduced analgesia. On the other end of the spectrum, ultrarapid metabolizers generally have increased concentrations of the active metabolites, increasing their risk of toxicity, which includes common adverse drug effects such as nausea, vomiting, light-headedness, sedation, shortness of breath, and constipation. Some patients may experience more serious adverse drug effects such as respiratory depression.
Multiple cases have been reported of children receiving codeine post-tonsillectomy or adenoidectomy and experiencing toxicity, including death in some cases. These children were later found to be CYP2D6 ultrarapid metabolizers. These cases have resulted in the FDA adding a boxed warning in 2017 to codeine-containing products, which includes a contraindication for use of codeine and tramadol in patients less than 12 years of age.
An important note: There is less evidence of an association of oxycodone and hydrocodone with CYP2D6 genotypes due an active parent compound, making the loss of CYP2D6 activity less clinically significant.
The opioid crisis
Prescription opioid addiction is a ubiquitous concern at this time, and a recent study noted that, while current pharmacogenetic evidence can assist with understanding drug metabolizing, it is unable to identify populations who are at increased risk for addiction.
That doesn’t mean that pharmacogenomics can’t help professionals work to prevent opioid misuse. Personalizing pain management based on the patient’s CYP2D6 genotype could help optimize pain control, which in turn, could help increase patient safety and decrease risk of adverse drug events. According to a 2009 study, 80% of the patients with adverse drug reactions had impaired CYP2D6 drug metabolism.
A few opioids are metabolized by CYP enzymes, and in patients with complicated treatment regimens, physicians may want to consider an opioid that is not metabolized via CYP enzymes. This is often difficult, but with the use of genomic information, a physician could prescribe an opioid and follow up with careful dose adjustments, since they would have an understanding of the drug metabolism.
Pharmacogenomics testing: Whom and when?
Some clinicians and specialties may already be well-versed in pharmacogenomics and the need for genomic screening when it comes to pain management, including those practicing oncology or working in behavioral and mental health fields. But more awareness and education of this emerging field and the support it can provide is still needed, particularly among primary care providers.
When identifying patients who may potentially benefit from genomic screening before prescribing pain treatments, clinicians may want to consider the following factors:
- History: Has the patient tried and failed many therapies in the past?
- Polypharmacy: Multiple medications can combine to create drug-drug and drug-gene interactions
- Age: 50-75% of the elderly population experiences chronic pain; analysis of Medicare prescription plans reveal that only one-third of those covered by the plans had access to treatments other than opioids due to the low cost of opioids
- Condition: Cancer patients and those suffering from post-surgical pain have been shown to struggle with longer-term management of pain
Despite the benefits that could be gained by understanding a patient’s genomic profile and potential to metabolize opioids and other pain medications, there are still many barriers to more widespread pharmacogenomics testing:
- Differences between labs, testing, and variability in reporting
- Insurance coverage: DNA sequencing costs continue to decline, but lack of consistent coverage and other regulatory restrictions can discourage patients
- Lack of data: Some evidence is often limited to retrospective and observational studies
- Accessibility: Future developments will more consistently include genomic results in the patient’s electronic medical record, but right now, results are not always accessible to every physician providing patient care
- Clinical implementation: Issues of validity (testing to predict the presence or absence of the drug-related phenotype or disease of interest) vs. utility (likelihood the test results will alter clinical outcomes or patient treatment decisions)
- Ethical concerns, including potential discrimination based on genomic results
- Variability in interpretation, stemming from lack of clear, curated guidelines which translate laboratory results into actionable decisions for specific medications. However, there are resources that clinicians can consult to better understand test results and support decision making. CPIC and the Dutch Pharmacogenetics Working Group have evaluated more than 100 gene-drug pairs. Lexicomp drug information solutions from Wolters Kluwer provide concise pharmacogenomics monographs for gene-drug pairs for point-of-care reference with links to full gene monographs for healthcare providers to use for more extensive research. Our team reviews and evaluates scientific, clinical, and product literature to create actionable content that includes testing recommendations, management, and discussion of the literature available
Education and awareness of pharmacogenomics has been growing over the last few years and will continue to do so. To advance the practice, it would require the creation of multidisciplinary team, bringing together physician, pharmacist, medical geneticist, laboratory personnel, and nursing staff, to establish pharmacogenomics testing as a part of daily patient care.
Kandace Schuft, PharmD, is Senior Clinical Content Specialist - Pharmacogenomics for Wolters Kluwer, working collaboratively within the drug information team to critically review and evaluate scientific, clinical, and product literature in order to create and maintain existing core pharmacology content, contributing to both referential and embedded products. She earned her Doctor of Pharmacy and Bachelor of Arts degrees from the University of Minnesota and completed a post-graduate pharmacy practice residency and pharmacogenomics certification program.
